1. Syndromes & more

Alzheimer & Early Onset Familial Alzheimer Disease (EOFAD) - ACMG & NSGC -

*Alz - most common cause (2/3) of dementia* Criteria: 1. Subtle memory loss -> interferes w daily function 2. -> Progresses to . Severe confusion . Poor judgement . Language disturbances . Agitation . Withdrawal . Psych illness: hallucinations . Mild cognitive impairment (MCI) Also: . Seizures . Hypertonia . Myoclonus . Spastic paraparesis . Parkinsonism Alz pathology: . Brain cortex shrinks (esp in hippocampus) . Ventricles enlarge . Amyloid plaques + neurofibrillary tau tangles AA + Hispanics >> white + non-Hispanics *F >> M (likely bcs women live longer)* Alz risk factors: . Age . Phx of diabetes, cardiovascular disease, MCI, TBI . Fhx of dementia *RR (if neg genetic test & no ε4 allele)*: --- *FDR 2-4x inc => 20-38%* (15-39%) lifetime risk Complex: ~100% multifactorial --- 30-60% susceptibility genes ------ 1% AD AD EOAD mtns: 40-80% of AD Alz; 1-5% of Alz 1. ****PSEN1**** [BORDZ] (20-70%) (*think Papa kbir bil SEN* --- Complete penetrance --- Onset 40-50 --- Rapid progression over 6-7y ------ Seizures ------ Myoclonus ------ Language deficits --- Caribbean Hispanic founder mtn: G206A 2. ****APP**** [BORDZ] = Amyloid Precursor Protein (10-15%) (*thik Papa*) 3. *PSEN2* [BORDZ] (<5%) --- 95% penetrance 4. ****APOε**** [BORDZ] = Apolipoprotein ε (3 isoforms (alleles): ε2, ε3, ε4) --- Pleiotropy (one gene causes several dx): ------ Alz ------ Hypercholesterolemia *May help confirm dx if symptomatic (NOT advised for predictive testing, DTC)* --- *ε4: risk modifier of LOAD genes => more amounts of amyloid plaques* ------ *Earlier AGE of onset* ------ *May inc Alz risk* --------- *if 1 ε4 -> 2-3x inc risk* --------- if homozygote-> 2-10x inc risk ------ Inc risk of coronary heart disease ------ Inc risk of atherosclerosis ------ May inc risk of open-angle glaucoma ------ May in risk of depression --- *ε2: protective of Alz genes* ------ *Inc risk for hyperlipoproteinemia type III* ------ *May inc risk for primary macular degeneration* *EOAD (does not mean genetic)*: . AD --- variable expressivity (20y gap within family) . Other Alz: 10-12% lifetime risk EOAD (5% of Alz): <60-65y (1-5%) (1/200,000 Americans) vs LOAD > 65 (1/9 Americans) 1. Sporadic (75%) = isolated relative / >3 degree relation . Most are sporadic LOAD . Sporadic EOAD (40% of EOAD) 2. Familial(15-25%):2 affected TDR . Most are familial LOAD (15-25% of LOAD) . Familial EOAD (47% of EOAD) ---AD Alz (<5%) = 3 affected in 2 generations (2 FDR to third) => always EOAD (not all EOAD is AD) ---other Alz dx test: *definitive dx if pos clinical+DNA / clinical+autopsy* --- Clinical test (80-90% DR): Mini Mental Status Exam (MMSE) Cerebrospinal fluid (CSF) biomarkers correlate w Alz+MCI: ------ Low beta amyloid peptides (Aβ1-42) ------ Hi total + phosphorylated tau --- Genetic test (1-5% DR): for adults (NEVER in children since no medical (late onset-no childhood tx)/ social benefit): stepwise 1. PSEN1 2. PSEN2 3. APP * Seq(detects most mtns)+deldup-> increases DR to 97% => *If no identified mtn, DEFINITIVE dx ONLY w AUTOPSY* neuropathology findings: . *Beta amyloid plaques (deposits of Aβ42)* . Neurofibrillary tangles . Amyloid angiopathy Predictive genetic test = presymptomatic test 1. *Presymptomatic protocol (based on International Huntington Association and World Federation of Neurology Research Group on Huntington's Chorea Guidelines* - *The HD Society of America's Guidelines for Genetic Testing for HD*: *gold standard for genetic testing for adult-onset conditions*): *in person/video, w expert support person . *2 pre-test sessions*: --- ≥3 generation pedigree --- Inform pt: no proven tx to reduce risk of developing Alz / stop progression --- Reinforce rslts cannot be "taken back" (although one can decide not to learn their test results after having test performed) *If testing elected*-> . *Neuro eval*-> --- Look for dementia signs --- Set up baseline . Assess state of mind. For presymptompatic test-> Psychologist/psychiatrist eval may be recommended --- if psych prob / at-risk-> psychotherapy referral *Confirm affected relative's Alz (rather than different form of dementia) w path/medical report* *If presymptomatic protcol complete -> can order genetic test* 2. *1+ post-test session*-> rslt disclosure: ---Consult *The Alzheimer Disease & Frontotemporal Dementia Mutation Database* molgen.ua.ac.be/ADmutations/ before disclosing rslts ---*Specific geno should not be used to predict pheno in dx / predictive test* If neg & affected relative passed & not tested=> uninformative neg! --*If pt not mentally able/psychosocial complications -> defer test* --If symptomatic pt gives inclination of being averse to test (doing bcs relative said so)-> test not recommended-> explore DNA banking Test if: . Symptomatic pt w EOAD w fhx of dementia / unknown fhx (e.g. adoption) OR . Fhx of 1+ EOAD . Relative w EOAD mtn (currently PSEN1/2 / APP) Prenatal test: *NOT recommended if pt plans to continue pregnancy w mtn* GC for symptomatic pts: *Should be performed in presence pt's legal guardian / relative* Tx: *No prevention or cure!* Slow progression: 1. Cholinesterase inhibitors 2. N-methyl-D-aspartic acid receptor antagonists Resources: . *Alzheimer Research Forum*: alzforum.org --- Presents scientific findings in AD research, including basic research and clinical trials. --- Maintains public databases of research data, including association studies and mutation databases . *AD&FTD database*: molgen.ua.ac.be/ADMutations --- Compiles mtns + nonpathogenic coding variations in genes related to Alzheimer disease (AD) & frontotemporal dementia . *National Institute on Aging*: nia.nih.gov --- Supports research related to aging and age-related diseases . *Alzheimer's Disease Education and Referral Center (ADEAR) and Alzheimer Disease Research Centers (ADC)*: nia.nih.gov/alzheimers --- NIA-sponsored ADEAR provides clinical information and resources, research studies, and current news related to AD. ADCs provide dx and management, volunteer research opportunities, and support services . *Alzheimer's: Association* alz.org --- Provides information, programs, and services for people with AD and their family members, caregivers, residential care staff, and healthcare providers. --- They also fund research . *GeneReviews* enetests.org --- Contains a comprehensive overview of early-onset and late-onset AD and provides details on geno/pheno correl when avail --- Lists resources for pts + families dealing w AD

21 Hydroxylase Deficient Congenital Adrenal Hyperplasia (CAH)

*Most common cause of CAH* *most common cause of pseudohermaph* 1/300 in Yupik Eskimos of Alaska *1/50 carrier rate in US* *AR* --- *1-2% de novo*! *46, XX*: - *CYP21A2* @ 6p21.3 Missense mtns, common dels Mtn: most *LoF* (10-15 common mtn), rarely missense (geno/pheno correl) Gene conversion events (common): segment of functional CYP21A2 replaced by segment copied from pseudogene CYP21A1P => renders CYP21A2 gene nonfunctional => disrupts nl translation of protein 21-hydroxylase converts androgen to cortisol/aldosterone-> excess adrenal adrogens -> ambiguous genitalia Sex-dependent pheno: . F: *pseudohermaph; feminizing puberty if x w cortisol* *Ovaries present* Possible fertility M: *early virilization* (early puberty) 1. Classic (null alleles): *3/4 saltwasting* (most common, most severe): -Low hormone production -Poor feeding, weight loss, dehydration -Loss of salt in urine-> lifethreatening-> neonatal death if not treated -Females virilization 2. *Simple virilizing* (less severe): -Female virilization (cliteromegaly & oligoamenorrhea or *irregular menstruation*, hirsutism, male pattern baldness -*NO salt wasting* 3. *Non-classic* (one not null allele) (least severe) Females: Normal genitalia Males: Nl / small testes and *PRECOCIOUS/EARLY PUBERTY* -*NO salt wasting* Test (non-molecular): -*Hi serum 17 OHP* (progesterone) on NBS -ACTH stimulation test: High ACTH -*Low cortisol * -Low sodium & hi potassium (indicative of hypoglycemia related to a potential salt-wasting crisis) Prenatal screen: *low uE3* of Quad Genetic test (80-98% DR): can confirm dx: Targeted mtn > deldup > seq Tx: -Genital surgery: trend towards waiting to preserve child autonomy for gender assignment, but no specific ideal time -Glucocorticoid and mineralcorticoid replacement: lifelong tx for salt-wasting CAH -> Replaces deficient steroids Suppress ACTH Reduce excess androgens Prenatal tx: ****No established tx**** [BOARDZ] . ****DEXAMETHAZONE**** (*still experimental*) administered to pregnant women whose fetus is at-risk for CAH (e.g. if previous affected child) - start before 8wk GA (ideally as soon as pregnancy confirmed) -> if CVS/amnio abn => ---If affected male fetus-> tx tapered over 2 wks then stopped to minimize side effects to mother + fetus ---If affected female fetus -> tx continued to term to prevent virilization

Osteogenesis Imperfecta (OI) *Connective tissue* - ACMG 2006 -

*Most common genetic bone fracture dx* *AD* (common) ---mild *APA* effect ---****100% penetrant**** [BOARDZ] ---*Most denovo but 5% GONADAL MOSAICISM* [BOARDZ]=> rec risks: if affected parent: 50% RR (bcs AD) *if affected sib: 0-50% RR* (bcs risk of gonadal mosaicism)!!! AR (very rare): 12 types (some type III, VI, all VII) XL rare ****COL1A1, COL1A2, IFITM5 (AD)**** (*think collagen*) ****BMP1, CREB3L1, CRTAP, FKBP10, P3H1, P4HB, PLOD2, PLS3, PPIB, SEC24D, SERPINF1, SERPINH1, SP7, SPARC, TMEM38B, WNT1 (AR)**** ****NBAS, MBTPS2, XYLT2 (XL)**** COL1A1+2 => encode chains of type 1 pro collagen = 2 alpha1 + 1 alpha2; which is the major protein of bone Mtns in COL1A1 and COL1A2 do not cause OI type V, VI or VII, which account for 8% of children w OI COL1A1 (17q21.33): more severe pheno w mtn bcs there are 2 alpha strands vs. 1 beta strand) COL1A2 (17q21.33) form protein triple helix ****Criteria****: Bone fragility, fractures (in extremities) ****WORMIAN BONES**** *Blue sclerae* Short Joint laxity Fragile skin + vessels Increased sweating Flexibility *Adult HL* Grey / brown (translucent) teeth Cardiopulmonary prob Dysmorphic face: -Macrocephaly -Triangular Face -Blue sclera -Dentinogenesis Imperfecta Less to most severe: Null/loss of funct/truncating mtn → less procollage=> Type I (haploinsuff) Point mtn → abn procollagen =>Type II, III, IV (dominant neg) *Type I = Classic* (*mild*; not dx prenatally; rarely, dx after 20wk based on fetal fracture) AD . *Brittle bones, fractures but NO bone deformity* . *BLUE SCLERAE* . *HL* (50%) *Nl stature* *collagen: nl quality, AMOUNT is reduced* ---Genetic test (100% DR) Type IV (not dx prenatally; rarely, dx after 20w based on fetal fracture; rarely after 18 wk) AD . Nl (to grey/light blue) sclerae . Mild/moderate bone deformity with fracture . Variable short stature . Dentogenesis imperfecta . Some HL ---Genetic test 70-80% DR Type V: OI type IV + . Calcification of interosseous membrane of forearm . Radial head dislocation . Hyperplastic callus formation Type VI: . More fractures than OI IV . Vertebral compression fractures Type VII: . Congenital fractures . BLUE SCLERAE . Early deformity of lower extremities . Coxa vara (deformity of hip and femur bone) . Osteopenia Type III: AD . Progressively deforming bones . Moderate deformity at birth . Fractures at birth . Very short . Blue sclerae . HL (common) . Dentogenesis imperfecta 18-20wk (rarely 16+ wk) US: *prenatal phenotype overlaps that of perinatal hypophosphatasia . Short long bones after 16-18 weeks . Short limbs . Thin ribs . Undermineralized skull ---Genetic test 60-70% DR *Type II*: *75% of the procollagen molecules are abn* => perinatal/neonatal lethal (within 30 days of life) Severe bone abn Fractures Blue to dark sclerae Dentinogenesis imperfecta 14-16 wk (rarely 12+ w) US: . Thin, beaded ribs . *UNDERMINERALIZED BONES* . *CALVARIUM (skull) abn, underminiralized* . Broad, crumpled, short limbs=MICROMELIA . Compressed femurs . Bowed long bones . Fractures . Platyspondyly = flattened vertebral bodies *Nl hands! ---Genetic test 98% DR *GONADAL MOSAICISM* abn collagen Don't forget: abuse is leading cause of unexplained fractures in infancy. Presence of fractures for which an explanation is not provided or for which the stated mechanism of injury is not consistent with the fracture type raises a concern for *nonaccidental injury (NAI)*. As NAI is the leading cause of fractures in infancy, a *child abuse evaluation is warranted* in such circumstances (http://nccanch.acf.hhs.gov in instances *when the clinical diagnosis of OI is not apparent and the only feature of NAI present is unexplained fractures, lab testing may be the best way to provide the child and family with all possible safeguards* *Type I collagen is a trimer composed of 2 alpha 1 chains and 1 alpha 2 chain. When there is a null mtn in one of the alpha 1 genes, as is seen with Type I OI, only half the amount of alpha 1 protein is produced. This results in half as many collagen trimers, but all of them are nl. However, the missense mutation in OI type II allows the synthesis of nl amounts of the altered collagen subunit. The resulting mutant alpha 1 protein can still form trimers, but causes abn collagen in the trimers which contain it. A missense mtn in one of two genes for alpha 1 causes half of the proteins produced to be defective, but when they combine into trimers w alpha 2, 75% of the resulting collagen strands are abn. The four types of trimers made are alpha1/alpha1/alpha2 (which is nl), plus the abnormal trimers: alpha1/mutated-alpha1/alpha2, mutated-alpha1/alpha1/alpha2, and mutated-alpha1/mutated-alpha1/alpha2 Dx: 1. *Biochem eval of type 1 pro collagen* 2. *COL1A1+2 seq > deldup* (90% DR) (most mtns unique to pt/family) *If possible, do panel of OI genes* *If no panel: start with COL1A1/1A2→ IFITM5* Prenatal dx: US + *CVS: biochem analysis of type I collagen synthesized by cultured chorionic villi*. (*only done on CVS bcs amniocytes synthesize inadequate amounts of type I procollagen*) (offer CVS if affected parent or sib; or US findings). TAT-3-4 wk *Not avail for OI type I since not reliable!* or CVS / amnio genetic testing if known familial mtn (7-14 d TAT) Test resources: Collagen screening and DNA-based testing are available at the University ofWashington pathology.washington.edu/clinical/ collagen) DNA-based testing is available at the Tulane UniversityMatrix DNA Diagnostic Lab (som.tulane.edu/gene_therapy/matrix/matrix_dna_diagnostics.shtml) Test sensitivity is high for both types of tests, but it is not clear if the sensitivity is additive Tx: PT, bracing/splints surgery Medication: bisphosphonates (osteroclast inhibitors) *blue sclerae occur in nl infants before 12 mos of age

Hemophilia A & Hemophilia B = Christmas *Bleeding*

*Most common hemophilia* (5/100,000 males) ****XLR, BUT 10% of females affected**** (<30% activity) ---*30% de novo (BUT if male w severe hemophilia A-> most likely INVERSION->98% chance mother carrier)* ---*GONADAL MOSAICISM* Type A: *Factor VIII* (F8) @ X ---*INTRON 22 INV -> del of C term due to aberrant homologus recomb* (50% of *SEVERE hemophilia*) ---*INTRON 1 INV* (less common, *SEVERE*) ---dels, insertions, point mtns, frameshift, splice site variants Type B: *Factor 9* (F9) ---*MISSENSE mtns in entire gene* ---promoter mtn in F9 only (Leyden variant)->severe in childhood, but resolves A + B same pheno! Onset: *INFANTILE* . *NOSEBLEEDS* . *Hemarthrosis (bleeding into joints): biggest concern is bleeding into joints* (1st joint bleed @ 2 y) -> *JOINT REPLACEMENT* . Epistaxis . Hematuria . Compartment Syndromes . Excessive, prolonged bleeding, easy bruising . Hemorrhage . Intracranial bleeds w mild/no trauma/procedure . Deep muscle hematoma after trauma . Excessive bruising . Severity inversely correlates w activity (<30% is lower limit of nl) Severe (<1%): spontaneous bleeding Moderate (1-5/15%): may bleed spontaneously excessive bleeding after sex Mild (5-20/30%): no spontaneous bleeding bleeding after sex Dx: . Nl pro-thrombin and platelet count (unlike VWD) . Prolonged PTT (partial thromboplastin time) . Mixing study corrects w addition of nl pool plasma . Nl PFA-100 or platelet aggregation . Abn Factor VIII + IX clotting activity . Nl VWFAg + VWF activity . Genetic test: ---*seq/deldup/inv in F8 + F9* ------*If severe-> start w targeted mtn analysis to identify intron 22 / intron 1 inv* homologus recomb - test w PCR / southern blot Tx: . *Factor infusions* 8/9, 2-3x weekly, starting in early childhood=> maintain factor level at 1% . Gene therapy: works better for hemB bcs smaller gene Tx complications: . Develop hemophilic inhibitors (30% of F8; 1-3% of F9), bcs IgG antibodies develop-> reduce infusion efficacy => Monitor inhibitors routinely . Contaminated concentrates (usually not a concern) . Complications of venous access devices (esp in children)

Kaullmann

. XL . AD . AR Many genes Major criteria: 1. No smell 2. Late/no puberty

Long QT (LQT) *Cardiovascular* *Arrhythmia*

1 in 3,000 QT = time interval for heart muscle to contract then recover *AD* --- *50-70% penetrance* --- Variable expression *13 subtypes*: . *LQT1* (60%): *KCNQ1* - triggered by exercise (*Think KC tall for LONG QT*) . LQT2 (35%): KCNH2 - triggered by sound / postpartum period . LQT3 (5%): SCN5A - triggered by rest/sleep . Others Modifier: *NOS1AP SNPs -> modify QT interval* *F >> M* Onset: *childhood / adolescence* Criteria: . *Syncope (fainting) usually w stress* . Presyncope . *Seizures w/out typical postictal (altered state of consciousness) phase afterwards* . Ventricular tachycardia (fast heart rhythm) . Ventricular fibrillation (chaotic heart rhythm) . Ventricular tachycardia torsade de pointes (TdP) . Seizures . Cardiac arrest . Unexplained sudden death <30 . Low heart rate for age . Congenital HL in some types *Genetic test (75% DR)* - *geno-pheno correl* ----> *can determine subtype* Dx: . *Long QT* --- > 460 ms in 1-15 y --- > 470 ms in adult female (higher risk of LQT in adult *F >> M*) --- > 450 ms in adult male . *Stress EKG* --- *Absence of nl QT shortening w exercise* . *Prolonged / abn T-wave* . *Ventricular tachycardia torsade de pointes (TdP)* Screening: . *EKG* for all FDR and if abn, their relatives (cascade family screening) . Eval by electrophysiologist Avoid: - *Competitive sports* - *Activities w intense physical activity / emotional stress* --- Amusement park rides --- Scary movies --- Jumping in cold water - Meds that prolong QT (50 prescription meds): Antibiotics *Erythromycin*, Clarithromycin, Gatifloxacin, levofloxacin, Moxifloxacin Sulfamethoxazole-trimethoprim (Septrin/Bactrim), Spiramycin, Pentamidine *Antihistamines* Terfenadine, Astemizole, Diphenhydramine, (These are particularly to be avoided (even in normal subjects) *in combination w* Erythromycin or *grapefruit juice* or the antifungals ketoconazole, miconazole, fluconazole or itraconazole) [Antihistamines that may be used *safely* are loratidine, cetirizine and fexofenadine, and *phenergan*] Appetite suppressants Fenfluramine, phentermine, sibutramine Asthma treatments The Beta-2 agonists (e.g. Terbutaline, Salbutamol, Salmeterol) both work against the B-Blockers given to subjects with long QT and lower blood potassium levels and therefore should be given only in hospital with careful monitoring. Inhaled steroids (e.g. Becotide/Flixotide) and Ipatropium (Atrovent) are safeR Decongestants Ephedrine, phenylephrine, phenylpropanolamine, pseudoephedrine Psychotropics/Antidepressants/Anticonvulsants The antipsychotics (including Thioridazine, Haloperidol , Ziprasidone, Mesoridazine, chlorpromazine), the antidepressants (including Maptiline, Amitriptyline, imiprmaine, fluoxetine, desipramine, paroxetine) and anticonvulsants Felbamate and Fosphenytoin are to be avoided Vasodilators (used to dilate blood vessels in treatment of heart failure angina or high blood pressure) Prenylamine Lidoflazine, Fenoxedil, Bepridil Antiarrhythmics -ironically- (*Pure Beta Blockers are safe*! (e.g. *Nadolol, Propranolol, Atenolol*)) Others are not safe e.g. Type IA *Quinidine* (particularly dangerous), Procainamide, Disopyramide, dofetilid Type IC Encainide, Flecainide Type III Ibutilide, Amiodarone, Sotalol, Sematilide *Liquorice* This *lowers potassium level* even in small doses, and is dangerous in big doses (more than one liquorice twist) or over long periods. Is present as Glycyrrhizinic acid (GZA), found in many sweets including Stimorol and Ben Bits Coolmint chewing gum, Fisherman's Friend, turkish Pepper and herbal medicines for gastric ulcer treatments. Drinks include Belgian beers, Pastis, Raki, Ouzo and Pernod. Miscellaneous *Adrenaline (epinephrine)*, Amantadine (antiviral and Parkinson's disease agent), Chloral hydrate (sedative), Cortocosteroids, diuretics (via electrolyte disturbance-low potassium, magnesium, calcium: Frusemide and other loop diuretics particularly dangerous), Chloroquine (antimalarial), Cocaine, Dopamine, dobutamine (used in intensive care), Dolasetron (anti-emetic), Droperidol (sedative), Foscarnet (antiviral), Halofantrine (antimalarial), Isoproterenol (adrenaline like substance), Levomethadyl (narcotic dependance), 1Midodrine (to treat low blood pressure), Suxamethonium and Atropine (anaesthetic agents), Ritodrine, Vasopressin, Cisapride (for oesophageal reflux- indigestion), Tacrolimus (to suppress immune responses), liquid protein diets. Your dentist should use *local anaesthetic w NO ADRENALIN* Tx . Electrical cardioversion . External defibrillation . *ICD* (Implantable cardioverter defibrillator) = pacemaker (*90-95% effective*, NOT 100%), placed if: ---- *Symptomatic*: SCD survivor / aborted SCD --- LQT1 ------ *β-blockers (antiarrhythmic drugs)*-> reduce epinephrine effect ------ No competitive sports ------ Avoid meds that prolong QT --- LQT2 ------ β-blockers (antiarrhythmic drugs)-> reduce epinephrine effect ------ No competitive sports ------ Avoid meds that prolong QT ------ Avoid hypokalemia ------ *Avoid AUDITORY triggers* --- LQT3 ------ *Mexiletine / flecainide (antiarrhythmic drugs) - benefit of β-blockers in LQT3 unclear* ------ *ICD (most useful in LQT3)* ------ No competitive sports ------ Avoid meds that prolong QT

Hepatitis B

200x inc risk for ca

PCR primer orientation

5'------------------------|||||||||||3' >

Lynch Syndrome (LS) = Hereditary Nonpolyposis Colorectal Cancer (HNPCC) *Cancer*

5% of all CC *AD* Mismatch repair (MMR) (TUMOR SUPRESSOR caretakers): ****MLH1 & MSH2**** (80-90%): missense, dels (MSH2 founder mtn in Americans: del exons 1-6) - ALSO - *EPCAM*: 3' end del (inherited)-> lead to inactivation of MSH2 promotor by hypermethyl (epimtn) *MSH6* (7-10%) (mild; 30% less risk for CRC; more frequent in families w endometrial ca) *PMS1* (rare) *PMS2* (rare) (mild; 15-20% risk CRC, 15% risk endometrial, 25-32% risk and Lynch-associated ca. If homozyg->child death) (works w MSH6) *Same as In E. coli, enz are called MutL & MutS 1. *CC (40-80%)*: *RIGHT (PROXIMAL)* *think oppostie of Left lynch*) Path: --- *SIGNET RING* (circumferentially around colon) ---- mucinous ---- tumor-infiltrating lymphocytes ---- medullary 2. *ENDOMETRIAL* ca = *UTERINE* ca (25-60%)(common w *MSH6*) 3. ****Ov**** ca (4-24%) 4. *GASTRIC* ca (10-20%) 5. *BILIARY TRACT* ca (18%) 6. *Small bowel* ca 7. *BRAIN* ca 8. Urothelial ca: urinary (10%) (ureter & renal collecting ducts) 9. Renal pelvis ca 10. Glioblastoma 11. Adenocarcinoma: . Sebaceous . Biliary . Small bowel . Pancreatic --*NO BR ca* ****TESTING**** [BOARDZ] Clinical dx criteria: *Bethesda criteria* (need one for MSI) CC<50 2 L tumors MSI hi CC <60 CC + FDR w L tumor (1<50) CC + 2 FDR w L tumor *Amsterdam criteria* (to *make dx REGARDLESS OF GENETIC TEST*: only 60-70% of pts who meet Amsterdam criteria have known mtn) FAP excluded Amsterdam I (for research in 1990): *3 relatives* w CC (1 FDR to other 2) *2 successive generations* *1 CC <50* -DR 61% and specificity 67% for identifying MSH2 & MLH1 mtns Amsterdam II (modified bcs original too strict): *Open to all LS tumor types* -DR 78%, but lower specificity *Amsterdam criteria limitations*: ---not perfect ---difficult in small families ---****HNPCC: families that meet Amsterdam criteria**** ---****Lynch: families w germline MMR gene mtn. if have Lynch gene mtn, make dx, whether meet Amsterdam criteria or not**** ---*Familial CCSyndrome X: HNPCC families w/out germline MMR mtn or Lynch pheno (no MSI/IHC/mtn)* Testing Stretegy: 1. *MSI/IHC on CC / endometrial ca*: MSI (MMR defect leads to DNA errors in short repetitive sequences called Microsatellite Instability = MSI) (MSI+ in 77-95% of LS tumors in multiple loci and in 10-15% of sporadic tumors-usually if BRAF mtn) & 2. IHC = Immunohistochemical staining -> identify which protein/gene* If loss of MLH1 IHC staining (no MLH1 protein)-> most likely representative of somatic mtn (somatic mtns in MLH1 are usually due to mtns in BRAF gene. Mutated BRAF-> hypermethylation in MLH1-> loss of MLH1 staining) *If MSI+ & MLH1 loss* (even if also loss of other ones)-> *3. BRAF V600E mtn test + MLH1 somatic methylation test* > *4. Multigene panel seq* Staining: MSH2 MSH6 PMS2 Management (annually): *Colonoscopy from 20-25y* Transvaginal US/endometrial bx from 25-35y Urinalysis w cytology from 30-35y ****Upper endoscopy from 30-35y*** (*unlike FAP*) Consider subtotal colectomy, hysterectomy, oophorectomy after childbearing Refer if personal hx / FDR: . CC / endometrial ca <50 . CC / endometrial 50+ & FDR w colon / endometrial ca . 2 primary colon / endometrial ca in person . Sebaceous adenoma / carcinoma & Lynch ca in same person / relative . CC high MSI / MMR loss on IHC . 3 relatives w Lynch ca . Brain tumor & 2 Lynch tumors in same person / relatives

Balanced translocation

70% inherited

Legius *RASopathy*

AD SPRED1 . CAL . Macrocephaly . Axillary freckling . LD *NO Ca *NF1-like*

Tay Sachs = GM2 Gangliosidosis Type I *Lysosomal storage* *Sphingolipidosis* *AJ* - ACMG -

AR ****HEXA**** --- Enz def: *hexosaminidase A (Alpha-subunit)*(hexoaminidase is composed of alpha + beta subunits. HEXA = TS; *HEXB = Sandhoff w pheno similar to TS*) 3+ AJ mtns: (98% of cases) --- *4bp ins = 1278insTATC* (82%) --- Exon 12 splice mtn = 1421+1G->C in IVS12 (12%) --- Gly269ser = G269S (6%) - mild Others ****AJ carrier freq 1/31**** [BOARDZ] *Today, majority of children born w Tay-Sachs disease have non-Jew parents (bcs of widespread carrier screening in AJ=> frequency decreased by 90%)* Disease pathology: neurons *NL @ BIRTH* Onset: *INFANTILE* <10mo (6-12 mos) , fatal by 2-4/5y (<6y)-> Neurodegeneration: progresses to . *Hypotonia*, floppy, weak, lose ability to sit and then head control . Hyperacusis/*EXAGGERATED STARTLE RESPONSE* . ****CHERRY RED SPOTS**** on macula eye exam . DD w decreased visual attentiveness by 1y . Seizures . Slowing development, loss of motor skills . Apathy . ID . Blind, deaf, loss of awareness . Progressive spasticity, vegetative state => death by 2-5y **NO HSM* Juvenile: symptoms at 2-10 y; death by 10-15 y Adult/late onset: symptoms in adolescence; *G269S mtn* . ****PSYHOSIS**** (40%) . Proximal muscle weakness . *Ataxia* . Tremor . Dystonia *nl IQ, NO epilepsy* *NO cherry red spot* *NOHSM* *NO dementia* Dx test: . *HEXA enz activity* (95-99% DR)→ if low (due to real mtn or pseudodeficiency allele)-> . Brain MRI: shows atrophy + white matter demyelination . *HEXA common mtn analysis (92-94% DR for AJ, 59% for others)* . HEXA seq (99% DR for AJ, per Counsyl) Carrier test: since 1969 *Enz analysis is gold-standard for carrier testing* - simple, inexpensive, and highly accurate --- *Serum hexA enz analysis accurate for non-preg+non-OCPs*. *Not accurate* during ****PREG / using OCPs**** => instead, test ****LEUKOCYTES (WBCs)**** also use when serum assay inconclusive) --- If non-AJ: enz analysis better; genetic test not helpful in non-AJ bcs most mtns not detected. if enz analysis pos > genetic test to rule out pseudodeficiency allele (35% of non-AJ heterozygotes are carriers of pseudodeficiency allele) --- *If AJ: mtn analysis + enz (for more accuracy)* --- *If French Canadian: enz analysis* Prenatal dx: Enz analysis (CVS/amnio) / genetic test if both prarental mtns known Tx: None, only supportive . Substrate reduction in trials . Pharmacologic chaperones . Anti-epileptics . Respiratory support . Supplement nutrition

Hemoglobin C

AR HBB @ 11p15.5 --- Glu6Lys Carrier freq: AA 1/50 Caribbean, west indian 1/30 West african 1/20-1/30

Rhizomelic Chondrodysplasia Punctata (RCDP) *Peroxisomal*

AR PRENATAL ONSET Stippling ID Seizures Nl VLCFA

Leigh = Subacute Necrotizing Encephalopathy *Mitochondrial* *Metabolic*

AR, XL = nuDNA (70%) Matrilineal = mtDNA (30%) . nuDNA of mt energy regeneration (most common cause): --- PDHC incl XL E1 alpha --- Electron transport chain ------ nuDNA complex 1 (NADH dehydrogenase): NDUFS 1,2,4,7,8, and NDUFV1 cause Leigh + leukodystrophy) ------ nuDNA complex 2 -> Leigh w paraganglioma + pheo ------ nuDNA complex 4 -> demonstrates low activity if mtn in assembly proteins: --------- ****SURF1**** (50%) [BOARDZ] --------- SCO2 --------- Cytochrome C Oxidase (COX10/15) . mtDNA: point mtns --- ATP6 (ATP synthase subunit 6), TL1, TK, TW, TV, ND1, ND2, ND3, ND4, ND5, ND6, CO3 ------ MT-ATP6 complex 5 subunit --------- ****T8993G**** (10%) --------- ****T8993C**** Heteroplasmy: --- <60% mtn heteroplasmy nl --- ****70-90% mtn heteroplasmy -> NARP => less severe****[BOARDZ] --- ****>90% mtn heteroplasmy -> Leigh****[BOARDZ] Onset: infancy-childhood (3-12 mos), often after viral infection Affects basal ganglia → progressive psychomotor neurodegeneration: . ***IMPAIRED BREATHING*** . *HCM* . ****ATAXIA**** . CRANIAL NERVE ABN . Lactic acidosis . Vomiting . Hypotonia . DD . Feeding prob . Developmental psychomotor regression . Seizures . Dystonia . Tremor . Movement disorders: chorea . Peripheral neuropathy . Pyramidal tract signs . HL . Dysarthria . GI prob, FTT . Eye: --- Blind --- Ptosis --- Strabismus --- Optic atrophy --- Nystagmus --- Pigmentary retinopathy => Childhood death (75% die by 2-3 y bcs of respiratory / heart failure) Genetic test: Targeted for 2 common MT-ATP6 mtns > nuDNA seq > whole mtDNA genome seq . Biochem: --- Blood and CSF levels: hi lactate --- pAA: hi alanine --- uOA: lactic aciduria . Brain imaging: specific brain lesions --- CT - bil symmetric hypodensities in basal ganglia --- MRI - bil symmetric HYPERINTENSE SIGNAL (stroke-like episodes) in inferior brain: ------- basal ganglia ------- cerebellum ------- brain stem . Muscle bx (preferred source) ---Rarely abn ---Can help w dx certainty ------ Intracytoplasmic neutral lipid droplets accumulation ------ Ragged red fibers (hallmark of adult-onset mt dx) ------ COX negative fibers . Respiratory chain enz studies of skeletal muscle --- Deficient activity of one or more complexes ------ Complexes I & IV abn (common)

Hypothyroidism *Teratogen*

HL ID

Hearing loss = Deafness - ACMG 2014 -

HL: loss of ability to hear (any degree) 2-3/1,000 significant HL (95% w hearing parents) Deaf = community w distinct culture + language shaped by experience of being deaf / hard of hearing; includes: . Deaf = complete / near complete HL . Hard of hearing = partial HL . Hearing Abn origin: . SNHL: inner ear . Conductive: middle ear's small bones . Mixed: inner + middle ear . Auditory neuropathy Congenital/childhood HL causes: -Idiopathic (25%) -Non-genetic (25-40%): . Premature . Low birth weight . Pre + Postnatal Infection: CMV, rubella, AIDS, toxo, meningitis . Ototoxic meds: thalidomide, retinoic acid, ECMO . Rh incompatibility . Birth hypoxia . Hyperbilirubinemia -Genetic (50%) ---Syndromic (30%): >400 syndromes ------ Pendred ------ Usher ------ Waardenberg ------ BOR ---Nonsyndromic (70%): ------- AR (80%): GJB2+GJB6 (50% of AR nonsyndromic HL; 15-40% of HL) ------- AD (15-24%): e.g. post-lingual HL ------- XL (1-2%) ------- mtDNA: ---------- 5% of children w postlingual HL ---------- ~1% in Western countries, slightly higher in Spain + East Asia (China, Mongolia, Korea, Japan) ---------- Moderate to profound HL on audiogram ---------- Bil ---------- Severe to profound ---------- Mtn in MT-RNR1 encoding mt 12S-rRNA + tRNA (A3243G) or MT-TS1 encoding mt tRNA Ser(UCN) => predisposition to aminoglycoside antibiotic (used commonly in Asia to tx sepsis) ototoxicity: develops in few days to wks after taking any amount (even 1 dose) -Ch ----Aneuploidy: T21, 13, 18, Turner ----Microdel: 1p36-, 22q11-, Wolf Hirschhorn, Williams . Age of onset: --- congenital --- prelingual (< speech acquisition) --- postlingual (> speech acquisition) --- adult-onset --- presbycusis = age-related HL (in 40-50% of 75y+): M >> F ------ Multifactorial: e.g. noise + genes previously implicated in other forms of HL (KCNQ4 + ACTG1), oxidative stress genes (GRM7, GRHL2, mt oxidative genes, N-acetyltransferase) . Laterality + symmetry . Stability: --- progressive --- nonprogressive --- fluctuating . Degree: ---slight (16-25 decibels (dB)) ---mild (26-40 dB) ---moderate (41-55 dB) ---moderately severe (56-70 dB) ---severe (71-90 dB) ---profound (91 dB or greater)) . Configuration (sloping) seen on audiometric analysis: ---flat ---rising ---midfrequency (cookie-bite) loss Empiric RR: . Sib of deaf child w hearing parents ----18% ----10-14% if neg GJB2/6 . Offspring of deaf person + hearing person ---10% (bcs could be AD) *Test for GJB2 . Offspring of deaf couple w no AD syndrome ---15% HL NBS: Started in 2001 Universal hearing screening recommended through childhood + adolescence Test (usually after pos NBS): GJB2+GJB6 / targeted gene (if syndrome suspected) > Multigene panel (now using NGS instead of single gene tests), WES considered + CMV (do concurrently w genetic test for infants w congenital HL. if done >6y, false pos risk higher since child may have been exposed) Test recommendation: ALL CHILDREN + ADOLESCENTS w HL of NO CONFIRMED etiology -> recommend eval for syndromic HL by clinical geneticist *Neg genetic test does NOT rule out genetic cause-> regular fwp may be appropriate Resources: . "Hereditary HL and Its Syndromes", by Toriello and Smith (review of conditions)

Urea Cycle Disorders *Metabolic*

Ammonia is a byproduct of AA metabolism and is very toxic. It is transported as either glutamine or glutamate to the liver where it enters into the urea cycle. In the urea cycle, free ammonia is converted into carbomoyl phosphate. *AR (except OTC XLR)* Def / no activity of: - 5 urea cycle enz: --- CPS1 --- OTC --- ASS --- ASL --- ARG or - Cofactor-producing enz => Hi ammonia => low pH => 1. Tachypnea (rapid breathing) -> Low pCO2 (exhaled) to inc pH => *PRIMARY RESPIRATORY ALKALOSIS* => Hi pH 2. Low HCO3 = bicarb (excreted to lower pH) (don't give supplemental HCO3) -> aggravates alkalosis => Secondary metabolic acidosis compensation Criteria: . Protein aversion-> *METABOLIC CRISIS DUE TO HI AMMONIA (MOST COMMON FEATURE)*-> nausea, vomiting, poor feeding, anorexia, FTT [BOARDZ] . Hyperventilation (not in OA) . Encephalopathy: cerebral edema bcs ammonia builds up (OA only has encephalopathy) . Tachypnea . Stupor . Tremor . Seizures . Soma . Death Onset: -Neonatal: Severe def / absence of NAGS, CPS1, OTC, ASS, ASL => --- Nl @ birth→ --- Onset: Hours - few days after birth, hi ammonia (requires hospital) => rapid development of: ------ Cerebral edema ------ Lethargy ------ Anorexia ------ Hyper / hypoventilation ------ Hypothermia ------ seizures ------ neurologic posturing ------ Coma -Later onset: Partial def of NAGS, CPS1, OTC, ASS, ASL: --- Nl @ birth --- Onset: Infancy / childhood / adulthood --- Episodic: First hi anemia episode may be delayed for mos / yrs --- Triggered by illness / stress / hi protein meal. Hi ammonia episodes in later onset UCDs are still life threatening (require hospital) - avoid hi protein diet ------ Vomiting ------ Lethargy ------ Irritability ------ FTT ------ DD Biochem test: . Hi plasma ammonia (>5-6x nl => highest of all metabolic dx; not specific to UCDs) (nl ammonia<85 mg/dL) --- Markers: pAA ------ Hi glutamine ------ Hi alanine ------ Hi glycine ------ Hi other specific AA unique to each enz . Use citrulline + arginine to differentiate . Low plasma urea . uOA: orotic acid may be abn . Blood gases: --- Hi pH --- low pCO2 --- low HCO3 NBS: Enz def not reliably detected w NBS: - CPS1 - OTC - NAGS Pathway: Protein -> AA -> Excess AA (e.g. hi protein diet) -> Body does not store excess AA -> Deamination: Amine group, -NH2 (N=Nitrogen) + H (hydrogen atom) removed from AA => Arginine + ammonia (toxic) (carbon backbone turned into carbs / fats) - in blood -> Urea cycle = ornithine cycle - in mt of liver -> Turns excess ammonia into urea (non-toxic) -> Blood -> Kidneys -> Urine Conditions: - OTC (*MOST COMMON UCD*) - *Carbamyl phosphate synthetase* def - Arginase def - N-acetylglutamate synthetase def Tx of acute crisis: . Reduce ammonia . Tx underlying illness . Reverse decompensation Long-term tx: . Diet: --- *No/low protein* --- Formula supplementing deficient AA --- Meet arginine requirements . Promote alternate pathways for NH4 waste nitrogen excretion: --- *Oral nitrogen-scavenging drugs: sodium phenylbutyrate*, sodium benzoate & glycine used to form hippurate w ammonia for alternate excretion --- Sodium phenylacetate . Consider *liver transplant* -> *usually cure*! . Avoid: --- Valproic acid --- Catabolic state due to long fasting/illness --- Large protein / AA boluses

Oligospermia

DAZ1 del (most common cause)

Barr Body

Dark staining body found in nuclei of female mammals that contain a condensed inactive X ch

Color Blindness

Deficiency in one or more of three cone types responsible for color vision Usually XL

Pedigree

Detailed (targeted) 3 to 4 generation pedigree (degree relation from proband or fetus)

Differential diagnoses

Discuss what most likely outcomes Avoid rattling off 100s of (all) possibilities!

Jackson Weiss *FGFR related Craniosynostosis*

FGFR2 --- GoF . Craniosynostosis . Broad medially deviated big toes . Abn feet tarsals *Nl hands

Nonsyndromic coronal synostosis = Isolated coronal synostosis *FGFR related craniosynostosis*

FGFR3 GoF

Maternal Lupus

Fetal heart block (slow heart beat)

Parovirus *Teratogen*

Fetal hydrops

Hyperthyroidism and Grave's Disease *Teratogen*

Fetal hyperthyroidism

Radioactive Isotopes *Teratogen*

Fetal thyroid hypoplasia

FISH

Fluorescence in situ hybridization (FISH) is a laboratory technique for detecting and locating a specific DNA sequence on a chromosome. The technique relies on exposing chromosomes to a small DNA sequence called a probe that has a fluorescent molecule attached to it. The probe sequence binds to its corresponding sequence on the chromosome. To tell if the gene/region is present or not.

Processed Pseudogenes

Formed by retrotranposition (not by mtn): transcription, generation of DNA copy of mRNA and integration of DNA copies back into genome

Mannosidosis *Metabolic* *Lysosomal storage*

Hepatosplenomegaly Tx: BMT

Romano Ward *LQT variant* *Hearing loss*

Heterozygous LQT 1, 2, 3, 5, 6 . KCNQ1 . KCNH2 . SCN5A . KCNE2 LQT

Cell Cycle

G1 (or G0) → S → G2 → M Cell cycle tightly regulated by different checkpoints: G1/S: cell monitors size and DNA integrity G2/M: cell monitors DNA synthesis and damage M: cell monitors spindle formation and attachment to kinetichores Regulation of cell cycle is mediated by cyclins and cyclin-dependent kinases

Beckwith Wiedemann syndrome (BWS) *Imprinting* *Microdeletion* (RARE) *Overgrowth*

****AD**** --- ****85% DE NOVO**** => *low RR* [BOARDZ] Imprinting defect @ ****11p15**** *Think 11 like W double U double 1* (2 imprinted domains) => *normally expressed in genes* *think "beck is a boy"* => *over-expression of genes* (growth factors, tumor suppressors) IC2: normally expressed in pat allele IC1: normally expressed in mat allele Domain 1: . Mat derived transl + inv . Pat UPD . Imprinting abn Domain 2: . Loss of imprinting in LIT1 . CDKN1C mtn Mtns: . ****Hypomethyl mat ICR2 (50%) => DMR2 (KCNQ1OT1)**** [BOARDZ] (loss of growth suppressor) . ****upd(11)pat (20%)****: due to *somatic* event as evidenced by *mosaicisim at single cell level* (so, *not meiotic nondisjunction*): usually isodisomy & *confined to 11p15* (distal short arm) (*PWS+Angelman involve entire ch 15*) . ****Hypermethyl mat ICR1 (5%)****: *biallelic expression of pat expressed insulin-like growth factor II (IGF2)* --- can be highly heritable . mat *CDKN1C* (cyclin-dependent kinase inhibitor 1C) mtn (5% of sporadic; 40% of familial): p57KIP2 . Hypermethyl mat DMR: (H19) gain of methyl (2-7%) . Duplication / inversion / translocation of critical region (<1% each) ---partial pat 11p15.5 trisomy (<1%) ---apparently balanced transl / mat inherited inv (<1%) Prenatal US: --- *20% of isolated omphalocele have BWS, 50% conceived w ART* ------ *~100% due to hypomethylation (vs 50% usually)* Criteria: "Beck Weidemann is a wide child w a big tongue. So wide like a balloon that abdomen pops open!!!" 1. OVERGROWTH: *MACROSOMIA* w organomelgaly 2. *MACROGLOSSIA* 3. *OMPHALOCELE*/abd hernia Other criteria: . Pre + postnatal overgrowth w hemihyperplasia: *BODY+FACE ASYMMETRY* . Embryonic tumors (6.5%): *Risk highest if upd(11)pat* --- *WILMS TUMOR*!!! --- *Hepatoblastoma* . *Neonatal hypoglycemia->ID, but generally nl IQ* (even though macrosomia) . Polyhydramnios . Prematurity . Renal abn . Dysmorphic Face: --- Mouth: macroglossia --- Ear: ------ *Fleshy earlobes* ------ Ear creases ------ Posterior pits --- Facial nevus flammeus Test: (karyotype can be done at same time as other genetic test) If no Fhx: *Methyl ICR1 + ICR2 (MS-LPA) > UPD > CDKN1C seq > array / karyotype* *If Fhx* => *CDKN1C seq first* ... *If pt w ID*: *Karyotype first* ... Management: Abd US every 3 mo until 8y Serum AFP every 3 mo until 4-5y: to monitor for hepatoblastoma *MZ twins most discordance for BWS (mostly females) *9x inc in risk w ART preg (6x increase in ART among children w BWS) (also for Angelman but not PWS)*

Benzene *Carcinogen*

****LEUKEMIA****

Confined Placental Mosaicism

*1-2% rate of placental mosaicism* *10% of placental mosaicism is true fetal mosaicism* (more likely if in cultured prep (type II) and if ch is one of common trisomies) Risks: . IUGR or IUFD (16-21% risk) . UPD (possible that trisomy rescue happened; especially if F/U amnio was nl) ---Ch due to *meiotic* nondisjunction and associated w UPD: 9 16 22 ---Ch due to *mitotic* nondisjunction and less likely associated w UPD: 2 7 8 10 12

Termination of Pregnancy Resource

*A Heartbreaking Choice*: aheartbreakingchoice.com

Birt Hogg Dubé (BHD) *Cancer*

*AD* *FLCN = folliculin* 1. Benign *SKIN LESIONS* (onset 30-40) on face & trunk: . ****FIBROFOLLICULOMAS**** (*pathognomonic*) [BOARDZ] . Perifollicular fibromas . Trichodiscomas|a . Acrochordons . Angiofibromas 2. *RENAL CELL ca* (16%)(onset <50): . ****CHROMOPHOBE**** . Oncocytoma . Mixed (hybrid) oncocytic . Clear cell (rare) 3. Lung blebs (cysts)-> MANY *PNEUMOTHORAX* [BOARDZ] Management: Yearly MRI start at 30-35y

Galactosemia *Metabolic* *Carbohydrate Metabolism*

*AR* *GALT* @ 9p13 Enz def: *galactose-1-phosphate uridylyltransferase* >160 mtns . Classic: *Q188R* (Gln188Arg) (70% of Caucasian alleles; carrier freq 1/128) . *DUARTE (NOT PICKED UP ON NBS)* (mild): N314D, common, carrier freq 1/27 - activity: D/N (75%), D/D (50%), D/G (25%) . LA (N314D+L218L) - 140% activity . Classical GALT: hi galactose, low GALT . Galactokinase (GALK): hi galactose, low GALK . Epimerase (GALE): hi galactose, low GALE Onset: *neonatal (before NBS rslt!)* *If there is still GALT enz activity/no clinical pheno after pos NBS => probably false pos due to Duarte variant galactosemia* . *CATARACT* . Jaundice, abn liver function tests (LFTs), hyperbilirubinemia-> Acute liver disease: renal enlargement and renal fanconi syndrome (identified w urine test)!!!-> skeletal rickers -> ****RENAL TUBULAR DISEASE****=> renal failure . ****E COLI SEPSIS**** . *Hi AA* . ****HYPOGLYCEMIA**** . *PRIMARY AMENNORHEA* . Bleeding diatheses, burising, coagulopathy . Feeding prob . Irritability, lethargy, poor feeding, vomiting, diarrhea, death Long term: ---DD, esp. expressive language delay ('verbal dyspraxia') ---Motor delays: ataxia, tremor ---POF, hypergonadotropic hypogonadism, low bone density NBS: Hi galactose, low GALT Limitation: . blood spot too thick . sample improperly prepared . liver immaturity . protein overload (newborns fed cow's milk) . heterozygosity for PAH def in premature babies *test done >24hr old bcs it takes that long for phe concentrations to show Dx test: . *LOW erythrocyte GALT enz activity* . Hi liver enzymes + bilirubin . Hi RBC Gal-1-P (GALT substrate) . Urinanalysis (can identify renal tubular disease): neg for glucose, hi Reducing Substances (RS) (glucose is most common RS; worry if neg for glucose but pos for other RS=> could mean galactosemia / fructose intolerance) . Coagulopathy . Gram negative bacteria Genetic test: *Q188R common mtn* Tx: Diet: no galactose, no dairy, breastfeeding, dairy. Replace w soy Consdier septic risk Treat liver disease & jaundice *NOT liver transplant*

Personalized Genomic Medicine (PGM)

Genetic Factors Involved: Cyto, Linkage, Association, GWAS Linkage Studies: good for identifying differences that have large effect Association Studies: good for identifying genetic differences that have smaller effect GWAS: looking at SNPs from cases vs controls - statistical threshold: p = 5 x 10(-8) GWAS Case Control Studies: Start w people w disease→ cases; find similar people without disease → controls Look at lots of SNPs across genome and see if any are more/less prevalent in cases vs. controls Is GWAS Valid: Testing multiple associations at once increases FPR Disease pheno variation (ER neg vs ER pos BrCa) Population stratification (cases/controls should be same ethnicity) Replication Note: Significance of association DOES NOT equal strength of association or clinical significance How are Risk Predictions Made: Weighted Risk Score: Each allele/genotype OR is weighted for its effect on disease risk Convert OR to RR using HWE→ adjusts for allele frequency and allows for risk to be compared to general pop Simple Multiplicative Model Multiple genotype RR for each SNP→ multiply that number by general population risk Risk Prediction / Medical Decisions: Risk estimates range from 0-100% but medical decisions are yes/no→ we need threshold to determine yes/no May be better to have risk 'categories' to determine intervention Clinical Utility: There are few examples of high-effect common variants influencing common disease→ is it worth it to test people for these SNPs? (maybe yes if it will improve health outcomes or benefits outweigh the costs) Personalized Medicine vs. Genomic Medicine: Personalized medicine: form of medicine that uses information about a person's genes, proteins, environment and behavior to prevent, diagnose, and treat disease Genomic medicine: application of genetic/genomic testing and principles to the provision of personalized medicine Goals of Personalized Genomic Medicine: provide tailored treatment to individuals⇒ Earlier detection Selection of optimal therapy More accurate dosing Reduce drug side effects Increasing patient compliance with therapy Shift from reaction to prevention Improved treatment outcomes Minimal lag time to accuracy Reducing the overall cost of healthcare Examples: PGM used for preclinical dx or prognosis: e.g. Oncotype dx PGM used for ca tx (different drugs for different problems: HER2, EGFR, KRAS, BRAF) PGM used for pharmacogenomics: part of phamacology that deals with the influence of genetic variation on drug response by correlating genetic variation with a drug's efficacy or toxicity Factors that contribute to inter-individual variability in drug disposition and action: age, ethnicity, weight, gender, co-occurring disease, co-occurring drugs, social, genetics! Drug Metabolism: Drug metabolism is a quantitative, complex trait: genetic variation affects: absorption, distribution to target tissue, drug target itself, metabolic processing, excretion Population is made of: Fast metabolizers Nl metabolizers Slow metabolizers Example: CYP2D6: CYP2D6 metabolizes 25% of commonly prescribed drugs=> does doesn't work; highly polymorphic Genotyping of CYP2D6 can reveal: UM, EM, IM, PM This can help better determine an accurate dose for individual e.g. Dosing (SSRIs w/ CYP2D6 ) Example: CYP2C9, VKOR1C Drug: Warfarin is an anticoagulant used to treat thrombosis and embolism→ overdoing leads to hemorrhage, underdosing leads to clots Regular blood tests are needed to monitor toxicity (INR) Large variability in the dose required to achieve therapeutic anticoagulation CYP2C9 and VKOR1C polymorphisms explain some variation in warfarin dose But, genotype-guided dosing strategy does not reduce major adverse events Example: HLA-B*5701: Drug: Abacavir is used to treat HIV; hypersensitivity occurs in 2-9% of patients bcs of HLA-B*5701 Screening for HLA-B*5701 reduces risk of abacavir hypersensitivity so genotyping before prescription has been widely adopted Adverse events (carbamazepine in HLA-B*1502) Example: CYP2C19 Drug: Clopidogrel is used with aspirin to reduce risk of post-angioplasty major adverse CV (cardiovascular) events The pro-drug is activated by CYP2C19 A common SNP in CYP2C19 results in a truncated protein with little activity→ increased risk for CV event (antiplatelet concerns) CYP2C19*2 allele! There is an online calculator that helps w dosing! Dosing of Clopidogrel can be based on the type of metabolizer UM/ EM should have standard dose IM/PM should use alternative antiplatelet

Finasteride *Teratogen*

Genital defects in male babies

Jervell & Lange Nielsen *Hearing loss* *LQT variant* *Cardiovascular*

*AR* --- *homozygous LQT *1, 2 . *KCNQ1* (common) @ 11p15.5 . KCNE1 @ 21q22.1-q22.2 1. *LQT* (QT >500 ms) -> 50% die <15y if untx 2. Congenital *SNHL* (*think can't hear the jingles*) Test: Sequential / multigene panel

Ultrasound Findings

If BD on US & nl karyotype→ *6% pathogenic CNV risk on array* 200,000-400,000 variants detected w WES Risk of ch abn: Cystic hygroma - 60% Holoprosencephaly - 47% TE fistula - 40% VSD - 38% Hydrops - 32% MCA - 29% CHD - 17% . Echogenic Bowel (soft marker) - Aneuploidy (LR=6) - CF - Fetal infection (CMV) - Intra-amniotic bleeding - Bowel abn . Hydrops = accumulation of fluid in 2 fetal compartments --- Immune (Rh antigen) hydrops --- Non-immune hydrops - Sign: middle cerebral artery-peak systolic velocity - Causes: --- Aneuploidy: Turner, T21, 13, 18 --- Syndromic: ------ Noonan ------ Pena Shokier ------ Myotonic dystrophy ------ Multiple Pterygium ------ Skeletal dysplasia --- Metabolic: ------ Galactosialidosis, ------ GM1 gangliosidosis ------ Sialidosis ------ MPS ------ Farber --- Infections ------ TORCH ------ Coxsackie virus ------ Leptospirosis ------ Trypanosoma cruzi ------ Parvovirus B19 --- Hematologic: ------ Alpha thal . Teratoma = tumor that steals baby's blood => hydrops. Usually in: --- Cervical region-> compress trachea => respiratory distress --- Sacral region *Deliver via ex-utero intrapartum tx . Dandy Walker Malformation = complete absence of cerebellar vermis; dilation of 4th ventricle; enlargement of posterior fossa --- Risk of CNS abn: 70% --- Risk of non-CNS BD: 20-33% Postnatal: --- Wide range of severity --- Inc hydrocephaly risk . Ventriculomegaly = lateral ventricle > 10mm; dangling of choroid plexus --- Prognosis difficult to predict (esp if isolated) --- Recommend: ------ Fetal MRI, karyotype, fetal echo, viral studies ------ Postnatal shunt . Agenesis of Corpus Callosum (ACC) = teardrop appearance of ventricles --- Risk of brain findings: 85% --- 175 syndromes --- If isolated -> nl/borderline development . Pierre-Robin Anomaly = mandibular hypoplasia due to posterior placement of tongue when cleft closes => --- U-shaped cleft palate --- Airway obstruction . AV Canal Defect (CHD) - 25-30% ch abn risk (esp T21) - Surgical repair within first 6 mos of life . Hypoplastic Left Heart --- Offer fetal array prenatally --- 3 step surgical repair postnatally . Diaphragmatic Hernia = diaphragm moves up -> restricts develop. of lungs --- usually L sided --- Lung to Head circumference can predict survival (50% don't survive) ---- Recommend: MRI, fetal echo, karyotype . Congenital Cystic Adenomatoid = malformation of lung; benign lung tumors; overgrowth of terminal bronchioles --- Usually unilateral --- Not associated w genetic abn --- Complications: polyhydramnios, hydrops . Duodenal Atresia = small bowel obstruction→ DOUBLE BUBBLE --- 1/3 have T21 . Polyhydramnios: --- Preterm labor . ****Posterior Urethral Valves**** = urethral valves, which are small leaflets of tissue, have a narrow slit-like opening that partially impedes urine outflow --- ***easily detected on routine US!!!*** --- Most common cause of bladder outlet obstruction in male children . Keyhole appearance of bladder: --- Usually sporadic . Oligohydramnios: --- Predicts poor outcome (long term outcome depends on renal function) --- Recommended: serial bladder taps + prenatal vesicoamniotic shunt --- Uretero Pelvic Junction Obstruction . Hydronephrosis: --- More common in males --- 20-30% bil --- Most cases resolve or remain stable prenatally; outcome usually good . Limb Reduction Defects: --- Usually sporadic --- ~ 50% bilateral --- Recommend: ------ Det US ------ Fetal echo ------ Prenatal consult w orthopedics/hand specialist . Polydactyly: --- Isolated ------ Usually AD trait (10x more common in AA) --- Syndromic --- ⅓ of kids have positive fhx --- M >> F . Clubfoot: --- Usually isolated, unilateral --- Usually multifactorial --- Prognosis is good w tx→ refer to orthopedics

Human Genome Project

International collaborative effort to map and sequence the DNA of entire human genome

Ultrasound Detection Rates

LI US for GA dating only! LII US DR: -VWD - 92% -Urinary tract - 91% -NTD - >90% -CHD - 13-35% (67% in targeted 2nd tri US) -CLP - 30% -Microephaly - 27% -Limbs - 25%

Kartagener = Primary ciliary dyskinesia (PCD) = Immotile ciliary

Male and female infertility

Progesterone like drugs *Teratogen*

Masculization of external genitalia of female fetuses

Testosterone *Teratogen*

Masculization of female fetuses Labioscrotal fusion (exposure < 80-90 days), Clitoromegaly (exposure > 8 wk) Virilizing Tumors

Haploinsufficiency

Mechanism of action to explain a pheno when: Diploid organism loses 1 copy of gene => left w 1 functional copy of that gene e.g. AD genes

Oligonucleotide ligation assay

Method for identifying specific mutations Advantages: Very low false positive rate Minimal handling Easily automated Older, being replaced

Glycogen storage disease type Ib *Metabolic*

Neutropenia -> infections

Familial Tall Stature

One family w --- Pectus excavatum + tall proband + Tall relatives => FBMN1 mtn in proband *No one w cardiovascular prob No systematic survey of tall individuals for other features of Marfan / FBN1 mtns

Genome

Ordering of genes in haploid set of ch of a particular organism

Streptomycin *Teratogen*

Ototoxicity (mt A1555G MTRNR1)

Dilated Cardiomyopathy (DCM)

Prevalence of IDC in US = 1/2,700 Can occur in adult / children Variable age of onset (av age = 40y) 40-80% penetrance Can be genetic / non-genetic: Non-genetic - acquired causes of DCM: Ischemic injury results from MI and/or CAD Meds etOH abuse CHD Valvular and congenital heart disease Toxins (ANTHRACYCLINES) Thyroid disease Viral infection Inflammatory conditions Myocardidtis Severe long-standing HTN Radiation Iron overload (hemechromatosis) Idiopathic dilated cardiomyopathy (IDC) - exclusion of all acquired causes Familial dilated cardiomyopathy (FDC) - 2+ closely related family members meet diagnostic criteria for IDC Isolated FDCM FDCM w cardiac conduction defects (DCM-CCD) Associated w mtns in lamin A/C -20-50% have fhx ---AD (80-90%) ---XL(i.e. DMD, BMD, Emery-Dreifuss MD, Barth) ---AR (i.e Alstrom w/ DCM ) ---Mt (i.e MERF, MELAS, isolated DCM) 5-30% have known mtn Metabolic Hemochromatosis Mt Disease Muscular Dystrophies Duchenne Muscular Dystrophy Limb Girdle Muscular Dystrophy Emery Dreifuss Muscular Dystrophy Sarcomere genes mtns *TTN* (20%) *LMNA* (6%) MYH7 (4%) MYH6 (4%) ACTC1 DES TNNT2 SCN5A PSEN1 PSEN2 Left ventricular enlargement (LV end-diastolic diameter >2.7 cm/m2) and systolic dysfunction (LV ejection fraction <50%) => Reduction in myocardial force of contraction (ejection fraction of <50%) Asymptomatic → SOB, chest pain/palpitations, exercise fatigue, heart failure, SCD Edema Orthopnea Paroxysmal dyspnea Fatigue Dyspnea on exertion Arrhythmias Thromboembolic disease Including venous thrombosus, stroke and MI Dx: Echo: LV enlargement and systolic dysfunction EKG: atrial and ventricular fibrillation Genetic test: Test for most common genes available at multiple labs DR = >20% in Familial DC Unclear what percent of Isolated DC caused by single gene Family Testing: Proband Positive: cascade family testing Proband Negative: cascade family EKG/echo/MRI Tx: No competitive sports (once evidence) B-blockers Heart transplant Limited/avoid alcohol Restrict salt and fluid intake daily endurance-type exercise for about 30 minutes, ICD, pacemaker Pharmacological therapy ACE inhibitors Diuretics Digoxin Cardiac Transplantation Screening guidelines: Echo (and EKG) Unaffected mtn carrier: Yearly in childhood + 1-3 y in adulthood FDR: Every 3-5 y / in response to change in symptoms

Dictyotene

Prolonged resting phase of gametogenesis only in FEMALES: --- Occurs during meiosis I from fetal life until ovulation

Short QT

Rare < 30 cases reported since 2000 AD ---Variable penetrance 3 genes: GoF mtns (unknown DR) KCNH2 KCNQ1 KCNJ2 Syncope Atrial fibrillation SCD Dx: Very rare, not standardized QT <320-340 ms Tall, peaked T waves Management: No recommendations

upd(14)pat

Skeletal abn: ---short-limbed dwarfism ---narrow thorax ---scolisosi Dysmorphic face ID Respiratory prob->decreased survival Dx: after identifying Rob transl / isoch involving ch 14 *More severe than upd(14)mat

Radiopharmaceuticals *Teratogen*

Skin reddening Cataracts

Deldup Testing

Southern blots RT-PCR Real time polymerase chain reaction MLPA Multiplex ligation-dependent probe amplification Array

46, XY Complete Gonadal Dysgenesis

Sporadic 46, XY Inheritance: sporadic SRY recombination Female external genitalia No ovaries, uterus Amenorrhea Infertility Gonadoblastoma

Goldenhar = Hemifacial microsomia, oculoauricular dysplasia = Oculo auriculo vertebral

Sporadic Criteria: Stapedial artery defect - 4th wk of GA => . Face --- Asymmetric face (hemifacial microsomia) --- Facial nerve palsy . Eye --- Benign epibulbar dermoid tumors . Ear --- Microtia --- Preauricular tags/pits --- Conductive HL --- Aural atresia . Vertebral abn --- Fused/missing vertebrae . Mouth --- Mandibular hypoplasia --- Lateral CL, CLP . Macrosomia . Renal abn . Coloboma . Genital hypoplasia . CHD . Radial ray anomalies Test: *NO genetic test* Tx: . Surgeries

Assisted Reproductive Technologies (ART)

Stats: Risk for major BD is 30% greater w ART than w general pop (ACMG practice Q) Inc risk of disorders of genomic imprint (BWS, Angelman, mat hypomethylation syndrome) Tx for Infertility: Ovulation Induction/ Controlled Ovarian Hyperstimulation Goal: induce growth of few mature follicles Options: Clomid Clomiphene Citrate blocks estrogen receptors in brain→ brain released more FSH, LH→ ovaries grow and mature an egg(s) which then ovulate (s) (then intrauterine insemination) Benefits: Relatively inexpensive Pill/oral form Less monitoring required Low risk for side effects Good success in achieving ovulation Risks: Small inc risk of multiples Small risk of ovarian hyperstimulation Possible small increased risk of ov ca if many cycles are used Injectable Gonadotropins FSH/LH given in injectable form→ mature eggs which ovulate (more aggressive) [Intrauterine insemination] Benefits: Higher success rates than clomid Less invasive that IVF No surgery required Risks: Increased risk of multiples Risk of hyperstimulation More monitoring Possible small increased risk for ovarian cancer (Esp. if over 6 cycles) Expensive, injections IVF Goal: induce growth of multiple mature follicles Procedure: Injectable Gonadotropins (higher dose) Controlled ovarian hyperstimulation w gonadotropins monitored by ovarian US & assay of serum estradiol concentrations Multiple Mature Follicles US guided Egg Retrieval to Remove Eggs from Ovaries Outpatient procedure; anesthesia given; low risk Fertilization in lab IVF: many sperm put in dish & egg fertilized (must ensure egg doesn't have extra sperm attached) ICSI: place single sperm in single egg Fertilization check: look at egg for 2 pronuclei Embryo Development Watch embryo development; esp. check it at day 3 and day 5 stage (by day 5 it's a blastocyst; blastocyst can now be bx) Embryo Failure: Reflects abn embryonic development Causes: Genetic: Inadequate regulation of gene expression, checkpoints, inadequate mat mRNA stores Non-genetic: inadequate levels of egg constituents (mt + metabolic stores) Interrelationships: abn mitosis Signs of bad embryo: Giant egg Egg w numerous vacuoles Fragmentation + uneven blastomeres Embryo selection & transfer to uterus Embryo selection: Embryo status determined by morphology, developmental rate and position in cohort (plus genetic makeup!) Embryo selection on Day 5 is often determined by its earlier performance on day 2 & 3 *DAY 5* reasons: Enables selection of high quality embryos that have successfully completed early stages of embryogenesis and thus have good prognosis for implantation following transfer to uterus Transfer to uterus lumen is physiologically appropriate Allows for selection of fewer embryos for transfer therby reducing risk for high order multiple gestation Factors that decide how many embryos to transfer: Patient age Number + outcome of prior IVF cycles Embryo quality Program specific embryo implantation rate Number of days that transfer follows retrieval Uterine cavity capacity Basically: balance btw increasing chance of pregnancy & decreasing chance of multiple preg bHCG testing @ 14 d Cryopreservation: Performed on blastocysts (day 5 or 6) OR zygotes (day 1 or 2) Method: vitrification Outcomes w IVF: Stats: Most IVF cycles use fresh non-donor embryos, followed by frozen non-donor embryos Number of livebirths w IVF is increasing W/out PGD, success rate of IVF decreases w age (esp after 40) W/out PGD, inc risk of miscarriage (35-50%) for women using IVF over 40 Majority of time, 2 embryos transferred (but hopefully will move toward single) Number of multiple pregna has gone down; number of single preg have increased Most of time, people are implanting day 5 embryos (some still use day 3) Adverse events: More likely to have adverse event w ART than w/out ART Rectal + large intestinal atresia higher for ART vs non-ART Ovulatory disorders & assisted hatching associated w increased risk in singletons 40% more likely than pop (i.e. about 4-5% risk) of non-chromosomal BD (slightly inc risk in women who had ovulation disorder) New in ART: Extended embryo culture Starting to implant blastocyst bcs this helps to improve preg rates Single embryo transfer Single embryo transfer is recommended to women w good prognosis bcs it reduces chance of multiples Trophectoderm bx PGD/PGS: Can assess for aneuploidy, mosaicism, single gene dx Can choose embryos to implant based on genetic makeup PGD basically ensures that you have 'young egg' so that pregnancy rates are basically same as w donor egg Frozen embryo transfer *Frozen embryo transfer has better pregnancy* outcomes than fresh; likely because endometrial receptivity is enhanced since there is time for uterus to recover after ovarian stimulation Oocyte cryopreservation Freezing eggs is no longer experimental and has 30-50% pregnancy rate No increased risk of congenital anomalies w frozen eggs Donor egg banking

Methadone *Teratogen*

Strabismus IUGR Dev/neuro/behavior prob Neonatal withdrawal Stillbirth Low birth weight

Proteomics

Study of all of an organism's proteins, including its identity, structure, interaction, and abundance

DNA and RNA

Synthesis of new DNA in 5' - 3' direction Transcription = Synthesis of RNA using DNA template DNA molecule has 40% G+C content Percentage each base contributes C. 20% C, 20% G, 30% A, 30% T Because of Chargaff's rule (C=G) if the total G+C content is 40%, half of the G/C bases will be C (20%) and the other half G (20%) Because G+C is 40%, the rest of the bases need to be either A or T, yielding a total of 60% A/T content, which again needs to be split in half to get the percentages for the individual bases (30% A, 30% T) Telomerase is a reverse transcriptase, which uses RNA as a template to synthesize DNA

Genetic Testing for Cardiomyopathies and Channelopathies

There are AD mtns that can lead to channel defects that can cause paralysis HRS/EHRA Expert Consensus Statement: GC recommended for all parties and relatives w familial heart disease and should include discussion of risks, benefits, and options avail for clinical/genetic testing Tx decisions should not rely solely on his/her genetic test result but should be based on an individual's comprehensive clinical eval It can be useful for GC/testing to occur in centers that are experienced in cardiac eval and family-based management Genetic Testing Recommended for: LQT (DR 75-80%) CPVT (DR 70%) HCM (DR 50-60%) DCM (DR >20%) SUND (DR 25-35%) Genetic Test not Recommended for: Brugada Short QT ARVC LVNC Genetic Test of Unaffected Individuals for Familial Mtn Recommended for: LQT CPVT HCM DCM Brugada ARVC SQTS LVNC

Radiation *Teratogen*

Threshold: *>5 rads* - usually for ca tx (most diagnostic radiation procedures will not pose big risk) Common radiation exposures: (1000 milirad = 1 rad) Extremity X-ray: 1 milirad Chest X-ray: 6 milirads Mammogram: 50 millirads Lumbar Spine X-ray: 250 milirad Abdomen X-ray: 290 milirad Upper GI series: 500 milirad Barium Enema: 800 milirad CT of abdomen: 1-5000 milirad Critical Period: *4-17 wk* ID: 8-15 wk Microcephaly: 4-17 wk *Microcephaly* *ID* Seizures IUGR, GR Minor ocular defects (micropthalmia) Possible inc ca risk

MALDI-TOF

To assess point mtn Matrix assisted laser desorption/ionization - time of flight Mass spectrometry based technique DNA fragments will have characteristic signature based on size and sequence

Carnitine

Total carnitine = free carnitine + esterified carnitine Free carnitine = 70-90% of total carnitine To evaluate: Carnitine transport defects FAO defects OA mtDNA disease If healthy/asymptomatic, low free (and high esterified) carnitine levels may indicate an unusual compound binding to free carnitine

Propylthiouracil *Teratogen*

Transient neonatal hypothyroidism (<5%) Fetal goiter

Schindler Disease Types I and II

Type I, classical form First appears during infancy Develop normally until 1y, when they begin to lose previously acquired skills that require coordination of physical and mental activities Type II, adult-onset form Development of clusters of wart-like discolorations on skin, permanent widening of groups of blood vessels causing redness of skin in affected areas, relative coarsening of facial features, and mild ID

Hereditary Melanoma = Familial Atypical Mole & Malignant Melanoma (FAMMM) = Dysplastic nevus = B-K mole = Cutaneous Malignant Melanoma *Cancer*

USA Caucasian skin ca risk: 50%! AD (incomplete penetrance) . ****CDKN2A = ARF (encodes p16 & p14ARF)**** [BOARDZ] . *CDK4* (rare) (part of apoptosis pathway) 1. *CUTANOUS & UVEAL MELANOMA* (50-90%), multiple nevi 2. *PANCREATIC ca* (11-17%) 3. *NEURO tumors* Dx criteria: (need all 3) . *>50 body melanocytic nevi*, including some clinically atypical . Nevi histology: architectural disorder, subepidermal fibroplasia, lentiginous melanocytic hyperplasia, dermal lymphocyte infiltration . Fhx of malignant melanoma in FDR / SDR Referral if: Rule of 3: *3 primary invasive melanoma in pt* *3 ca: 1 invasive melanoma & 2 other melanoma / pancreatic ca in FDR / SDR* Management Derm Exam, 10, Every 12 mos *In U.S., Caucasian risk of skin ca: 1/2!*

Herbal Drugs *Teratogen*

Unclear effect (no studies / regulations by FDA)

Serrated Polyposis

Unknown genes Serrated Polyps (SPs)-> CC Dx: difficult . Hyperplastic polyps . Sessile SPs / adenomas . Serrated adenomas Refer if personal hx / FDR: . 5 SPs proximal to sigmoid colon (two >1 cm in diameter) . >20 SPs in large bowel . SPs proximal to sigmoid colon + fhx of serrated polyposis

Penicillamine *Teratogen*

Use: . Tx too much copper in the body (Wilson's disease) . Tx rheumatoid arthritis . Prevent kidney stones in people too much cystine in urine (cystinuria). Connective tissue defects CHD

Carbamazepine = Tegratol *Teratogen*

Use: Fabry Antiepileptic Pain Bipolar 1% risk of NTD (RR=10)

Angiotensin Converting Enzyme (ACE) Inhibitors *Teratogen*

Use: *HTN* (widen blood vessels) => *The only HTN drugs that cause BD* ****2nd + 3rd tri**** Prenatal: . ****Renal tubular dysplasia**** => → ****OLIGOHYDRAMNIOS**** → *Lung hypoplasia* => lung hypotension → *Potter seq* (craniofacial abn) → Limb contractures . IUGR . Low placental profusion -> fetal hypotension -> hypocalvaria manifested by large anterior fontanel --- Vasodilation . Fetal demise Postnatal: . Premature . Neonatal hypotension . Anuria/oligura (no/low urine) + renal failure . Hyperkalemia

Tetracycline *Teratogen*

Use: *antibiotic* *> 4th mo* . Primary teeth defects (*Think T for teeth*): --- ****Yellow stained teeth**** [BOARDZ] --- Enamel hypoplasia . Diminihed growth of long bones

Aminoglycosides *Hearing loss*

Use: *antibiotics* => *mtDNA mtns* => *HL* Common to see HL in *China* and other *Asian countries* where they use aminoglycosides to tx *sepsis in newborns* *Safe antibiotics: --- *penicillins* ------ *amoxicillin* ------ *ampicil*

OLA

Uses three oligos in one reaction One pair is a set of ASOs, hybridizes to typical or to mutant sequence Third oligo hybridizes adjacent to the first, to sequence in common to typical and mutant Label on third oligo After hybridization, ligase added Probes designed so that variable base is at 3' end If typical allele probe is added to sample containing mtn, last base won't hybridize, ligation doesn't occur Need some method of detection Gel electrophoresis MALDI-TOF Capillary electrophoresis With appropriate conditions, can be very high throughput Variation for SNP analysis, allele specific primer extension

Mitral Valve Prolapse (MVP)

Variable expressivity AD (some families) Isolated or w asthenic (slim) habitus Syndromes w valvular abn: DCM Myotonic dystrophy FraX MASS EDS Bicuspid aortic valve Stickler

Whole Exome Sequencing (WES) & Whole Genome Sequencing (WGS) - ACMG -

WGS: Entire genome WES: Exomes (protein coding) only --- Exomes: 1-2% of entire genome: protein-coding region incl. 85% disease-causing mtns WES + WGS use NGS (next gen seq) Method: extract DNA→ massively parallel seq→ read alignment to reference genome→ consensus sequence *ACMG criteria for returning rslts from NGS*: - Proof of validity - Risk for disease is significant - Disease has important health implications - Proven tx/intervention *DR: 25-50%* Technical Details: Massive amounts of data Each lab has their own bioinformatics pipeline (allele freq, conservation , inheritance, pheno, in silico predictors) Findings can be: ---VUS ---Incidental ---Candidate gene Interpretation Challenges: Reduced penetrance variable expressivity multifactorial disease epigenetic factors phenocopies UPD XL mtns in affected females => Detailed clinical + family information essential for accurate interpretation WES most informative when done in trio Indications: - Non-specific pheno or fm hx that strongly implicates genetic etiology but does not correspond w specific genetic dx - Patient w defined genetic disorder that demonstrates high degree of genetic heterogeneity - Specific genetic tests avail for that pheno failed to provide dx - Fetus w likely genetic dx in which specific genetic tests (including targeted seq tests) have failed to make dx Benefits: More data Single, sequential gene testing is costly + not always informative Identifies atypical presentations of well-described syndromes Best approach (significant diagnostic yield) for non-specific symptoms w high genetic heterogeneity (i.e. *epilepsy*) Novel gene discovery Limitations: Long TAT Not covered by insurance, expensive *Limited detection of: large rearrangements/CNVs, mt DNA mtn, trinucleotide repeat expansions* *Not all exons targeted & not all targeted exons well-covered* *Will not detect mtns in regulatory and untranslated regions* What to do about incidental findings - what should be reported, who owns information, discrimination Risks: Discovering undisclosed paternity family relationships Incidental = secondary Findings Findings unrelated to the indication for ordering testing, but of medical value/utility to ordering provider/pt Medically actionable condition, carrier status, pharmacogenetic variants Recommendations *Incidental findings on the minimum list (57 genes - cancer, cardiac, connective tissue, hypercholestermia) should be reported by laboratory, regardless of testing indication (regardless of age)* Labs should seek and report only types of variants within these genes that we have delineated (i.e. report previously reported pathogenic variants, some LoF genes, some variants-for certain conditions) It is responsibility of ordering physician/team to provide comprehensive pre- & post-test counseling to pt *These recommendations reflect limits in current technology and therefore focused on disorders caused by point mtns and small ins/del, not those primarily caused by structural variants/repeat expansions/CNVs* Refine and update minimum list annually Clarification - *pt autonomy: pt CANNOT opt-out of items on minimum list* Incidental findings in kids: Clinical lab considerations Result communication Prediction of disease likelihood Many VUS Results may have implications for other family members Identifying novel suspected pathogenic variant w little/no clinical data Future Insurance Counseling: Pre-Test: Background of genetics/exome Pt/family perception of testing Likelihood of finding dx Possible rslts: positive, negative, VUS, incidental (results are NOT static) Unexpected rslts: undisclosed family relationships, implications for relatives *Choices: opt in/out: carrier status, pharmacogenetic* *No covered: multifactorial disease, adult-onset disease w no cure, parent's genetic status* Informed consent Post-Test: Pos rslt: explain; also talk about incidental findings; still may be no tx Neg rslt: possibility of WGS, research VUS rslt: testing other family members, lit review, seek research collaboration, talk to lab, re-run in the future *WES does not detect the 5 most common neuromuscular dx*

Sex Chromosome Translocation

X-Autosome Translocation in Female: X Inactivation in Balanced Carrier: Balanced X-autosome carriers have der(X) and der(autosome) → the der(X) can be inactivated and the der(autosome) cannot be inactivated For balance, both parts of the X chrom involved in the translocation must be active→ nl X chrom is non-randomly inactivated X Inactivation Unbalanced Carrier: Pattern of inactivation favors the least amount of functional imbalance→ inactivation of abn X => at risk for partial Turner, partial XXY, partial XXX Y-Autosome Translocations: Loss of SRY can result in female-appearing offspring with XY ch Loss of genes on Yq can cause infertility (loss of azoospermic factors) Basically if Y-autosome translocation => main pheno is infertility => 50% of female carriers and ~all male carriers are infertile Each translocation needs to be assessed individually to determine risks

3-MCC defect in leucine metabolism *Metabolic*

XL

X Linked hydrocephalus

XL *L1CAM* . *Aqueductal stenosis → hydrocephalus* ---→ Macrocephaly ---→ Hypertonia ---→ Spastic ---→ ID . *Adducted thumbs* . Agenesis of corpus callosum

X-Linked Protoporphyria (XLP)

XL ALAS2 (GoF) Enzyme Deficiency: aminolevulinate synthase 2 Acute photosensitivity (indistinguishable from EPP) Liver disease (more comon than EPP) Distinguish EPP from XLP: EPP has more free zinc XLP has more zinc-chelated erythrocyte protoporphyrin Tx: Sun protection Afamelanotide - stimulates melanin production

Opitz G/BBB

XL Body midline abn: 1. Laryngeal cleft 2. Larynx trachea / esophageal malformation

46,XY females DAX1

Xp21.3 dup ---DAX1: has dosage dependent effect on SRY => excess DAX1 bcs of dup => suppresses nl male-determining function of SRY 46, XY females

Nomenclature

_ _, _ _ (Chromosome Number, Sex Chromosomes; i.e. 46, XX) q = long arm p = short arm Centromere Location: (ch bands are labeled out from centromere) Metacentric: 1, 2, 3, 19, 20 Submetacentric: 4, 5, 6, 7, 8, 9, 10, 11, 12, 16, 17, 18, X Acrocentric: 13, 14, 15, 21, 22, Y Abn Ch: Der: derivative ch: e.g. der(22) Dup: duplication: e.g. 46, XX, dup (21)(q21) Inv: inversion: e.g. 46, XX, inv(9)(p12p13) Mar: marker: e.g. 47, XX , +mar Mat: maternal Pat: paternal T: translocation: e.g. 46, XX, t(1;2)(p21;p24)

Isochromosome

chrom w identical arms

Mitochondrial Disorders *Metabolic*

mt genome: . Double-stranded . 16.5 kb . 37 genes: --- 13 proteins encoded by mtDNA & translated on intra-mt ribosomes --- 22 t-RNAs --- 2 r-RNAs . 1 jb control region . *No introns* . No homologous recombination / meiosis . Continuous replication . Hi mtn rate (10x higher than nDNA): bcs of exposures to hi concentratin of oxygen free radicals from ox phos, lack of protective histones, ineffective DNA repair -> no introns so random mtns usually affect coding seq -> mt efficiency declines through adulthood -> contributes to aging and age-dependent penetrance/severity . Multiple mtDNA copies in every cell/tissue/organ . Sperm contain few mt but eggs contain many mt => mat inherited . mtDNA goes through genetic bottleneck during oogenesis: # of mtDNA molecules reduced, then amplified to create a larger than typical number in mature oocytes (compared to other cells) mt dx: . Genetic defects affecting ability to make ATP (energy) . Some studies suggest that *some mt dx (LHON + MELAS) are amongst most common genetic dx* . Any disease manifestation . Any degree of severity . Any age of onset . Any mode of inheritance . Neuromuscular / multi-system . *Transient, intermittent as energy supply and demand change over time, especially in response to illness ("brownout" model)*. Acute exacerbations w stress/hi energy demand: fasting, illness, fever, temperature, exercise, excitement, allergy, meds (steroids) . ****Progressive, intermittent, static or improve over time**** . Many neurodegenerative dx have a mt component: Alzheimer, Parkinson, amyotrophic lateral sclerosis => Trials w anti-oxidant tx Lately, importance of proteins involved in mt fission (dividing) + fusion became apparent: . Outer membrane fusion: mitofusins Mfn1 + Mfn2 (causes Charcot-Marie Tooth type 2A) . Inner membrane fusion: OPA1 (first described in hereditary optic atrophy) --- OPA1 + Mfn2 mtns =>neurodegenerative dx Mouse knock-outs reveal lack of essential components in individual mt, includ some w/out mtDNA Mixing of mt essential for neurons ****mtDNA mtns****: point - usually inherited *del - usually sporadic => low RR for sibs* dup - usually inherited *beware del/dup combo - usually inherited* *if initial rslts show del=> ask lab to double check if there is dup => bcs changes RR* Conditions: Electron transport chain subunits (last step after krebs cycle to make ATP)=> so does not matter what you eat mtDNA tRNA & rRNA genes Electron transport chain assembly factors, co-factors (Menkes) mtDNA regulatory factors (most are AR, AD KSS) Mitochondrial membrane transporters Krebs cycle enzymes PDHC (E1 alpha, other subunits) FAOD, carnitine cycle . *nDNA (common)*: --- Proteins involved in mt import (electron transport chain) are mostly nuDNA: ------ Electron transport chain subunits - PDHC: --------- Complexes 1, 3, 4, 5 all composed of mtDNA + nDNA encoded subunits --------- Complex 2: only nDNA encoded subunits --- mtDNA changes in depletion are caused by nDNA mtn (AR) --- POLG polymerases => proof reads mtDNA (AD) --- Trinucleatide repeat *Most infantile* . mtDNA (less common) --- Mat inheritance: theoretically, all children of affected mom are affected (not entirely true bcs of heteroplasmy) ------ *Large dels in mtDNA (large dels usually sporadic due to post-zygotic mtn)* ------ Heteroplasmy (most mtDNA) determines penetrance + severity = nl + mtn mtDNA in same cell / tissue: when cell divides -> division of cytoplasm/mitochondria random = genetic drift => cell w more nl mt and less mtn mt (or vise versa) produced => affects pheno => RR difficult to predict ------------ Threshold = specific heteroplasmy load for specific mtDNA mtn that tissue tolerates before symptoms show ------------ Unstable ------------ Bottleneck = small mtDNA copy number during pre-oocyte formation -> different ova/zygotes having widely different proportions of mtn + nl heteroplasmy => drastic difference in heteroplasmy rates btw relatives in same family ------------ More mtn mtDNA=> more severe dx --- Most adult onset Severe infantile onset . ****AR**** (MOST COMMON like other metabolic dx) - ****sibs similar pheno (+severe congenital lactic acidosis)**** . ****Mat - extreme variable expressivity btw sibs**** . XL - sibs similar + severe pheno Mild late onset . Mat - extreme variable expressivity btw mother / daughter . AD (rare) - variable expressivity btw sibs -> progressive myopathy and/or multiple mtDNA dels . *2+ idiopathic neuro/muscular/endocrine (hormonal)/renal tubular disease dysfunction* [BOARDZ]: *most involve multiple organs + severe neurologic and myopathic features (except: LHON)* - Common CNS features: --- *Seizures* --- DD --- Dementia, Alzheimer, Parkinson --- Complicated migraine --- Stroke / stroke-like episodes (in 30s) --- Ataxia --- Spastic --- Dysautonomia --- Loss of milestones --- Tremor --- Leukodystrophies - Other: --- *DEPRESSION*, bipolar, schizophrenia --- *BOWEL DYSMOTILITY*, irritable bowel --- *RENAL TUBULAR disease* -> renal fanconi syndrome (identified w urine test) --- Ptosis --- External ophthalmoplegia --- Proximal myopathy --- Exercise intolerance --- Cardiomyopathy --- SNHL optic atrophy --- Pigmentary retinopathy --- Diabetes --- Growth --- Acute fatty liver --- Autism --- HTN --- Ca --- SIDS --- Aging ****Nl eyes - NO CATARACT!**** ****Diabetes + renal tubular acidosis involve tissues w high energy requirements => most expected to occur as rslt of mt dx**** Factors modifying pheno: . Heteroplasmy . Remainder of mtDNA seq (haplogroup, other modifying polymorphisms) . nDNA background & environment Test: . Biochem: while pt stressed --- Body fluid metabolites --- Hi uOA: hi sensitivity on stress/ill sample. Non-specific (generalized organic aciduria: detects all causes of mt dysfunction, including shock) --- Hi Krebs cycle intermediates --- Hi dicarboxylic acids (ethylmalonate + glutarate) --- Hi lactate (lactic acid) = lactic acidosis (plasma; or CSF in children w severe neuro): low sensitivity + specificity --- Hi ketones --- Hi ammonia: bcs first part of UC is in mt & abn environment can interfere --- Hi lactate/pyruvate ratio --- Hi 3-methylglutaconate --- Plasma carnitines . Brain imaging: MRI, MRS . Tissue Bx (in selected cases): Skeletal Muscle (most common), Liver, Skin: Abnormalities in cristae, paracrystalline inclusions --- Histology w special stains, electron microscopy, electron transport chain activities, pyruvate dehydrogenase and other enz activities (can sometimes identify def), mtDNA analysis --- Suggestive but sensitivity not perfect. Nl biopsies common in mtDNA mtn. Also, they may show multiple complex deficiencies (especially C1&4) --- Non-specific fiber size variation mt proliferaiton, bizarre mtDNA ch shape --- Ragged-red fibers occur w deficient mtDNA protein synthesis (rare in children). Lesser degrees of mt accumulations beneath plasma membrane (subsacrolemmal), elongated or otherwise abn shaped mt, and increased lipid . Genetic test (very helpful if pos BUT only *7% DR*!!!=> prenatal test usually NOT avail. DR higher for mtDNA mtn (bcs genome smaller)): single gene, multigene panel, mtDNA genome exome seq and/or WES) mtDNA: --- Standard mtDNA analysis: ------ PCR for common point mtns (A3243G, A8344G, T8993G/C) ------ PCR / southern blot for large rearrangements --- Full mtDNA seq (if mat inheritance + standard mtDNA analysis neg): ------ NGS: detects heteroplasmy as low as 1.2% (useful in some pheno (COX def, MNGIE, mtDNA depletion, multiple dels, AR/AD CPEO/KSS) ------ Sanger seq: only detects heteroplasmy as low as 50% (use when seeing pt who already had testing) * If single mtDNA del-> presence of dup must be addressed before assessing RR. If dup present, RR higher and mom should be tested for presence of dup. If dup absent, RR low (can still offer prenatal dx) --- nDNA seq: ------ Panels ------ WES *if genetic test neg -> muscle bx for respiratory chain function* Prenatal test: -Electron transport genes: . Molecular - if familial nDNA mtn known (e.g. SURF1, PDHC, MNGIE, POLG) . mtDNA (avail for some - G8993C) - not avail for most mtDNA! -Geno doesn't predict pheno well bcs of heteroplasmy: . Enz and/or metabolic test is avail for some dx Dx: - Structured approach: *Walker & Modified Walker criteria* *Nijmegen criteria* (also uses brain MRI/MRS, incl leukodystrophy) --- *"Mito pedigree": Ask about problems often excluded: migraine, dysautonomia, SIDS, LDs, psychiatric illness (fhx usually neg since most AR)* --- Blood and/or CSF lactate concentration --- Neuroimaging --- Cardiac eval --- Genetic test RR: (*mtDNA usually denovo*) . Full sib: 1 in 24 . Symptomatic mom: 1-4% ? . Asymptomatic mom: up to 50% ? *RR for single mtDNA del: low (in absense of dup) since usually sporadic*, but rarely can be hereditary Tx: Supportive, suboptimal ---Increase energy supply + decrease demand ---Fasting avoidance ---Anticipatory guidance Exceptions - Complex I/ II deficiency: riboflavin oral administration - Ubiquinone (coenz Q10) def: Q10 coenz oral tx - MNGIE: BMT . Increase energy supply --- Exercise: Moderate + careful training: decrease exercise intolerance, but over-exercise dangerous. Rhabdomyolysis (muscle breakdown) occurs w over-exercise, illness, fasting => moderate & careful training key --- Shunt more electrons via complex I or II: high doses of vit - riboflavin (-> flavin = component of ETC compelxes), coenzyme Q10 (shuttles electrons in ETC) --- Metabolite tx --- Enz activators --- Antioxidants (most commonly used in adult-onset dx) --- Small, frequent, low-fat, high fat meals for GI dymotility --- Carnitine supplement -> increase strength + bulk (hi-energy store in muscle) --- Ez cofactors: ------ Co-enz Q10 (Co-Q): shuttles electrons in electrontransport chain (to complex 3) ------ L-carnitine ------ Creatine ------ Riboflavin(metabolized to flavin, which is co-factor in complexes 1, 2, 3) . Decrease energy demand ---Avoid fasting (w/without hypoglycemia)=avoid catabolism ---Avoid other high-demand situations: over-exertion, environmental temperature extremes, illness . Protect mt from reactive oxygen species (ROS) produced . Avoid mt toxins: --- Valproic acid --- Antiretrovirals --- Statins --- Aspirin --- Beta blockers --- Steroids . To prevent in offspring: mt replacement therapy (not avail in US)

Familial Scoliosis

"Idiopathic" scoliosis w familial predisposition No systematic survey for other features of MFS or FBN1 mtns

Gaucher *Metabolic* *Lysosomal storage* *AJ*

****MOST COMMON AJ Dx**** (1/400-1/1000 AJ) [BOARDZ] *Most common LSD* *AR* ****GBA**** on 1q21 Enz def: *beta glucocerebrosidase* Sphingolipidosis Disease pathology: macrophage AJ common mtns: ---N370S = 1226G (neuroprotective for CNS) ---84GG (5.6 DR) more severe ---L444P (2.1 DR) more severe ---IVS21G3A (0.9%) more severe ---D409H = cardiac variant *AJ carrier freq 1/18* (type 1): AJ carrier screening recommended by ACMG Defect in sugarfat molecule breakdown distinct cells named for the disease (macrophages filled with glucosylcerbroside) Criteria: hepatosplenomegaly nose bleeds, reduced platelets (anemia, thrombocytopenia, bruising, slow clotting, bleeding) Bone diease: ****ACUTE + DEEP BONE PAIN**** ("crises"), bone deterioration, bone infarcts, fractures lung disease Growth retardation Neutropenia=> predisposition to infection acute and deep bone pain. Type 1: Most common Non-Neuropathic Variable age of onset (into adulthood) Nl CNS HSM Cytopenia Hypersplenism Bone pain (pseudo-osteomyelitis)/lytic lesions Abn pigmentation, Abd pain Fatigue Blood Lung prob Parkinson (5x inc risk): earlier age of onset and higher rate of cognitive difficulties/dementia compared to typical parkinson Type 2: Acute neuropathic Rapid progressive neurodegenerative Onset: in 1st yr (<2y) Progressive CNS disease HSM Opisthotonus (muscle spasms) FTT No AJ predilection Type 3: Neuronopathic + Slower progressive CNS disease Onset: adolescent Perinatal-lethal and cardiovascular types clinically diagnosed Dx: . Glucocerebrosidase enz activity - gaucher cell infiltrate marrow and other tissues 'crumpled paper' cytoplasm . GBA genetic test Tx: Preventative: ERT, BMT . ERT for type I, II, III: most effective if started b4 symptoms ->improves anemia, platelet counts, reduces size of liver/spleen, and improve skeletal findings; however NOT effective at reducing or reversing neuro symptoms Type I, II, III: Ceredase Type I: Cerezyme replaces glucocerebrosidase Type I: Zavesca (substrate therapy) if no response to ERT . *BMT for type 3 !!!* . Substrate reduction (miglustat): Enz inhibition to reduce substrate toxin production . Pharmacologic chaperones Symptomatic: Splenectomy Pain meds Joint replacement

Huntington Disease (HD) *Triple Repeat Expansion* *Neurologic* *Movement*

*AD* *HTT = Huntingtin gene* @ 4p16.3 - plays role in nerve function ****CAG**** (*think "I take my CAt+doG=CAG for hunting!"*) *repeats in EXON 1* (*PROTEIN-CODING region @ 5' end*) = *polyglutamine* (toxicity maybe due to aggregation of polyglutamine that break, but mechanism not fully understood) More repeats => earlier onset, more severe GoF (*Think need to go hunting*) Anticipation: expansion ---More likely in ****PAT (MOST)**** [BOARDZ], *bigger jumps* [BOARDS] ---Also occur in mat *Doesn't expand from nl range to disease-causing Onset: mid 30s-mid 40s y Disease duration: 10-25 y after motor symptoms Death: 54-55 y Criteria: Progressive brain atrophy, neuronal dysfunction=> 1. Movement abn: Involuntary Motor - chorea (voluntary and involuntary clumsiness), rigidity, tics, dystonia, tremor, myoclonus/muscle jerks Voluntary Motor (gait difficulty, nystagmus, speech, prob/end stage swallowing) 2. Psych illness (usually before cognitive abn): (personality changes, affective psychosis, schizophrenia, depression, anxiety, OCD, apathy) 3. Dementia-cognitive abn (all aspects of cognition: executive function problems: difficulty with attention, planning, judgement, lack of insight, speech difficulties ), loss of attention 4. Bhvr abn (social disinhibition, aggression, outbursts, apathy, sexual deviation, increased apetite, depression, irritability) Repeat size: . Nl (10-26) (avg 19): nl: repeats in this range do not expand . Intermediate = premutation (27-35): no HD but offspring at-risk (3-10% risk of expansion when pat transmission) . Reduced penetrance (36-39)-> late onset (after 60s) + mild. not everyone with this size repeat gets HD . Fully penetrant mtn (40-60)-> affected: full penetrance, early onset, Apathy . Juvenile (60+) (5-10% of cases) - more severe presentation, rapid decline, seizures (<10y) Dx test: Genetic Targeted mtn analysis to detect CAG length . PCR-based (<115 repeats) . Southern blot only for rare >115 or homozygous Test recommendations: No minors Prenatal test ONLY performed if parent already tested & plan to TAB if affected fetus (otherwise→ no valid reason) Use ****Presymptomatic Testing Protocol**** for *ALL* presymptomatic neurodegenerative testing: can be offered to any relative who requests it as long as they go through presymptomatic testing protocol *3 Visit Model*: *Must bring support person to ALL appts: partner, friend (another at-risk person may NOT be good)* 1. *Pretest counseling* Test is voluntary Information provided should be up-to-date and relevant in order to facilitate informed decisions Only available to legal adults Test should be independent of financial ability to pay for test Discrimination should not occur as a result of test Awareness of need to address/care for situation in which test in one person would reveal information about another person who has not requested test 2. *Psych eval*: Can they handle any result? For pt w serious psych condition, test should be delayed and support services put in place Neuro eval: Are they symptomatic now? Test and Consent=>Blood draw 3. *Posttest counseling* Rslts Fwp Tx: None In research: MicroRNA

Parvovirus = 5th Disease *Teratogen*

*ECHOGENIC BOWEL* [BOARDZ] Facial rash +/- Circumoral pallor Adult arthralgia/arthritis Fetal anemia/hydrops IUGR Pleural & pericardial effusions => Death

Phenylketonuria (PKU) = Phenylalanine hydroxylase (PAH) deficiency *Metabolic* *Amino acid* - ACMG 2014 -

*PKU name bcs of characteristic phenylketones in urine* *1st metabolic dx identified through population screening* *AR* *PAH* @ 12q *Enz def*: *Phenylalanine Hydroxylase: phe-> tyrosine + other compounds* *Deficiency => PKU to hyperphelyalaninemia* 100kb, 13 exons *>600 mtns identified*: ---*R408W* [BOARDZ] *point* (common): *missense-> abn PAH prtn folding* ---del, dup ---insertion => pheno-geno correl w phe tolerance and tetrahydrobiopterin (BH4) responsiveness: not perfect but best predictor of severity in PAH def (sibs similar severity). In compound heterozygotes, less severe mtn determines severity BH4: cofactor necessary for PAH activity. If defected => secondary PAH def Carrier freq: Turkish 1/26 Irish 1/33 Caucasian & East Asian ****1/50**** => incidence 1/10,000 Japanese 1/200 AJ 1/225 Carrier testing: Genetic test *Prenatal dx: genetic ONLY* *NBS - tandem mass spec (99% DR)*: widespread in 1960s-1970s: tandem mass spectrometry (MS/MS) from the Michigan screening program (used to be using bacterial inhibition assay for PHE) Hi blood phe >130 µmol/L (w a range of 65-234 µmol/L) and PHE:TYR ratio >3 as: blood drawn @24h+ after birth (for PHE concentrations to show) Dx (non-molecular; *NOT enz analysis bcs PAH enz activity is ONLY detectable in hepatic + renal* tissues*): After +NBS-> send blood for confirmatory biochem test before starting restricted diet, but *low-phe diet initiated PRIOR to getting rslts* (can take several d): 1. *Quantitative blood pAA*: (mean nl phe: 60 µmol/L): *Hi Phe & Phe to Tyr ratio* ---classic PKU: phe >1,200 µmol/L = 20mg% ---hyperphelyalaninemia >nl but < 1,200 *Measure blood PHE a 2ND TIME: bcs possible false pos on NBS*: . Blood spot too thick . Sample improperly prepared . Liver immaturity . Protein overload (newborns fed cow milk) . Heterozygosity for PAH def in premature babies 2. PHE:TYR ratio (low plasma TYR) 3. Complete aa profile 4. Rule out BH4 def: . Urine (or blood) pterin metabolites: Nl neopterin and biopterin cofactor metabolism . Nl whole blood erythrocyte dihydrobiopterin reductase (RBC DHPR) ---if abn pterin levels-> enx testing for: . GTP cyclohydrolase . 1,6-pyruvoyl-tetrahydrobiopterin synthetase . dihydropteridine reductase . pterin carbinolamine-4α-dehydratase *Nl @ BIRTH* Untreated/poorly controlled PKU: 1. *MUSTY, MOUSY (ACMG), SWEET ODOR* (esp ear wax) 2. *LIGHT SKIN/HAIR* = hypopigments (bcs of of tyrosinase inhibition) 3. *EPILEPSY* 4. Irreversable DD, severe ID (correlated w plasma phe levels), 5% have autism! Behavior outburts, aggression 5. Mental illness in adults: . anxiety . depression . phobia 6. Nonintellectual psychological: deficits in executive functioning in adults. related to age of onset of therapy, lifelong PHE levels, and adherence to tx 7. Skin rash: dry scaly skin, eczema 8. Microcephaly Asymptomatic at birth (Similar clinical features btw untreated sibs) Tx (offer PAH genetic testing for improved therapy planning) 1. Gold standard control blood phe w diet=>effective in preventing severe ID BUT subtle intellectual + neuropsychiatricmay may show w time even w tx (except: Approximately 2% of individuals with clinical features of PKU do not benefit from diet bcs their clinical features of PKU are due to mtn in tetrahydrobiopterin . Reduced phe diet: used to be for phe levels >600µmol/L, but currently start tx if PHE >360) . Phe-free proteins or AA (formula) to ensure sufficient intake of other aa & nutrients (vitamins, minerals): e.g. Modified low-protein foods; Glycomacropeptide, a natural by-product of cheese production, has a very low PHE content so several medical food products have recently been developed using it as a protein source ---Start ASAP(1st wk of life; goal of having blood PHE in tx range within first 2 wk of life): even severely intellectually disabled adults with late-dx PAH def improve in behavior when lowering blood PHE ---4LIFE: if diet relaxed after 12y-> IQ stable, but other functions deteriorate: neurocognitive and psychiatric outcomes, including deficits in executive functioning and psychiatric symptoms such as anxiety, depression, and phobias 2. Pharmacotherapy: . Vit to stimulate enz activity: Biopterin cofactor supplementation (5-20mg/kg/day): Sapropterin dihydrochloride = commercial synthetic BH4 cofactor = Kuvan (only FDA approved med for PAH def!-> boosts residual enz activity in 25-50% of pts. It's a class C med-> may be used in preg if benefits outweigh potential (mild PAH w residual enz activity most likely to respond) - all PAH-deficient pts should be offered this trial to assess responsiveness except those with 2 null mtns in trans. 30% is often cited in the literature as evidence of effective PHE reduction. Experience with sapropterin under the age of 4 years is limited. Response not predicted by genotype-> need for formal PHE level testing . Large neutral amino acids (LNAA): in clinical trials: by blocking uptake of PHE from intestine and at blood-brain barrier (currently for adolescents and adults. Do not use in preg for mat PKU bcs limited info on teratogenicity) . Polyethyleneglycol-conjugated phenylalanine ammonia lyase (PEG-PAL) injection in trials Gene therapy in trials Hepatocyte transplant in trials * Test newborns at-risk to be affected w blood phe (in addition to NBS) if not tested prenatally for quick dx & tx Tx target range: 120-360 in ALL AGES 4 LIFE (relaxed diet no longer acceptable!) . <12y 2-6 mg% = 120-360 µM . >12y 2-10 mg% Reference concentration range: Nl: 30-90 µmol/L (i.e. µM) Benign hyper: 120-600: if btw 120 and 360 µmol/L->no tx but follow for first 2 y of life to ensure that levels do not go up w higher protein intake. If tx not required before 2 y of age, monitoring on an annual or biennial basis Hyper: 600-1,000 Abn (>1,000) >1,200 = >20 mg% Resources: . Genetic Metabolic Dietitians . International/Southeast Regional Newborn Screening and Genetics Collaborative (GMDI/SERC): info on dietary management of PAH def (incl recommendations for PHE, TYR and prtn intake)

Ultraviolet Radiation *Carcinogen*

*SKIN CA*

Temple = mat14UPD

*mat14UPD* *PRECOCIOUS PUBERTY*

Pleiotropy

1 gene causes 2+ dx e.g. (many): APOe --> hypercholesterolemia + Alz Mitochondrial dx

Percutaneous Umbilical Cord Blood Sampling (PUBS)

16 weeks 1-3% fetal loss rate Rapid karyotyping (used historically bcs of 48 hrs TAT, tho less of an advantage today w interphase FISH on amnio/cvs) Indications: Rh compatibility Fetal blood profile for genetic conditions Detection of infection Dx of hemoglobinopathies Confirmation of CVS/amnio rslts

Organic Acidemias = Organic Acid Disorders (OAD) *Metabolic*

1:10,000-15,000 *AR* OA = AA minus NH4 (nitrogen) removed by UC Enz def in breakdown of branched chain AA, lysine, FA, carbs, steroids Excess non-amino OA => accumulation in body -> interferes + inhibits UC -> secondary hi ammonia -> excretion of acid in urine Excess OA->LOW pH => *PRIMARY METABOLIC ACIDOSIS* -> body consumes bicarb to inc pH-> Low blood HCO3 -> Tachypnea (rapid beathing)->Low pCO2 (to increase pH) => *SECONDARY RESPIRATORY ALKALOSIS* Criteria Neonatal onset: unexplained acute illness vomiting poor feeding protein aversion lethargy progressing to coma Neutropenia and thrombocytopenia-> infections, pancreatitis FTT Encephalopathy within few days=> hypotonia seizures DD, ID coma, death -In older children, adolescents and later-onset forms: loss of intellectual function ataxia or other focal neurologic signs Reye syndrome recurrent ketoacidosis psychiatric symptoms DD Biochem: during crisis Specimen: urine Can be quantitative or qualitative Slight elevations are common (may be difficult to interpret) Most metabolic disorders have large elevations *METABOLIC KETO ACIDOSIS*: Blood gases (Low pH, low pCO2, low HCO3) with anion gap Hi urine ketones: KETONURIA Hi uOA Hi glycine (OA block glycine oxidation) +/- plasma AA +/- acyl-carnitine profile +/- HI AMMONIA +/- Ketotic (nl) hypoglycemia (vs. hypoketotic hypoglycemia in FAO) +/- anemia, neutropenia, thrombocytopenia=> infections +/- abn liver function tests (usually nl liver) Tx: -Dietary restriction of the precursor amino acids and supplementation of other essential amino acids. -Supplement adjunctive compounds to (a) dispose of toxic metabolites or (b) increase activity of deficient enzymes. -Supplement carnitine if secondary carnitine deficiency is present. -Decompensation caused by catabolic stress (e.g., from vomiting, diarrhea, febrile illness, and decreased oral intake) requires prompt and aggressive intervention *Long-term complications may not be avoidable even with tx

Sex Reversal

46,XY,del(9)(p24)

Orphan Diseases

< 1/200,000 in US Program by US to incite pharmaceutical companies to create drugs for rare diseases

Cyclic Vomiting *Mitochondrial*

<50% matrilinial (mtDNA) mtDNA mtns mostly in D-loop The control region (D-loop): Controls: mtDNA replication mtDNA transcription Has both highly conserved and highly polymorphic regions

Disorders of Glycosylation = Carbohydrate Deficient Glycoprotein (CDG) *Metabolic*

>100 dx Glycosylation is the process by which sugar 'trees' (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs. Most common: CDG 1a phosphomannomutase 2 deficiency Multi system (broad spectrum): CNS Eye Skeletal Immune system Inverted nipples Progressive liver disease Abn subcutaneous fat deposition Clotting abn->bleeding diathesis ID Ataxia RP Test: To detect: ---****isoelectric focusing (IEF) of transferrin (which is a glycopretein)**** => detects abn trasnferrin pattern => standard test for CDG dx [BOARDZ] ---carbohydrate-deficient transferrin

Familial Gastrointestinal Stromal Tumor (FGIST) *Cancer*

AD 1. KIT 2. PDGFRA 3. SDHB 4. SDHC 1. KIT: . Hyperpigmentation . Mast cell tumors . Dysphagia 2. PDGFRA . Large hands Wild-type GISTs = no mtn in KIT, PDGFRA, or BRAF Sporadic wild-type GISTs-> 12% have mtns in: . SDHB . SDHC (in another series, 12% had mtns in SDHA) *Pts w NF1 can also develop FGISTs

Gardner *Childhood Cancer*

AD APC @ 5q21-22 FAP variant Polyps (FAP) +... Osteomas Soft tissue skin tumors Desmoid tumors of abd wall Supernumary teeth CHRPE Epidermoid cysts

Prothrombin

AD F2 @ 11p11.2-12 --- Common mtn: G20210A Test: Hi blood prothrombin 6-18% of venous thrombosis Thrombophilia => . SAB . Stillbirth . IUGR . Preeclampsia . Placental abruption

Beals = Congenital Contractural Arachnodactyly (CCA)

AD FBN2 @ 5q23-q31 Dx: usually clinical 1. Physical exam 2. Fhx 3. Echo 4. Dilated eye exam (to exclude Marfan) 5. Consider FBN2 seq (75% DR) . *Marfanoid body*: Arachnodactyly, . Kyphosis/scoliosis (progressive, severe) . *Congenital joint contractures of elongated hips, fingers, elbow, knees* . *Crumpled outer ears*=helix of the ear shows overfolding . Muscle hypoplasia . Mild, stable aortic dilation (rare) . MVP (rare) *typically, nl eyes & heart*!!! *rare severe infantile form Tx: Physical therapy improve contractures

Best = Vitelliform Macular Degeneration

AD Fat accumulation in macula → macular degeneration → progressive vision loss Childhood-onset vision loss

Classic Ehlers Danlos syndrome (EDS) (Type I & II)

AD ---50% de novo COL5A1 @ 9q34.2 COL5A2 @ 2q31 ---50% . Skin: smooth, soft, stretchy velvety skin; molluscoid pseudotumors; subcutaneous spheroids *Strongest skin pheno of all subtypes . Joint hypermobility w dislocations, pain, subluxations, hypotonia, hernia, chronic pain . Muscle hypotonia (delayed motor development) . Easy bruising . Tissue extensibility and fragility (hiatal hernia, anal prolapse, cervical insufficiency) . Aortic dilatation (rare) Surgical complications: postoperative hernias slow wound healing w/ wide ATROPHIC SCARS Beighton dx criteria: Touch hands flat to floor without bending knees (1 point) Knee bends backwards (1 point/knee) Elbow bends backwards (1 point/elbow) Thumb bends back to touch forearm (1 point/thumb) Little finger bends back beyond 90 degrees (1 point/pinky) Test Electron microscopy on collagen, protein analysis on cultured fibroblasts > seq (50% DR) *biochem test - not helpful

Primary Torsion Dystonia (PTD)

AD (15% penetrance) CIZI ANO3 Onset: Adult Site Onset: eyelid Distribution: focal Involuntary, sustained muscle contractions Twisting/repetitive movements Tx: DBS

Gorlin = Nevoid Basal Cell Carcinoma (NBCC) *Cancer* *Microdeletion*

AD (30% DE NOVO) (complete penetrance, variable expressivity) *PTCH1* @ 9q Tumor supressor gene Patched mtns *Microdel PTCH1+FANCC->ID* Major criteria: 1. *> 5 BCC / BCC <30y not after radiotherapy* (onset 20s) (99%) 2. *JAW KERATOCYSTS* (mandible) in teen 3. *PALMAR / PLANTAR PITS* = cysts 4. ****FALX LAMELLAR CALCIFICATION****<20y 5. *FDR w NBCC* Minor criteria: 1 . Rib / vertebral abn on X-ray 2. *MACROCEPHALY*, forehead bossing (occipital frontal circumference >97th percentile), coarse face, face milia (keratin cysts) 3. Benign cardiac (2%) + ov fibromas (20%) 4. *Childhood medulloblastoma* (ca) (primitive neuroectodermal tumor (5%) 5. Lymphomesenteric / pleural cysts 6. *CLP* 7. Preaxial or postaxial polydactyly 8. Eye abn: . Cataract . Developmental defects . Retinal epithelium pigment changes Dx Criteria: Lamellar calcification of the falx Jaw keratocyst Palmar/Plantar pits (2+) Multiple (>5) BCCs FDR w Gorlin Management: Avoid radiation therapy Derm Exam, Childhood, Every 12 months PEx and Dev Assessment, Infancy, Every 6 months Monitor HC, Childhood, Every 6 months Orthopantogram, 8, Every 12-18 months Refer if personal hx / FDR: 2 criteria (major/minor) in person (e.g. medulloblastoma <18 & another criteria)

Amelogenesis Imperfecta

AD (common) Teeth: small, discolored, pitted, grooved prone to wear and breakage

Campomelic Dysplasia *Skeletal dysplasia* *Disorders of Sexual Development*

AD, de novo ****SOX9 w XY**** Dysmorphic face: *PIERRE ROBIN SEQUENCE w cleft palate* *AMBIGUOUS/FEMALE GENITALIA* Internal genitalia (testes/ovaries/both) Infertility Skeletal: *Bowed/short long bones*, *MISSING RIB*, club feet *LARYNGOTRACHEOMALACIA*-> respiratory insufficiency -> *NEONATAL DEATH* Test: Seq (90% DR) + deldup (5% DR, look for del)

Hutchinson Gilford Progeria = Hutchinson Gilford *Nuclear membrane = laminopathies*

AD, de novo LMNA @1q (lamins: multifunctional filamentous proteins of nucler lamina, under inner nuclear membrane) G608G (1824C>T)-> activates cryptic splice site Nl at birth, childhood onset! . *PREMATURE/RAPID AGING* starting in childhood . Arteriosclerosis . Failure to thrive . Heart attack . Stroke *Nl IQ/motor dev* => av age of death 13y Test: targeted mtn

Fanconi Anemia group C *AJ*

AJ mtn: IVS4+4A->T (>99%)

Niemann Pick C *Metabolic* *Lysosomal Storage*

AR *NPC*1 (95%) NPC2 (5%) Enz def: *NPC intracellular cholesterol transporter 1 + 2* => deficient transport out of endosome/lysosomes to cell membrane Onset: mid-late childhood Nl development→ progressive neurodegeneration: Vertical supranuclear gaze palsy Ataxia Dysarthria Dystonia Cognitive deterioration Feeding difficulty => death in 2nd-3rd decade *Similar pheno to A & B Dx Foam cells in marrow Nl sphingomyelinase Cholesterol Processing Test: low cholesterol esterification Hi unesterified cholesterol in lysosomes NPC1, NPC2 genetic test Tx: Symptomatic and supportive Substrate reduction: Miglustat

Fructosemia *Fructose*

AR ALDOB Enzyme Deficiency: fructose-1-P Aldolase B Vomiting, lethargy, irritability, seizures Liver and kidney dysfunction Hypoglycemia Liver failure, acidosis, growth failure Dx: Pos urine reducing substance for fructose ALDOB genetic test Tx: Dietary restriction of fructose

Carvajal Syndrome *Cardiomyopathy*

AR DSP NCCM (cardiomyopathy) Woolly hair Palmoplantar keratoderma

Erythropoietic Protoporphyria (EPP)

AR FECH (low expression allele common→ concerns for future pregnancy) Enzyme Deficiency: ferrochelatase Onset: childhood Skin symptoms in minutes: Swelling Burning Erythema Redness *No blistering Mild chronic changes: Pitting scars Skin thickening Liver cirrhosis (20-30%) Tx: Sun protection

Fumarase deficiency *Metabolic*

AR Krebs cycle defect

Familial Lipoprotein Lipase Deficiency *Dyslipidemia*

AR LPL Enzyme Deficiency: LPL Recurrent abdominal pain and pancreatitis HSM Xanthomas by age 10 Dx: LPL enz activity LPL genetic test Tx: Dietary fat restriction (supplement w MCT oil)

Pycnodysostosis *Metabolic* *Lysosomal storage* *Skeletal dysplasia* - ACMG -

AR Lysosomal enz: Cathepsin Abn skull, maxilla and phalanges Osteosclerosis Short Bone fragility

Mucolipidosis IV *Metabolic* *Lysosomal storage*

AR MCOL1 ---IVS3-2->3G (77%) ---Del6.4kb (18%) AJ carrier freq 1/127 (95% DR) AJ carrier screening (recommended by ACMG) -severe psychomotor delay by end of 1y-> spasticity -progressive retinal degeneration and corneal clouding in 1st decade-> blind -ID, most never speak, walk -strabismus

McKusick Kaufman

AR MKKS . Polydactyly . CHD . Genital abn . Supernumerary nipples

Werner *Progeria*

AR WRN . Rapid aging in 20s . Bird-like face

Cystic Fibrosis (CF) - NSGC and ACMG -

AR CF carriers: ---Heterozygote advantage - resistance to cholera and salmonella ---Asthma ---Chronic rhinosinusitis ---Idiopathic pancreatitis ---Primary sclerosing cholangitis -N. Euro: *1/25* (85-90%) -S. Euro: 1/25 (70%) -AJ: 1/26 (97%) -Hispanic: *1/46* (57%) -African american: *1/60* -Asian: *1/90* (30%) -Other <=70% CFTR = Cystic Fibrosis Transmembrane conductance Regulator @ 7q31.2 Codes for chloride transporter -> mtns => Affects chloride (Cl-) transport across epithelial cell membrane => Low chloride transport across apical membrane of epithelial cells => abn epithelial ion & fluid transport . Hi intracellular sodium . Low extracellular water 24 exons 1,800 mtns identified (sickkids.on.ca/cftr) BUT few responsible for most CF: ΔF50 (80% of caucasian mtns). Most are private mtns ---Seq variants (98%) ---Large del / dup / rearrangement (1-2%) *Geno does not always predict pheno ACMG 2004: The Working Group recommendation: If mtn prevalence <0.1%-> remove from screening panel (e.g. *1078delT*) Classes of CFTR mtns: I: *Nonsense / frameshift* mtns that prevent transcription + translation of full CFTR prtn (no synthesis=null production) - G542X, W1282X (classic CF) *II*: *Trafficking*: structural alterations to CFTR prtn + prevent it from moving to cell surface: *ΔF508* (classic CF) = 3 bp in-frame ****DEL**** of phenylalanine. Primary effect is on protein folding Protein remains in ER until degraded Pts homozygous for this mtn make potentially active protein, but it never gets to cell membrane III: Regulation: CFTR reaches cell surface but rslts in little / no functional CFTR channel activity - G551D (classic CF) IV: Conservative, missense. CFTR reaches cell surface but chloride secretion is reduced - R334W, R347P (non-classic CF: PS CF, later onset, CRD, acute/recur pancreatitis, chronic pancreatitis) Reduced CFTR function V: Partial reduction - Quantitative defect in amount of CFTR protein that reaches cell surface due to decreased stability of mRNA - 3849+10 kb C-T (non-classic CF: PS CF, later onset, CRD, acute/recurrent pancreatitis, chronic pancreatitis) Reduced CFTR function VI: Cause rapid turnover of CFTR proteins that reach cell surface which decreases overall amount of functional CFTR - 4279insA PolyT/TG (in cis to each other) tracts - in TRANS w classic CFTR mtn -> decrease splicing efficiency (errors) in intron 8/exon 9 splicing -> exon 9 skipping (missing exon 9)-> 5-30% nl mRNA -> CFTR prtn w no chloride channel function The longer the tract, the more likely that exon 9 will be present in final mRNA Exon 9 encodes essential part Lack of exon 9 gives non-functional protein PolyT tract = Poly-Thymidine (polypyrimidine tract) in intron 8: most to least severe . ****5T (≥10% of Caucaians!) - severe CFTR reduction**** . *7T - moderate*/nl CFTR reduction . *9T - nl* . *5T(alone) - CF mut = CBAVD* . 7T or 9T(alone) - CF mut = unaffected carrier . 5T - 5T = CBAVD R117H/Poly T tract alleles - most to least severe: . *R117H/5T(cis) - CF mut = classic, non-classic CF, PS CF, CBAVD (most common mtns in CBAVD)*! . R117H/7T(cis) - CF mut = --Males: non-classic CF, CRMS, CRD, CBAVD -- Females: nl . R117H/9T(cis) - CF mtn=> nl TG tract = Thymidine/guanine in intron 8 (5' of polyT) - most to less severe: . *TG13 - most severe* . *TG12* . *TG11 - least severe* 5T/TG tract alleles: . *5T/TG13(cis) - CF mtn = non-classic CF, CBAVD, PS CF (hi chloride sweat=>pos NBS) may act as a CF-causing mtn* . 5T/TG12(cis) - CF mtn = nl, non-classic CF, CBAVD, PS CF (can have hi chloride sweat=>pos NBS) may act as a CF-causing mutation . 5T/TG11(cis) - CF mtn = nl, fertile (rarely hi chloride sweat but less than 12/13=>pos NBS) unlikely to act as a CF-causing mutation *possible to have CBAVD w R117H w 5T in trans ****For Genetic Testing if R117H→ test polyT tract→ determine if in cis / trans => if in cis => classic (w 5T)/non-classic CF (7T)**** NBS: . Hi immunoreactive trypsinogen IRT in blood spot +/- . Genetic test (sensitivity increased w DNA test, but not included w regular NBS) e.g. In NY, IRT levels (> 170 ) & 41 mtn panel Dx test: (sweat test is NOT for carriers) - Pos sweat chloride (concentration in sweat): >60mEq/L Cl (intermediate/borderline=30/40-59; nl <30-40) (pos in >90% of pts) - Genetic test: seq > deldup - Transepithelial nasal potential difference (PND) used for borderline sweat test w/out identified mtn Homozygotes→ sweat test→ hi sweat chloride→ CF Heterozygotes→ sweat test→ hi sweat chloride→ CF Heterozygotes→ sweat test→ nl sweat chloride→ carrier Prenatal US: *echogenic bowel* -> 2-3% CF risk Offer dx test to: -Pos CF NBS -Symptomatic pt -Fetal echogenic bowel/calcifications (0.6-2% incidence on routine US-> 2-3% risk for CF) -FHx of CF NBS (50% DR) Following pos NBS, dx given if: 1 pheno feature + . Two pos sweat chloride (>60) OR . Abn transepithelial nasal potential difference OR . Two CFTR mtns Nasal Potential Difference w Clinical Features Can confirm dx in difficult cases Carrier screen: 1. Expanded mtn panel: 25 mtn (present in >1/1,000 pts i.e. >0.1% of CF mtns) Standard Carrier Screening: ****The ACMG-CF Mutation Panel (ACMG/ACOG): 23 mtn panel for general pop (90% DR for caucasians)****[BOARDZ] ->Lower sensitivity in non-caucasians *panel reduced 25→23 --- I148T - benign polymorphism in LD w 3199del6 [deleterious mtn] --- 1078del T (frequency is <0.1%) May consider doing a larger panel if: Individual is partner of a carrier/pt w CF Family has known mtn not on panel Non-caucasian pt > Seq (98% DR of mtn and VUS) > deldup (limitation: VUS) ---*if R117H (OR male w CBAVD OR pts w non-classic CF)* > *intron 8 polyT & 5T/TG tract alleles status including cis/trans studies* => *R117H pathogenic if in cis w 5T (likely PI)* (*PolyT & TG tract studies NOT recommended as part of routine population-based carrier screening, in absence of R117H mtn. offer ONLY as reflex if R117H found*) ACOG 2011: *Offer carrier screen to*: . *ALL precon/pregnant women (+ partner if woman pos)* . *Pt w CF fhx* Offer genetic test if: . *Fetal echogenic bowel / dilated bowel / peritoneal calcifications on US* . *Pos NBS* . *Symptomatic pt* . *Fhx of CF* Median survival: 35y Blocked ducts: blocked enz secretion → malabsorption/malnutrition Degraded vas deferens 1. Lungs: . Chronic progressive lung disease: nl in childhood, obstruction w age - influenced w genetic (worst if PI mtns) + env factors Bacterial infection: P. Aeruginosa → wheezing, coughing → Inflammation, chronic infection → end-stage lung disease → major cause of death . Finger clubbing 2. Pancreas / Endocrine: . Pancreatic Insufficiency (PI)(85-90%) ---- Longer survival if pancreatic sufficient (PS) => CF-related diabetes (occurs in PS+PI, BUT higher risk if PI) 4. GI: . *Meconium ileus* (bowel obstruction): pretty much *diagnostic*, but do confirmatory test. Most newborns w it have CF (15% of newborns -> may require neonatal surgery) - associated w PI mtns (env factors also contribute) . *RECTAL PROLAPSE* (20%) . Chronic metabolic alkalosis . FTT . Liver prob 5. Reproductive: . *Male infertility (≥98% of males)* due to --- *CBAVD* = Congenital Bil Absence of Vas Deferens, if 2 CFTR mtns in trans (regardless of mtn class) ---*Obstructive azoospermia*-> father offspring via donor sperm or sperm aspiration w IVF . Females: may have reduced fertility bcs poor nutritional status / high viscosity in cervical mucosa . Pregnant females w CF: risk of pulmonary stress and preterm delivery 6. Sweat: Salt loss 7. Sinuses: nasal polyps => Death 32y→40y if born in early 2000's Types: 1. Classic: . Hi sweat chloride . 2 mtns . Symptomatic 2. Atypical: . Meets dx criteria . Pancreatic sufficiency . Fewer symptoms 3. CFTR-related disorder (CRD): . Some clinical symptoms: pancreatitis / chronic sinusitis / absence of the vas deferens . Don't meet dx criteria *Usually intermediate-nl sweat chloride* 0-1 mtn =>still at risk to develop CF Ongoing fwp 4. CFTR-related metabolic syndrome (CRMS): Pos NBS (sweat chloride) + Asymptomatic + Abn sweat chloride @ 2 & 6 mos OR pos mtns but only 1/none disease-causing mtn => Fwp until CF ruled out / dx of CFTR-related metabolic disorder Management: . Airway clearance, antibiotics (for infection), mucolytic agents, bronchodilators, beating chest, vibrator vest . Pancreatic enzyme supplementation (if PI) 4 times per yr (more frequently in 1st yr) (better nutrition→ better pulmonary function + survival) . Avoid smoking / second-hand smoking . Prophylaxis against early RSV infection may also impact the progression of pulmonary disease . Lung transplantation considered when pulmonary function < 30 % of nl, but not all pts choose this option, despite improving outcomes . Small molecules + other tx: . Compound "Ivacaftor" has been FDA-approved for pts w 1+ copy of G551D mtn & is under investigation for pts w other CFTR mtns . Epithelial Ion Transport . Infertility: ICSI / other ART . Digestive: pancreatic enzymes, vitamin supplements, antacids, high calorie/protein diet . During pregnancy: success of pregnancy correlates w nutritional and pulmonary status at conception Resources: CF Foundation (CFF) patient mtn database CF Consortium

Allele Specific Primer Extension

Automated, very high throughput reaction (GoldenGate) Variation on OLA Relies on: SNPs at 3' end of primer (like OLA) Common sequence at 5' end Extension, ligation Amplification using fluorescent PCR primers Can be done on beads, look at thousands of reactions at once

Sialidase deficiency

Cherry red spot

Burkitt Lymphoma

Childhood jaw tumor Involves reciprocal transl of myc proto-oncogene from ch 8 to 14 & Involves regulation near immunoglobulin

Submetacentric Chromsome

Chromosome arms of unequal length

Batten Disease

Common in Northern European Scandinavian AR CLN3 Juvenile form of group of progressive neurological disorders known as neuronal ceroid lipofuscinoses (NCL) Accumulation of fatty substance (lipopigment) in brain, as well as in tissue that does not contain nerve cells Vision failure (optic atrophy) and neurological disturbances, which may begin before eight years of age May cause deterioration of both intellect and neurological functions

Trisomy 20

Common on amnio T20 mosaicism (on amnio) usually in: --- bladder --- kidney --- intestine => Low abn risk (most nl pheno)

Bioinformatics

Computer technologies used to study genome

N Acetylglutamate Synthase Deficiency

Few cases (rare) NAGS AR UOA: Nl / low orotic acid pAA: Low citrulline Low arginine

Uniparental Disomy (UPD) = Isodisomy -ACMG -

Gamete: . 2 copies of ch (disomic) . no copy of ch (nullisomic) . nl single copy of each ch (haploid) Isodisomy: 2 identical ch in pair are from one parent Heterodisomy: 2 non-identical ch in pair are from one parent Causes of UPD: 1. Trisomy rescue: Non-disjuntion (usually MAT MEI I)-> trisomy (usually 2 mat ch + 1 pat ch)->trisomy rescue (usually MAT)=diploid gamete and haploid gamete form trisomic conceptus -> loss of one homologue, which could lead to nl biparental zygotes / uniparental zygote (UPD, usually MAT bcs of loss of pat ch!) When non-disjunction in meiosis I->trisomy rescue->HETERODISOMY(*regions of isodisomy may result from meiotic recombination) . MAT UPD . HETERODISOMY . Trisomy rescue of trisomy conceptus from Rob transl carrier rslts theoretically in UPD in 50% of cases 2. Monosomy rescue (less common than trisomy rescue)=Egg / sperm (usually egg) missing ch is fertilized by another gamete w that ch. Ch (usually monosomic pat ch from sperm) duplicates itself resulting in both copies from same parent (UPD, usually pat)=>*ISODISOMY* of whole ch . *PAT UPD* . *ISODISOMY* -> can lead to 2 copies of deleterious gene mtn . Monosomy rescue of monosomic conceptus resulting from meiosis I nondisjunction and fertilization of nullisomic gamete Duplication (through isoch formation) of the only copy of a homologue would result in isodisomy in 100% of cases . Since majority of nondisjunction occurs in mat meiosis, most cases of isoch arising through this mechanism would result in pat isodisomy 3. Post-fertilization error (somatic recombination or gene conversion) 4. Gamete complementation (egg missing ch is fertilized by sperm w extra ch) 5. Somatic replacement of derivative ch UPD also results from presence of structurally abn ch, inc: Rob transl Isoch Reciprocal transl Derivative ch Inversions Marker ch (Rob transl and isoch of acrocentric ch are most common structural anomalies in UPD) UPD test methods: . DNA-based, polymorphic markers should be utilized: short tandem repeat markers (e.g., CArepeats) are usually used These markers are suited for multiplex PCR -> allows for 2-4 loci to be tested simultaneously . Parental blood needs to be tested along w child/fetus . PCR assay can be performed on extracted DNA / cell lysates of: ---uncultured CVS ---amniotic fluid ---blood specimens . ****Dx reporting of rslts: ---includes at least 2 fully informative markers from each ch of interest -> to distinguish UPD from del ---Reported using ISCN 1995 guidelines: uniparental disomy is abbreviated upd (lowercase), followed by ch in parentheses, then parental origin [e.g. upd(15)mat]**** . if UPD detected, test at least 1 other ch to show biparental inheritance and consistency w correct paternity (discuss possibility of uncovering non-paternity w UPD test) ****Offer UPD if****: 1. prenatal dx of mosacisim or rob transl for ch 6,7,11,14,15 . CVS: complete/mosaic (LII/LIII) trisomy of ch 6,7,11,14,15 > amnio => if nl amnio => up to ****25% UPD risk**** [BOARDZ] (e.g. if ch 15 => 11-25% PWS/AS risk) . Amnio: LII mosaicism for ch 6,7,11,14,15 . Fetus w rob transl (inherited / denovo) / isoch involving ch 14 / 15 (e.g. non-homologous rob transl) ---Prenatal dx of rob(13q14q)-> 0.6% UPD risk ---Prenatal dx of homologous acrocentric rearrangements, for which majority are isoch (i.e. ch derived from dup of single parental ch)-> 66% UPD risk . Fetus w balanced homologous acrocentric rearrangement 2. Pt w UPD features: . Fetus w UPD pheno . Pt w MCA / DD / ID and rob transl involving chr 14 / 15 . Newborn/infant w neonatal diabetes . Pt w RSS pheno . Pt w BWS pheno w nl karyotype and no dup of 11p15.5 by FISH . Pt w features of PWS / AS and abn methylation UPD test: using polymorphic markers!!! on DNA from Mother+Father+child/fetus Ch w UPD w DEFINITE pheno effect (ACMG 2001) due to imprinted genes / 2 copies of deleterious gene mtn: 5 ch: ****6,7,11,14,15**** -upd(6)pat -upd(7)mat -upd(11)pat -upd(14)mat -upd(14)pat -upd(15)mat -upd(15)pat unclear evidence for: -matUPD2 -matUPD16 -matUPD20 -patUPD20 *For most ch, UPD has no pheno effect

4HPPD deficiency *Metabolic*

HI PLASMA TYROSINE

Cancer Family History

If pt says person had lung / bone cancer→ assume this was metastasis and ask for primary site

Glycogen Storage Disorder (GSD) Bleeding Metabolic Glycogen storage Carbohydrate metabolism AJ Cancer - ACMG -

Incidence: 1/100,000 AJ = 1/20,000 Types: IA (G6PC) IB (SLC37A4) Hypoketotic hypoglycemia! *AR* Variable expressivity AJ carrier freq 1/71 (94% DR) G6PC G6P translocase SLC37A4 90% type 1a 10% type 1b Nl @ birth . Neonatal (sometimes): ---hypoglycemia in infancy when the interval between feedings is extended to 3-4 h ---lactic acidosis ---irritable . Dysmorphic: ---doll-like face w fat chubby cheeks . 3-4 mo: ---*HEPATOMEGALY* ---thin extremities ---renomegaly ---hypoglycemia ---hyperuricemia ---hyperlipidemia ---GR, short ---bleeding tendency ---Seizures ---Muscle weakness =>Primary symptoms improve w age =>After 20-30 y . *LIVER CA* (hepatocellular adenomas) . Fat build up in liver, kidney, intestines->chronic renal disease, gout, . Low-nl IQ *Type Ib: neutropenia, impaired neutrophil function, and inflammatory bowel disease Dx • Blood/plasma hypoglycemia, lactic acidosis, hypercholesterolemia, hypertriglyceridemia, hyperuricemia 3-4h post feed, consistent w GSD type I. Lactic acidosis w nl lactate/pyruvate ratio and hypoglycemia • Neutropenia suggests GSD Ib; however, neutropenia can be seen in GSD Ia also. Neutrophil counts may be nl in GSD Ib during first yrs of life • Dx should be confirmed by G6PC and SLC37A4 seq • If liver bx performed, histology typically shows fat and glycogen in hepatocytes w/out fibrosis. Glycogen content mildly increased as compared w other liver GSDs (especially GSD III and GSD IX). Dx often made by measuring G6Pase enz activity on piece of snap-frozen liver bx tissue; however, G6Pase enz activity on a piece of snap-frozen liver biopsy tissue will not detect GSD Ib • Targeted mtn analysis is useful for prenatal dx and carrier test for pts w known private family mtn and may be useful when knowledge of common mtns for specific ethnic groups is avail Prenatal dx: Genetic test (not enz or biochem bcs expressed only in liver) Tx goals: Maintain blood glucose+avoid fasting=>prevent hypoglycemia Maximize growth/development Tx: Frequent small servings of complex carbs carbs, uncooked cornstarch Calcium, vitamin D, and iron supplements Cornstartch to improve glucose levels Medications to lower lipid levels and treat kidney disease Liver tumor surgery Kidney/liver transplant if liver adenomas continue to grow Type 1b - antibiotics GCSF Prognosis: effective treatment can result in normal growth, nl activities

Cigarette smoking Teratogen

Infertility Ectopic pregnancy Miscarraige Placental abruption Placental previa Fetal growth restriction (dose dependent) Preterm delivery SIDS Orofacial clefts Abnormal placentation ADHD Food allergies Decreased birth weight Genetics: Polymorphisms in TGF-alpha influence risk for orofacial clefts

Meiotic Drive

Intragenomic conflict where one or more loci in genome manipulate meiotic process to favor transmission of one or more alleles over another, regardless of its pheno expression e.g. *Female carriers of balanced rob transl*: passing on Rob ch favored over passing on nl ch

Cytosine Arabinoside *Teratogen*

Malformation risk: 1/8 Limb defects Microtia Atresia of external auditory canals

Toluene *Teratogen*

Microcephaly GR Craniofacial anomalies like Fetal Alcohol

Trisomy 8

Myeloid neoplasia

Transient Hyperammonemia of Newborn

NH4 >50uM <24h in preterm *NOT A METABOLIC DX*

Female Infertility

Ovulatory Deficiencies: hypothalamic-pituitary failure, hypothalamic-pituitary dysfunction, ovarian failure Genetic Etiologies: 1. FraX premutation carrier 2. X-chromosome related karyotype abnormalities Polygenic Contributions: PCOS Tubal Factors: Pelvic Inflammatory Disease (PID) Septic abortion Endometriosis Ruptured appendix Tubal surgery or ectopic pregnancy

Pulmonary Arterial Hypertension (PAH)

PH = HTN in lungs Signs and symptoms of PH occur when increased pressure can't be fully overcome, and blood flow to the body is insufficient Causes of PH: No identifiable cause Lung Disorders Loss of lung tissue Chronic liver disease Obesity Drugs/toxins Low oxygen levels Heart failure HIV Genetics Two types of PAH: - Primary - no underlying cause - Secondary - underlying medical cause (heart/lung problem) 1,000 new cases per year in the US - Twice as common in females (females more likely to have symptoms) - Avg age at dx = 35 Minority of PH are PAH: caused by narrowing of blood vessels in lungs . Sporadic . AD --- 20% penetrance only!!! --- Anticipation Known gene (20% only) --- BMPR2 (70% of known genes) ------ common promoter mtn: 946_947GC>TA ------ >140 known mtns . Regulates amount of cells in tissue . Mtns promote cell division / prevent cell death ---- Results in overgrowth of cells in small arteries throughout lungs => causing them to narrow . Modifier genes probably play role in development of PH Constriction of small pulmonary arteries => Increase in pulmonary artery pressure => Right side of heart has to work harder to pump blood => Right side of heart becomes much more muscular → Less blood can circulate through lungs => Progressive HTN in pulmonary artery Symptoms Shortness of breath (60%) Fatigue (19%) Syncope (8-13%): Chest Pain (7%) Palpitations (5%) Leg Edema (3%) Raynaud's Phenomenon (10%) (95% female) Cardiac catheterization to measure right heart pressure Heart catheterization -Pulmonary Arterial Hypertension -ventricular hypertrphy on echo -Patent foramen ovale Dx test: -Chest x-rays: pulmonary arteries enlarged -Electrocardiography/Echocardiography: thickening of right ventricle -Pulmonary Function tests: extent of lung damage -Measurement of blood pressure in right ventricle and pulmonary artery for clinical dx 1) Confirmation of presence of PAH Mean pulmonary artery pressure >25 mmHg at rest , or >30 mmHg during exercise 2) Exclusion of other known causes of PH Genetic Test: Isolated PAH: BMPR2 PAH w HHT: ACVRL1, ENG, SMAD4, GDF2 PAH w Lipodystrophy: CAV1 Screening and management: . At-risk individuals every 3-5 y: ---ECG ---X-ray ---Echocardiogram . Special Concerns: ---Avoid heavy and strenuous exercise ---Discuss ALL medication use w MD ------Sedatives, decongestant cold medicines, etc -Caution when considering pregnancy Drug therapies: -Vasodilators ---Dilate blood vessels -Endothelin receptor blockers ---A substance in blood that causes constriction of the vessels -Diuretics ---Assist right ventricle in maintaining nl volume -Anticoagulants ---Thins blood so that it pumps more easily Other tx: Oxygen -May reduce blood pressure in pulmonary arteries and relieve shortness of breath Lung Transplant -Established method of treatment -Only used in individuals w severe disease who are healthy enough for surgery

Array = Microarray - ACMG 2010 -

Placing thousands of gene sequences in known locations on gene chip (glass slide). DNA / RNA sample placed in contact w gene chip Complementary base pairing btw sample + gene sequences on chip => light measured => identify genes expressed in sample Advantages --- *Live cells NOT required* (POC: array used if no cell growth when karyotype ordered) Cannot detect --- Balanced rearrangement --- Nature of rearrangement --- Low level mosaicism ------ mosaicism for trispmy detected at 10% level ------ mosaicism for deldup detected at 20-30% level --- Some aneuploidies: e.g. XYY if wrong gender control used --- Some marker ch, depending on size, marker composition, array coverage of specific region . polyploidy like triploidy not detected by some forms of array Prenatal . 1+ BD on US (array instead of karyotype, if no BD, karyotype OR array) (ACMG) . Multiple fetal losses . POC after SAB / stillbirth (array instead of karyotype) Postnatal ACMG: 1st Tier Test for: . MCA (no known syndrome) . Non-syndromic/unexplained DD/ID: standard of care for ID work-up (ACMG) . ASD 2nd Tier Test for: . Growth retardation . Speech delay . Other less-studied indications Oncology . To direct tx in Leukemia + lymphoma Conventional CGH --- 3-10 Mb --- Similar to high-resol karyotype --- Uses BACs / oligos instead of nl metaphase spread genome as probe => inc resol . BAC = bacterial artificial ch (cloned) --- Probes: 75,000-150,000 bp → lower breakpoint specificity --- CNVs vs . Oligo (synthesized) --- Probes: 50-60 bp --- CNVs => --- Better reproducibility --- Less batch-to-batch variation . array CGH (aCGH) Purpose: genome-wide screening to detect imbalances Control sample TO pt sample: Control DNA labeled w fluorescent dye + pt Method: patient and control DNA are labeled with fluorescent dye and applied to microarray→ patient and control DNA compete to attach to microarray→ the microarray scanner measures the fluorescent signal→ computer software analyzes and generates a plot Used for: dels, dups, subtelomere dels, aneuploidy (not polyploidy) --- 15-20% DR --- CNVs: 50-150 kb --- Benign CNVs ------ <500kb ------ 90-95% of CNVs ------ aCGH detects ~ 20 per healthy person ------ mean number of benign CNVs per person can be as high as 800 or more --- Pathogenic CNVs ------ >500 kb vs . SNP array Purpose: genome-wide screening to detect imbalances Method: Usually combo oligo-SNP array - same as array CGH but smaller fragments used *Large control data set TO sample data* --- Detection by quantitative change --- 15-20% DR --- CNVs: < 30 kb (<1-2 Mb) --- Large regions of homozygosity (LOH), consanguinity --- UPD --- Triploidy --- Not good for: balanced rearrangements, produces many VUSs . Targeted: --- Probes localized around genes associated w disease --- Lower VUS rate vs . Whole Genome --- Probes across genome --- Identifies exact breakpoints --- Higher VUS rate DR (above karyotype): - AMA or pos screen: 1.7% - BD on US: 6% (above karyotype) (Wapner, R. N Engl J Med. 2012) ROH = "copy number neutral": . <3 mb common in general pop . if on one ch => often UPD . if across genome => often --- Identical by descent (IBD) = shared ancestor --- Consanguinity ------ if >10% across genome & 2-5 Mb or larger => FDR / SDR ===> risk for AR dx/ imprinted dx if UPD ch . Hybrid SNP/oligo => CNVs + ROH ****if VUS=> family SEGREGATION analysis recommended**** [BOARDZ] RR: . As hi as 50% . Most microdel de novo -> BUT still important to offer parental test --- Reduced penetrance --- Variable expressivity --- Germline mosaicism Resources: [BOARDZ] . *International Standards for Cytogenomic Arrays consortium* --- Investigates feasibility of establishing standardized, universal system of reporting and cataloging array to help providers . *UCSC Human Genome Browser database* --- genome.ucsc.edu . *Toronto Database of Genomic Variants* --- dgv.tcag.ca/dgv/app/home . *DECIPHER (Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources)* --- www.sanger.ac.uk/PostGenomics/decip . *ECARUCA (European Cytogeneticists Association Register of Unbalanced Chromosome Aberrations)* --- ecaruca.radboudumc.nl:8080/ecaruca *Newborn*: --- If rapid TAT needed => STAT G-banded karyotype - 48h TAT ------ *NOT array especially if urgent + trisomy suspected*

Heroin *Teratogen*

Preeclampsia (40-50%) Strabismus Low birth weight Neonatal withdrawal (40-94%) LD, behavior prob but nl IQ Stillbirth, SIDS

Southern blot

Provide information about size of fragments May detect deletions, insertions, trinucleotide expansions May be possible to identify heterozygotes Will not see point mutations, small deletions Requires a lot of DNA, time consuming, labor intensive Still used for assessing size of trinucleotide repeats in FraX, Friedreich ataxia

Capillary malformation arteriovenous malformation (CM-AVM) *Vascular*

RASA1 --- Encodes p120-RasGAP protein: controls RAS/MAPK signaling Capillary abn

Mental illness = Psychiatric Disorders

RR for FDR . Major depression: 35-40% (vs 15-20% background) . Schizophrenia (mild APA effect), bipolar, schizoaffective disorder: 5-15% (for each) (vs 1-2% background) . Generalized anxiety: 20% (vs 5% background) . OCD: 10-25% (vs 2-3% background) Inc risk for mental illness in general

Major Depressive Disorder (MDD)

RR: . Sib 20% . Inc if relative w several episodes + young

Lead *Teratogen*

SAB Stillbirth Low birth weight Premature delivery Learning and behavior prob

Metabolic Cardiomyopathies

Sarcomere mtns: . MYL2 (3%) . MYL3 (1%) . ACTC (1%) . TNNI3 . TPM1 . TNNC1 . TTN

Enzyme Assay

Specimen: blood, bx specimen

Acylcarnitine Profile

Specimen: blood, urine (tandem mass spec) Reported by carbon chain length and number of double bonds Clinical: Used in NBS

Mohr Tranebjaerg *Hearing loss* *Mitochondrial*

XL DDP1 gene (nuDNA) => mt import protein defect: protein imported into mt (most imported mt proteins are nuclear encoded) SNHL Dystonia Dysphagia Cortical blindness Paranoia

Triploidy Placenta

[BOARDZ] If dad gave extra set: ANDROGENIC TRIPLOIDY - two sperm (60%) / diploid sperm (*less common*) Large cystic hydropic placenta Partial mole IUGR Syndactyly Nl head or microcephaly If mom gave extra set: DIGYNIC TRIPLOIDY IUGR Assymetric trunk wasting Small monocytic atrophic/wasted placenta Relative macrocephaly

Wolman *Metabolic* *Lysosomal storage*

AR LIPA = Lysosomal acid lipase Severe HSM

Galactokinase Deficiency *Organic Acidemia*

AR Gene: GALK1 Enzyme Deficiency: galactokinase 1 Cataracts

Metacentric Chromosome

Centromere is in the center => arms almost equal in length: . Ch 1 . Ch 3

Danazol *Teratogen*

Cliteromegaly Fused labia Urogenital sinus formation

Alstrom

Dilated Cardiomyopathy

Carbamazepine (Tegretol) *Teratogen*

Spina Bifida (1%) Craniofacial anomalies DD

Mercaptopurine *Teratogen*

Use: ca & autoimmune diseases Inc risk if pat exposure

Molecular Techniques

"Conventional" CGH 3-10 Mb Karyotype: The process of karyotyping is performed by photomicroscopy at metaphase Low resolution (5 Mb) High res karyotype: 2-3 Mb Blood→ culture WBCs→ colchicine→ lose WBCs→ hypotonic solution→ slide/stained/picture => Extra/Missing Ch; large gains/losses 4% DR Can detect numerical and gross structural anomalies Genome-wide Limited resolution - misses small loss/gaines; tells you nothing about genes Obvious ch problems Fm hx ch rearrangements Hx multiple SABs Prenatal dx aneuploidy Indications for Cytogenetic Testing: Prenatal diagnosis Confirmation or exclusion of chromosome syndrome Unexplained ID without dysmorphic features Monogenic disorders associated with ID or dysmorphic features Abnormalities of sexual differentiation or development Infertility Recurrent miscarriages or stillbirth Neoplastic conditions (i.e. leukemia, lymphoma, solid tumors) Types of Tests Karyotype: Purpose: Organized picture of the chromosomes Method: draw 5 mL of blood→ separate off RBCs→ add culture medium to white cell suspension→ incubate for 3 days at 37C→ colchicine added (arrests metaphase)--> separate off WBCs→ hypotonic solution added→ cells dropped onto slides→ stained→ photographed→ karyotyped Used for: detecting aneuploidy, large chromosome rearrangements Practice Guidelines: For patients with obvious chromosomal syndromes, FM HX of chromosomal rearrangements, hx of multiple miscarriages, prenatal dx of aneuploidy Not good for: small chromosome changes FISH: Hi resolution 1-100 kb (40-250 kb) Purpose: examine presence or absence of particular sequence or evaluates the number or organization of a chromosome/ chromosome region Mix fluorescent labeled probe and denatured DNA→ detect fluorescent signal identify chromosome of interest and nl control, THEN, mix fluorescent probe and denatured chromosome of interest→ detect fluorescent signal→ if present: no deletion; if absent→ deleted Extra/missing ch; gains and losses- whatever you look for 85% (DR) Fast, Targeted: rapid diagnosis of aneuploidy, translocations, marker chromosomes, specific microdel syndromes Not good for: unknown dx (i.e. you have to know exactly what you are looking for), each region analysed separately Mass spectrometry-based technique MALDI-TOF Seq (WGS and WES) Array SNP CGH MLPA: Method for detecting del/dup Result: see peaks of product that correspond to different exons; compare to control DNA-- peaks that are del (absent peak) vs dup (larger peak) will appear different Positive result indicates a region of genome is missing/duplicated Negative result is less definitive

Analytes & Cell-free DNA Screening & Diagnostic Testing - NSGC, ACOG, ACMG -

*% of AMA pts getting prenatal testing since 1984 has not changed (per old ABGC "pre-test") *Produced by fetus: AFP*, uE3 *Produced by placenta: uE3 (metabolized by placenta), hCG, Inhibin A, PAPP-A* Ethnicity: *AA* ---*Higher AFP*, PAPP-A, hCG ---Lower inhibin A Asian + Hispanic --- Higher uE3 Twin preg: *Analyte levels ~ 2x higher* ---*except uE3 1.6-1.7x higher* # of fetuses Diabetes: *If pregestational insulin dependent diabetes* -> *AFP reduced (by up to 20%) vs women not on insulin (BUT higher risk for ONTD)* Smoking: *Higher inhibin, AFP* Lower hCG, uE3, PAPP-A Twins: *Higher ONTD risk* ART: IVF/ICSI *Alter analytes to mimic T21=>. (without adjustment, screen positive rate 2x higher)*: --- PAPP-A 15% lower in IVF/ICSI --- Free beta-hCG 9% higher in IVF/ICSI Previous false pos rslt: If false pos in one preg -> false positive more likely in another preg 1st tri serum: DR: 80% FPR: 3% Combined 1st tri: not easily available at all centers (need NT practitioners) 1st tri serum+NT (if completed, MSAFP only; 2nd tri for ch aneuploidy NOT indicated) ****DR: 80-86%****; twins 70% --- *T21: 78-91* % --- *T18: 91-96* % *Can also detect T13* ****FPR: 4-5%**** *Second tri (quad): w cut off of 1/270* 15-21w6d ****DR: 82-85%**** (twins 50%) --- T21: 75% (if<35), 80% (if>35) (pos screen rate 5%) FPR: 7-8.5% *During quad*: *inhibin A - stable* (*think inhibit*) *hCG - decreasing* *uE3 - increasing* *AFP - increasing* *if US GA > GA by EDD* *hi AFP (bcs AFP goes up across GA)* *low hCG (bcs hCG goes down across GA)* *hi uE3 (bcs uE3 goes up)* *nl or slighlty hi inhibin (bcs flat)* *If US GA < GA by EDD* *low AFP* (bcs AFP goes up across GA) *hi hCG* (bcs hCG goes down) *low uE3* (bcs uE3 goes up) *nl or slightly low inhibin* (bcs flat) Triple screen: AFP, hCG, uE3 DR: --- T21: 65% --- T18 70% Penta screen: quad + invasive trophoblast antigen (ITA) DR similar to Quad Serum integrated: 1st + 2nd tri => Rslts only after 2nd tri ****DR: 93-94 %**** --- T21 (87-88 %) --- T18 (82 %) FPR: 11% (2.6% w cutoff 1/270) Integrated NT + 1st + 2nd tri (recommended by ACOG for ALL pregnanct pts who present for care in 1st tri) Results only after 2nd tri DR: 90% (similar to sequential integrated); 45% for twins ---T21 (94-96 %) ---T18 (91-96 %) FPR: 5% Sequential integrated: NT + 1st + 2nd tri Results after 1st tri + 2nd tri DR: 90% (similar to integrated); 45% for twins Pos screen rate: 2-3% FPR: 9% Contingent NT + 1st tri -> . intermediate risk -> 2nd tri (but few pts come back for second draw) . low risk-> no 2nd tri . hi risk-> dx test DR and FPR similar to integrated Fetal Demise: *Large NT (6 mm)* *Recent demise*: ****Hi AFP + all other analytes low (1st+2nd tri)****[BOARDZ] *Distant demise: *Low AFP + all other analytes low* Factors: GA *mat weight (bigger, lower medians)* *mat age (as it increases, DR and FPR inc*: e.g. ---20y: 45% DR, 3% FPR ---40y: 92% DR, 40% FPR Risk cut offs on CAPNS: *T21 - 1/150* *T18 - 1/100* *SLOS - 1/250* AFP *Affected by weight, IDD, ethnicity (NOT affected by age) Only marker for ONTDs Fetal liver Measurable at end of 1st tri, increases + peaks at 32 wk rise steadily through 2nd tri *INDEPENDENT OF MAT AGE* (not adjusted for age) Cutoff levels for ONTD screening: 2.0 - 2.5 MoM in singleton 4.0 - 5.0 MoM in twins At 2.5 MoM, DR: ---NTD: 75-90% (+ US >90% DR; +US+AF-AFP+AChE >99% DR) ---Anencephaly: 95% ---AWD: 85% SPR 5% or less FPR 1-3 % Optimal time for NTD screen 16-18 wk If there GA discrepancy >10 d=> reinterpretation Women who have first tri screen and/or CVS should be offered MS-AFP and/OR US exam for NTDs US dating best and more accurate than LMP dating: BPD better at detecting NTD because fetuses w open spina bifida have BPD 2 wks smaller than GA If have high MS-AFP => offer amnio to measure AF-AFP if AF-AFP >2.0MoM→ measure acetylcholinesterase (AChE) AChE also indiciated, even if nl AF-AFP if: Previous hx of ONTD Fhx Abn US ****Repeat MS-AFP if 2-3 MoM @ <18 wk (depends on center)*** ****2 consecutive ↑ MSAFP @ 16-18 wk => 1/20 risk**** Reasons for ↑ AFAFP -Ch abn -ONTD (w other analytes nl) -*Anencephaly (w LOW uE3)* -underestimated GA -recent SAB, *FETAL DEMISE* (w all other analytes low) -multiples preg -fetal / mat blood contamination => high AF-AFP and pos AChE -AWD (omphalocele, gastroschesis) -IUGR -congenital skin defects, pilonidal cysts, GI defects, cloacal exstrophy, cystic hygroma fluid (inadverentent aspiration), sacrococcygeal teratoma, renal anomalies (polycystic kidney, absent kidney, congenital nephrosis) -OI -obstruction, liver necrosis, urinary obstruciton -Placental abn: chorioangioma, placental vascular lesions, placenta accreta -Mat uterine abn -OB complications: low birth-weight, oligohydroamnios, decreased mat weight, IUGR, antepartum hemorrhage, abruption, preterm delivery, gestational HTN Low AFP: (<0.25 MoM) Ch abn: T21, T18 Single gene dx: SLOS Preterm birth SAB, stillbirth Infant death Macrosomia hCG (human chorionic gonadotropin): Whole molecule hCG / free beta hCG (β-hCG) (slightly higher DR) Placental rise rapidly early on, ****peaks @ 10w then decline btw 10-20 wk**** Hi hCG (2-4 MoM): Ch abn: triploidy, Turner w hydrops Placental abn: molar pregnancy, placental chorioangiosis, placenta accreta Multiple preg Fetal demise, SAB OB complications: IUGR, preterm delivery, gestational HTN, velamentous cord insertion Low hCG (<0.5 MoM) ---low birth weight ---SAB (if very low) ---T18 ---SLOS uE3 (unconjugated estriol): fetal adrenal glands+liver, metabolized by placenta ***rise throughout pregnancy*** Low uE3 (<0.5 MoM) Ch abn: T21, 18 BD: anencephaly *Mat antibiotic / corticosteroid tx* [BOARDZ] *Fetal demise (esp if hi AFP)* [BOARDZ] *Primary antiphospholipid antibodies* [BOARDZ] Metabolic: ---*Steroid sulfatase deficiency = x-linked ichthyosis: very low* [BOARDZ] ---*CAH* ---*SLOS: very low 0-0.15 MoM* [BOARDZ] ---*Placental aromatase def* ---*Antley-bixler* OB complications: IUGR, fetal death, oilgohydramnios *stable for 10 days, if older sample-> no detectable uE3 Hi uE3: No adverse outcomes Dimeric inhibin A (DIA): Mat ovaries + fetal placenta rise in 1st tri, decline after 10 wk, stable 15-20 wk Hi Inhibin A: . T21 (2x higher in T21) . OB Complications: IUGR, preterm delivery, fetal demise, gestation HTN . If very hi: ---Tirploidy ---HELLP ---Loss of one twin in 1st tri Low inhibin: No adverse outcomes PAPP-A (plasma protein-A): Placental (+fetal) Increases over gestation detectable as early as 8 wk Hi PAPP-A: No adverse outcomes Low PAPP-A (0.4-0.5 MoM) Ch abn: T13,18,21 OB Complications: IUGR, preterm delivery, fetal demise, low birth weight, SAB, preeclampsia, gestational HTN HTN, preeclampsia, assocaited w PROM, IUGR, placental abruption, fetal demise, placental dysfunction, 50% risk of complications: AFP 2.5 MoM hCG 2.0 MoM: PROM / IUGR not usually seen w hi hCG alone Elevation in either marker can be associated with HTN, pre-eclampsia, or fetal and perinatal demise Hi AFP + hCG (>2-3 MoM): if both hi-> very high risk of poor outcome Hi inhibin (>2-2.5 MoM) Low PAPP-A (<0.35-0.38 MoM) Hi AFP + hCG => inc risk of placenta accreta Hi AFP + Inhibin-A => inc risk of preterm labor, fetal loss, and preeclampsia ACMG 2013: MMS and/or US for aneuploidy screening: Pos screen rate: 5% DR 50-95% ---T21: 5% FPR w 1/270 cut-off ------if AMA -> 15-20 % FPR ---T18: 0.5% FPR w 1 in 100 cut-off ACOG 2007 + ACMG 2008: *All women should be offered MSS+dx test before 20 wk, regardless of mat age* ACOG 2007: - *Amnio SAB risk 1/300-1/500* (0.2-0.3%) - Healthcare providers determine which SCREENING options best serve their practice/pts US DR: -T21 ---60-82% (NT) ---50-70% (det US) -T18 ---71-82% (NT) ---80% (det US) *FPR 20-25% for T21/18 (NT) cfDNA: . Pts who desire screening information may be offered cfDNA w counseling+informed consent . Recommended for high-risk pts . Validated btw 10-21w6d <1% FPR DR: T21: 99% T18: 97 % T13: 79-92 % Turner: 94 % CVS - also for: ---Biochem abn ---Collagen abn Amnio - also for: ---Bioch abn ---ONTD Early amnio: <15 wk -Risks (ACOG, 2007): ---SAB: 2 % ---Clubfoot: 1.3-1.7 % vs <0.1 % in routine amnio ---Fluid leakage: 3.5-4.4% vs 1.7% routine amnio

XYY = Jacob

* As common as XXY* *Sporadic* --- *pat meiotic nondisjunction during m II (NO age effect)* *RR <1%* Criteria: . *Nl pheno* . Tall . IQ 10-15 points < sibs . Behavioral prob (sometimes) Dx: - Karyotype --- usually @ infertility workup Tx: Not usually required

Noonan *RASopathy* *Cancer* *Bleeding*

****AD**** --- *variable expressivity* (*if 2 affected children from nl parents => 50% RR*) --- *50% de novo* 8+ *RAS-MAPK* pathway genes: *GoF (vs LoF in LEOPARD)*: . ****PTPN11**** (most common) . ****SOS1**** (10%): stimulates conversion of RAS to GTP-bound active form . ****KRAS**** . ****RAF1**** . ****NRAS**** . ****BRAF**** . SHOC2 ****Criteria****: . ****SHORT**** . *CHD*: [BOARDZ] --- ****PULMONIC STENOSIS*** [BOARDS]-> *HEART MURMUR* --- ASD --- ToF . *HCM (geno-pheno correl)* [BOARDS] . *DD* . ****BLEEDING**** . Ca --- *LEUKEMIA* --- *RHABDOMYOSARCOMA* --- *NEUROBLASTOMA* . *Lymphedema* . Large NT/BOARD ****WEB NECK**** . *LENTIGINES: small brown skin patches* [BOARDZ]. Rarely present @ birth, develop during childhood, inc in number until puberty & darken w age . Low posterior hairline . Cryptorchidism . Skeletal: --- Pectus deformity, shield (broad) chest --- Scoliosis . Dysmorphic face --- Triangle face --- Eyes ------ Hypertelorism ------ Downslanted palpebral fissures ------ Thick eyelids ------ Ptosis ------ Blue/green irides --- Ears ------ Low set posteriorly rotated ears w fleshy helices . Renal abn . Feeding prob

Spinocerebellar Ataxia (SCA) *Triple repeat expansion* *Neurological* *Movement*

****AD**** !!! (often) [BOARDZ] 17+ types: ATXN1,2,3 etc. *Type 3 = Machado Joseph *CAG* repeats = *polyglutamine* - in *EXON 1* (coding region) ****PAT ANTICIPATION**** [BOARDZ] (except SCA8 mat anticipation) Onset: early adulthood; survive 10-20 years after symptom onset Neurologic Symptoms: Ataxia Dysarthria, dysphagia Spasticity Opthalmoplegia, nystagmus Cognitive impairment Over time: sensory neuropathy, dystonia, muscle atrophy, fasciculations

LCHAD Deficiency *Metabolic* *Fatty Acid Oxidation*

****AR**** LCHAD Enzyme Def: long chain 3 hydroxyacyl CoA dehydrogenase *Nl@ birth*! After common viral infection/sickness/illness=>*SEVERE FASTING INTOLERANCE* (as all FAOD) => hypoketotic hypoglycemia => acute brain dysfunction =>*myopathy*, *hypotonia*, *cardiomyopathy* -Liver dx -Pigmented retinopathy -Neuropathy (SIDS) Usually linked w fatty liver of preg (compared to other FAOD) Dx test: -Acylcarnitine: hi C16-OH -LCHAD genetic test Tx: -Avoid fasting w frequent feeding + IV -Dextrose when ill -Supplement: cornstarch, MCT oil, hi carb/low fat diet -No carnitine

MUTYH Associated Polyposis (MAP) = MYH Associated Polyposis *Cancer*

****AR**** (vs. related AD syndrome) [BOARDZ] *MUTYH*=*MYH* @ 1p: *DNA base excision repair* (BER) enz!!! *European* mtns: 2 most common mtns (80%): *Tyr179Cys*: c.A536G *Gly396Asp*: c.G1187A Other common Euro mtns: Y165C G382D 1395delGGA Test if: . *10+ COLON ADENOMA polyps (but < 1,000 unlike FAP)* . *CC < 50 w nl MSI/IHC (after Lynch ruled out)* - 15-100 (sometimes >100) adenomatous colon polyps (later onset 20-50)-> CC (70%) !!! -*Duodenal* ca (4%) -*Bladder* ca -*Ov* ca -*Skin* ca -*Sebaceous tumors* -*Thyroid nodules* *Carriers have inc risk of ca (7%): CC Tumor testing: . ****colon tumor test: 64% of MAP colon tumors have somatic KRAS mtn (G34T in codon 12) => hallmark of MAP**** [BOARDZ] . *MSI stable* (rule out Lynch) Genetic Test to establish dx: *MUTYH seq (if European: targeted mtns>seq) > MLPA/deldup* Management Colonoscopy, 25-30, Every 1-2 y Endoscopy, 30-35, Every 3-5 y Refer if personal hx / FDR: . *10+ adenomatous colon polyps* OR . *Nl MSI/IHC CC <50*

Maternal Syphilis *Teratogen*

****Hutchinson teeth**** *Fetal hydrops* *SAB, stillbirth, neonatal death* *ID* *Desquamation (peeling skin rash)* Prematurity Visceral and skin lesions Osteitis Pneumonia HSM Mucocutaneous lesions Lympadenopathy Snuffles (copiois nasal secretions) Osteochondritis Pseudoparalysis Edema Hemolytic anemia Thrombocytopenia HL Palate perforation Periosteal reaction Tx: avail

MCAD (Multiple Acyl-CoA Dehydrogenase Deficiency) *Metabolic* *Fatty Acid Oxidation*

****MOST COMMON FAOD**** [BOARDZ] 1/10,000-1/15,700 in US AR *ACADM* @ 1p31 -Enzyme Def: medium chain acyl-CoA dehydrogenase -Common mtn in Northern European ancestry: p.K304E ---Most common in Northern Germany ---Also common in Southern Germany & Netherlands . *NL @ BIRTH* Onset: . 3-24 mo (although dependent on stress level, may present much later) Criteria: [BOARDZ] Vomiting Lethargy Seizures *HSM & acute liver disease* *FASTING INTOLERANCE* => acute brain dysfunction => *COMA*, sudden death, ****SIDS**** Dx test: -Abn urine acylglycines: suberylglycine suggests possible dx of MCAD (obtain when pt sick) -Hypoketotic Hypoglycemia during metabolic crisis -Hi anion gap -Hyperuricemia -Hi LFTs -Hi CK -Mild hyperammonemia -Plasma (blood) acylcarnitines: ****Hi MEDIUM CHAIN ACYLCARNITIES (C6,8,10)*** ---C8 (but not pathognomic) ---mildly hi C6 & C10 -uOA ---Nl if stable ---If times of stress, hi C6, C8, C10 (w C8 being peak) ---Low ketones . ACADM genetic test Test sibs Tx: Simple carbs by mouth *AVOID FASTING* --- frequent feeding --- carbs when ill=> hospitilization/ER if necessary -> IV dextrose Cornstarch before bed Supplement: cornstarch, carnitine, high carb/low fat diet (*NO MCT (medium-chain triglycerides) oil*)

Kearns Sayre Syndrome (KSS) *Metabolic* *Mitochondrial* *mtDNA microdel*

****MT**** [BOARDZ] . *SPORADIC* (de novo) single large 4.9kb mtDNA del: m.8470_13446del4977 (⅓ of affected!) (also causes Pearson) . AR, AD (rare) Single del / dels / dups *HETEROPLASMY* ---Usually, deletions are present in all tissues ---Rarely, deletions are undetectable in blood cells → muscle biopsy required Onset: *CHILDHOOD* (<20y) Dx criteria: 1. Progressive early-onset *OCUAR MYOPATHY* (Progressive External Ophthalmoplegia=weak eye muscle) + *DROOPY EYES* [BOARDZ] (*think sayra mabetshouf*) 2. Pigmentary retinopathy: atypical retinitis pigmentosa + Minor criteria: . CNS: cerebellar *ATAXIA* (unstable walking) (ID, dementia, HL) . *CARDIAC CONDUCTION DEFECT* => arrhythmia . *HI CSF PROTEIN* > 100 (neuromuscular degeneration) . Abn of brain, heart (heart block, cardiomyopathy), renal tubules (renal tubular acidosis) and endocrine glands (diabetes, hypoparathyroidism, growth hormone def->short), skeletal muscle (ptosis, Dysphagia, Exercise intolerance, Muscle weakness) => young adult death Test: -Hi lactate & pyruvate -Brain MRI → leukoencephalopathy -Echo and ECG → conduction defects -Muscle biopsy → ragged-red fibers -Biochem studies of respiratory chain enzy in muscle extracts → low activities of respiratory chain complexes containing mtDNA-encoded subunits Genetic test: deldup (southern blot: preferred method) RR - Mother of proband is usually unaffected & does not have mtDNA dels in her tissues - Sibs RR very low - Affected women have small but finite risk of affected child: 1 in 24

Leber Hereditary Optic Neuropathy (LHON) *Metabolic* *Mitochondrial*

****Most common mt dx**** ****mtDNA**** --- 40% have no fhx (due to difficulty tracing fhx) --- de novo (rare) mtDNA complex I of ETC (electron transport chain) *MT-ND1 (electron transport chain)* MT-ND4 (electron transport chain) MT-ND4L MT-ND6 *90% have one of 3 common point mtns*: [BOARDZ] *G11778A in ND4 subunit* (most common): severe, little chance of recovery *T14484C*: best prognosis, occasional visual recovery *G3460A*: intermediate 10% have other mtDNA mtns (point mtns & dels): T14459A in ND1 subunit (most severe, less sex bias) *HOMOPLASMY* - most (*unlike most mtDNA dx*) Heteroplasmy (10-15%) -Degree of heteroplasmy in blood usually >70% -Risk of blindness is minimal if mutational load <60% Reduced penetrance => cause / predispose ("susceptibility" nucleotides in many) Sex bias penetrance: M >> F 50% of M (4-5x more likely) => blind 10-15% of F => blind (so can appear XL) Peak age of onset: 15-30 y Age of onset: 18-30 y (teens-20's) = young adult - 95% before 50 y Criteria: Rapid bil, painless, subacute subacute/acute loss of vision: Acute phase: → *Blurry/cloudy central vision* in one eye → Similar symptoms appear in other eye 2-3 mos later (25% both eyes onset simultaneously) Atrophic phase: optic disc atrophy (death of optic nerve cells) within 6 wks of onset => Eventually legally *blind* (visual acuity ≤20/200) (*think alhakon al takathor and you went blind*) Optic Neuropathy Peripapillary telangiectasias Other criteria: Cardiac arrhythmias Neurologic Involvement (rare): dystonia, tremor, peripheral neuropathy, myopathy, movement disorders, MS-like Dx: Ophthalmologic eval Imaging looking for characteristic pathological findings Genetic test: *3 common mtns > mtDNA seq* Test: . Eye findings . Targeted test of specific mtn in MT-ND1, MT-ND4, MT-ND6 Management: Limit smoking & drinking Cardio, Opthal, Neuro Evals Avoid mt toxins

Rett = MECP2

****XLD**** --- DE NOVO --------****MOST are LETHAL IN MALES but NOT always**** -------- ****VARIABLE EXPRESSIVITY bcs SKEWED X INACTIVATION**** in females (or XXY) => some females have very mild/nl pheno *MECP2* Nl @ birth Onset: 6-18 mos -> progressive neurodevelopmental => . *Regression in language+motor skills*-> severe ID, autism, ***LITTLE/NO SPEECH*** (4% of females w autism have Rett) . Repetitive, ****STEREOTYPIC HAND MOVEMENTS**** (*wringing*) . *Acquired microcephaly* . *Grand mal seizures* . Gait ataxia (ataxic limb movement) + apraxia . Spacticity . Breathing prob . Sleep prob . Tremors . QTc prolongation *Can have atypical Rett which is similar to Angelman* Test: *Seq (80% DR) > deldup (8% DR)* [BOARDZ]

Pyruvate Dehydrogenase Complex (PDHC) deficiency *Metabolic* *Mitochondrial* *Lactic Acidosis*

****XLR**** --- Males ------ lethal (often) ------ if 3' point mtn => partial def --- Females ------ rearrangements w null activity ------ unfavorable skewed lyonization PDHC E1 alpha (often) --- entry way to Kreb cycle *PRENATAL ONSET* 1) Neonatal, severe: . ****CONGENITAL SEVERE LACTIC ACIDOSIS (ACIDEMIA)****: AMMONIA (NH4) >50uM @ <24hrs *in FULL TERM* baby --- nl lactate/pyruvate ratio --- nl glycemia . BD: BRAIN + KIDNEYS --- ****CYSTIC BRAIN LESIONS**** --- ****RENAL CYSTS**** => Lethal 2) Intermediate: . Neurocognitive disease 3) Late onset: . Carbohydrate-induced episodic ataxia

Hunter = Mucopolysaccharidosis type II (MPS II) *Metabolic* *Lysosomal storage*

****XLR**** [BOARDZ] (2/3 of mothers carriers) *IDS* Enz def: *iduronate sulfatase* Substance stored (GAG): --- dermatan sulfate --- heparan sulfate => accumulate Onset: <1-4 y < 1 y Frequent upper respiratory infections Hernias > 1y Face: ****COARSE****, macroglossia Poor growth + developmental regression Skeletal: claw hands Otitis media, nasal congestion HSM Dysostosis multiplex DD Neurodegeneration HL Macrocephaly Hoarse voice Short ****NO corneal clouding**** (*"Hunters need to see clearly"*) [BOARDZ] *Milder than Hurler* => Death: 10-20 y Dx Urine GAGs: hi heparan + dermatan sulfate Iduronate sulfatase enz activity IDS genetic test Tx: . ERT: idursulfase (for non-neurologic complications) . BMT (less successful than Hurler)

Alport Syndrome (AS) & Thin Basement Membrane Nephropathy (TBMN) *Hearing loss*

****XLR**** mtns (80%) (*COL4A*5), *10-15% de novo* *AR* (15%) (COL4A3, COL4A4) *AD* (5%) *KIDNEY+EYE+EAR* (*needs good ears and eyes and kidneys to work at the airport*) . ****Post-lingual progressive SNHL (late childhood/early adulthood)**** . Kidney: --- Microscopic *HEMATURIA* --- *PROTEINURIA* --- *HTN* =>>>>>> renal scarring => *RENAL FAILURE* *ESRD* (almost all males w XL, ~10% of females) Nephritis . Eye: *ANTERIOR LENTICONUS*= misshapen lenses affecting vision . HL due to abn inner ear function anterior lenticonus TBMN AD only, *benign* condition (mild course of persistent microscopic hematuria) Test: IHC analysis of basement membrane type IV (skin / renal) collagen expression Multigene panel (can start w COL4A5 if XL) Tx: Treat w ACE inhibitors if proteinuria Renal transplant for ESRD

Maternal Hyperthermia (fever) *Teratogen*

*101 F* or more *0-6 wk* (neural tube top closes by 26-28d, bottom by 28-30d) . ****NTD**** [BOARDZ] --- inc risk, but *low* . AWD . CHD

Miller Dieker *Microdeletion*

*17p13.3-* --- *de novo* (~100%) --- *TERMINAL DEL* --- *LIS1*: critical for lissencephaly ****Prenatal US****: ****LISSENCEPHALY****! Microcephaly Postnatal: LISSENCEPHALY type 1 / 2-> Hypotonia, little-no development Microcephaly Feeding prob Spacticity Seizures, DD, ID Breathing prob Dysmorphic face: . Forehead: high forehead, vertical ridging + furrowing of forehead . Nose: small nose, anteverted nostrils . Eyes: upslanted palpebral fissures . Mouth: protuberant upper lip w thin vermillion border => Almost no developmental milestones => Childhood (2y) death Differential: LIS1 del (35%) / mtn (15%) => isolated lissencephaly Genetic test: Karyotype (70% DR) > array / FISH

Lithium *Teratogen*

*1st tri* CHD: 30x ****EBSTEIN'S ANOMALY**** (heart valves)

Varicella = Chicken Pox *Teratogen*

*1st+2nd tri*: 7-20 wk Primary mat infection => *25% risk of fetal infection* => *1-3% of fetuses w infection are symptomatic* *Limb underdevelopment/hypoplasia* *Cicatrix (zigzag skin scarring)* Eye abn DD/ID Brain abn IUGR Chorioretinitis Rudimentary digits

Hirschsprung

*20% familial*: . *AD* . *AR* . *Multigenic* --- Genetic heterogeneity: allelic & locus --- Reduced penetrance --- 4M >> 1F --- Variable expressivity: intra + interfamilial Isolated vs. syndromic Short vs. long segment Reduced + sex dependent penetrance RR depends on proband's sex + pheno *RET* (*think rat in your bowel*) *EDN*RB EDN3 GDNF NRTN Criteria: . Congenital intestinal aganglionosis (condition of large intestine (colon) => causes difficulty passing stool) . Neurocristopathy (neural crest cell disease) => Constipation, obstruction, failure to pass meconium, abd distension, enterocolitis Dx: histopathology

Branchio Oto Renal (BOR) = Melnick Fraser *Hearing loss*

*2nd most common AD HL* *AD* --- de novo (10%) . *EYA1* @ 8q13.3 (>40%) . *SIX*1 @ 14q23 (rare) . SIX5 (rare) Mtns: . Point . Deldup (10%) Criteria: . BRANCHIO - *branchial arch abn* --- 2nd branchial arch (lung): ------ *Branchial cysts / cleft / fistulas in neck + throat* . OTO - EAR: --- External abn: ------ ***EAR PITS***/ tags ------ Overfolded helices --- Inner abn --- ****HL**** (*ANY TYPE*): ------ Middle (intermediate) / inner ------ SNHL / conductive HL / mixed HL . RENAL: --- ****RENAL ABN****: ------ Hypoplasia ------ Agenesis --- Renal failure (late onset) => common cause of death . Asymmetric face Dx: . Clinical . EYA1, SIX1, SIX5 seq (<50% DR) Management: . *Renal US*

Frontotemporal Degeneration = Frontotemporal Dementia (FTD)

*2nd most common dementia after AD in pts <65* 25-50% of presenile dementias 5-15% of all dementias reported on autopsy *Associated w ALS + Parkinson* Often misdiagnosed as AD / psychiatric dx AD (known mtn in 15-50% of cases) Mtns in sporadic & familial FTD + ALS *C9orf72* (5-20%) *MAPT* (5-10%) PGRN Mtns: *hexanucleotide repeat GGGGCC* >30 repeats is usually cut off for mtn Onset: 40-75 (avg=56) . Fixation w food . Behavioral Variant: changes in personality, judgement, inhibition, mood, inappropriate behaviors . Primary Progressive Aphasia: loss of speech, word-finding, comprehension . Movement: corticobasal syndrome, progressive supranuclear palsy, FTD w ALS . Psych illness *Families/pts can have just FTD, just ALS, or a combination of both diseases* Pathology: pos for *TDP-43 protein inclusions* Types: AD w complete penetrance GRN (5-10%) Onset: 40-60 Pathology: abn tau protein accumulates in brain AD; age-dependent penetrance Onset : 60s Parkinson features Pathology: tau-negative; pos for TDP-43 protein

Parkinson *Neurologic* *Movement*

*2nd most common neurodegenerative dx* *Sporadic / complex* (most) --- Late-onset --- Low penetrance *Familial (10-15%)*: --- *AD* *LRRK2* (1-2%): 20-74% penetrance (*Think park on Lark st*) SNCA (complete penetrance) G2019S: most common mtn GBA (reduced penetrance) VPS35 (reduced penetrance) Rare; pheno same as adult-onset Parkinson --- *AR* *PARK2* (50%) (*think PARK*) PINK1 (rare) DJ-1 (rare) Onset: juvenile (<20) & young onset (<40) Prolonged & mild Good response to oral L-dopa tx --- XL *TAF1*: very rare; only found in Philippines --- Multifactorial; Risk factors: Aging Male Brain injury Toxins Selective degeneration of dopamine neurons in substantia nigra w inclusions (Lewy bodies)→ dopamine-mediated movement def => *Tremor 1st symptom, esp while resting* Rigidity / stiffness of limbs / torso Bradykinesia (slow movement), akinesia Postural instability: impaired balance + coordination Change in emotions + cognition-> depression, visual hallucinations, dementia, sleep prob Other: shuffling gait, soft voice, constipation Symptomatic test Presence of strong fhx / young age of onset Multigene panel, unless suspected gene based on ancestry / features Presymptomatic/carrier Test of symptomatic relative first strongly recommended Discuss reduced penetrance Pathology: *Lewy bodies* Dopamine neurons loss Tx: No cure, but meds + surgery to treat symptoms Meds: carbidopa/levodopa (LDOPA), dopamine agonists, anticholinergics, MAO-B inhibitors, COMT inhibitors Surgery: deep brain stimulation

Recurrent Miscarriages = Recurrent Pregnancy Loss (RPL) - NSGC -

*3+ clinically recognized (documented by US / histopathologic exam) consecutive OR non-consecutive SAB prior to fetal viability (<24w)* *At least 50% of first tri SABs have abn ch* 30% of couples have 1 SAB 1-2% of couples have RPL (2% 2+; 1% 3+) => ****50-75% chance next preg maintained**** ---*if 2 SABs => 75% chance next preg maintained* ---*if 3 SABs => 65% chance next preg maintained* Eval may be considered after 2 SAB, especially considering mat age and length of time spent trying to conceive Incidence: 1 SAB (10-15%) 2 consecutive pregnancy losses (>2%) 3 consecutive pregnancy losses (0.4%-15) Causes: Uterine/cervical factors: Acquired and congenital mullerian/uterine anatomic abn (10-50%) Endocrine: diabetes thyroid issues luteal phase defect PCOS Immunologic factors: antiphospholipid antibody syndrome blood group alloimmunization Genetic factors: Aneuploidy Ch Rearrangement ****4%**** Single gene disorders (Hb Bart) Thrombophilia Env: chem agents smoking illicit substance use infection SAB of multiple male fetuses => Consider: XLD (lethal in males): 1. Incontinentia pigmenti 2. Chrondodysplasia punctata 3. Focal dermal hypoplasia 4. Goltz 5. Rett 6. Aicardi Recommendations: 1. Thrombophilia eval: . Factor V Leiden . Prothrombin G20210GA (can consider alpha-thal for some grps) *MTHFR NOT justified; no protein C or S* 2. Parental karyotyping 3. Ch analysis/array + path eval on POC

Retinoblastoma (RB) *Cancer*

*40% hereditary* (due to mtn) AD ---If neg genetic testing in parents => could be bcs: ------*DE NOVO (90%)* [BOARDZ] ------*GERMLINE MOSAICISM (10%)* [BOARDZ] => recommend screening for other children since cannot rule out germline mosaicism) ---if pos genetic test in healthy parent=> bcs *INCOMPLETE PENETRANCE* (esp. if residual activity (classic 2-hit hypothesis condition) *RB1*@ 13q14.2 (TUMOR SUPRESSOR gatekeeper) LoF mtn Protein inhibits cell cycle progression, acts at G1/S checkpoint Sequesters transcription factors CDk4/cyclin D1 complex phosphorylates pRB. If pRB absent->ca Allelic het: missense del insert hypermethylation of promoter Onset <5y: sporadic (1-2y), hereditary (<1y) -*Retinoblastoma* ---*60% UNIL*: dx at 2y, more likely sporadic --- 40% BIL: dx at 15 mos, more likely hereditary 70% risk for other ca: in adolescence + adulthood -*OSTEOSARCOMA* -*SOFT TISSUE SARCOMA*, radiogenic sarcoma -*PINEAL* tumors = PINEALOMA = pinealoblastoma, or neuroectodermal brain tumors -*MELANOMA* -Leukemia Other criteria: *LEUKOCORIA* (white pupillary reflex), *strabismus* Genetic test: RB mtn/del( (90% DR) Management: *CA RISK INCREASED W/ EXTERNAL HIGH BEAM RADIATION (AVOID RADIATION THERAPY)===>OSTEOSRCOMA* Refer if Personal / Fhx of RB

Gamma Polymerase (POLG) *Mitchondrial*

*AD PEO* w or w/o parkinsonism (w or w/o other features) *AR PEO* w or w/o parkinsonism (w or w/o other features) *nuDNA: DNA polymerase gamma gene* => Replicates and proof-reads mtDNA (exonuclease) => Abn mt formation: deletions in mtDNA phenotype varies, but PEO is common *POLG mts* . Wide variety of brain and muscle disorders, like most mitochondrial disorders . Male sub-fertility in men and premature menopause in women *Progressive External Ophthalmoplegia (weakness of extraocular eye muscles)*=> Ptosis Ophthalmoplegia Generalized myopathy Dysarthria Seizures SNHL Axonal neuropathy Ataxia Neuropathy Spectrum Depression Parkinsonism Hypogonadism Cataracts SANDO (Sensory Ataxia, Neuropathy, Dysarthria, Ophthalmoplegia) Male subfertility (more or less than the usual 10 repeats in a trinucleotide repeat) Premature menopause Cataracts Alpers-Huttenlocher Syndrome = Alpers syndrome Onset: infantile-childhood Progressive psychomotor regression and severe encephalopathy Progressive Intractable epilepsy Liver failure Childhood Myocerebrohepatopathy Spectrum Infantile / childhood onset DD Dementia Lactic acidosis Myopathia FTT Liver failure Renal tubular acidosis Pancreatitis Cyclic vomiting HL Myoclonic Epilepsy Myopathy Sensory Ataxia: Epilepsy Myopathy taxia *No ophthalmoplegia . *SANDO (Sensory Ataxia, Neuropathy, Dysarthria, Ophthalmoplegia)*. . Progressive external ophthalmoplegia (PEO, eye muscle weakness) and parkinsonian symptoms

Phelan McDermid *Microdeletion*

*AD* *22q13-* (incl *SHANK3 del*) (*think del for SHArK ate (deleted) MurMaID* Criteria: . *LARGE FLESHY HANDS* (*think like a FISH*) . No sweat . Unusual toenails . ID . No speech *Nl growth Test: --- SHANK3 seq --- array

Pseudoachondroplasia

*AD* *COMP* Criteria: *Short-limb dwarfism (not noticeable until 2nd y)* *Hypermobile joints* (*except elbows*) Waddling gait Chronic joint pain Radiographic: scoliosis bowed leg flattening of vertebral bodies lordosis *Nl head + face* Tx: Surgery meds for pain

Muenke *FGFR related Craniosynostosis*

*AD* *FGFR3 (NOT 2!)* ---*Pro250ARg* .*Uni/bil CORONAL CRANIOSYNOSTOSIS* (*like a monkey who can't hear*) . *2-3 SYNDACTLY* . *HL* . *DD* . *Asymmetric face* . *Ptosis* . Macrocephaly . Ears w/small pinna, prominent crus, SNHL . Fused carpal and tarsal bones . Low frontal hairline . Strabismus . Cleft palate . Short . Board great toes . *Similar to Saethre Chotzen, but Muenke more DD + HL*

Greig Cephalopolysyndactyly = Greig Cephalodactyly

*AD* *GLI3* (*think G for G*) --- *Allelic w Pallister Hall* . *MARCOCEPHALY* => hydrocephalus . *PREAXIAL CROSSED POLYDACTYLY on feet* . *Cutaneous syndactyly* . Wide thumb / big toe . Ocular hypertelorism . DD/ID . Seizures Test: GLI3 seq (70% DR) Tx: . Polydactyly corrective surgery . Monitor for macrocephaly (for hydrocephalus)

Multiple Endocrine Neoplasia Type 1 (MEN1) = Wermer *Cancer*

*AD* *MEN1* (*MENIN*) on 11q, 10% denovo ****3P's**** (2 of): Clinical dx criteria: . *PARATHYROID GLAND tumors (99%)***-> HYPERPARATHYROIDISM (90% by 20-25%, 100% by 50y) & hypercalcemia by 20's****Blood test for parathyroid hormone & calcium levels more sensitive than genetic test for pt w/isolated tumor .*Anterior PITUITARY GLAND tumors* (10-60%): prolactinoma .*PANCREATIC NEUROENDOCRINE ISLET CELL tumors* (in gastro entero pancreatic tract) Other criteria: 1. Neuroendocrine ca (10%): . *ADRENAL tumor*: adrenocortical . Pancretatic: ---Gastrinoma = tumor in pancreas / duodenum-> secretes excess gastrin ---Insulinoma ---Glucagonoma ---VIPoma 2. Non-endocrine tumors: .*Facial angiofibromas* . *BRONCHIAL-> lethal* .*Lipomas* . Thymic . Collagenomas . Meningiomas (benign nerve) . Ependymonas (benign nerve) . Leiomyoma 3. Reproductive dysfunction: . Oligomenorrhea . Amenorrhea/galactorrhea in females . Sexual dysfunction in males 4. Zollinger-Ellison syndrome: . Gastric acid hypersecretion -> ulcers . Hyperplasia/neoplasia of pancreatic islet cells ****DOES NOT INVOLVE THYROID*** (*unlike MEN 2*) Genetic Test: MEN1 seq+deldup *Parathyroid hormone + ca levels more sensitive than genetic test if pt w isolated tumor* Management: -Yearly biochem mo (blood calcium, gastrin, prolactin) start in childhood -Abd CT/MRI -Head MRI start in childhood every 3 y -Yearly parathyroid hormone and ca levels start at 8 -Yearly thoraco-abdominal CT scan start at 20 Refer if personal hx / FDR: . 2 MEN1 tumors (adrenal / parathyroid / pituitary / pancreas / thymic / bronchial carcinoid) in person . Gastrinoma . 2 pancreatic enuroendocrine tumors in person . Parathyroid adenoma <30y . Parathyroid adenomas in many glands . Parahyroid adenoma + fhx of hyperparathyroid/MEN1 tumors

Hereditary Neuropathy with Liability to Pressure Palsies (HNLPP) *Microdeletion*

*AD* *PMP22* @17p --- *del* --- mtn (rare) *dup=>CMT* Onset: adolescent - early adult Criteria: . *Neuropathy* - peripheral nerves very sensitive to pressure => Recur --- Numbness --- Tingling --- *Palsy episodes* --- *Carpal tunnel* --- *Foot drop* => Permanent - Muscle weakness - Loss of sensation *Nl life expectancy* Test: deldup > seq

Malignant Hyperthermia

*AD* *RYR1* (*think R for Really hot hyperthermia*) *CACNA1S* Criteria: *Muscle rigidity*within 30 min Late sign: *Fever* *Tachycardia* (rapid heart rate) *Rhabdomyolysis (muscle breakdown)* Tachypnea Respiratory acidosis Rapid increasing temp Hi serum CK => Death if untx Test: . Contracture test of biopsied muscle . Abn EKG . RYR1 + CACNA1S seq Management: Avoid *certain anesthetics / muscle relaxants* bcs lead to => *Hi calcium* => *hypermetabolism* + *rhabdomyolysis (muscle breakdown)* => hyperthermia

Hereditary Hemorrhagic Telangiectasia (HHT) = Osler Weber Rendu *Cancer* *Bleeding* *Microdeletion*

*AD* *SMAD4* = *SMADH4* (*microdel SMAD4 + Juvenile Polyposis syndrome*) (*think smashed in the hall bcs so juvenile*) *ENG* *ACVRL1* GDF2 Criteria: . ****NOSEBLEEDS**** (epistaxis) - *90% by 2nd decade* [BOARDZ] . Visceral AVMs --- ****GI bleeding**** [BOARDZ] --- cerebral (in childhood) --- pulmonary --- hepatic → *telangiectasia* . *Mucocutaneous telangiectasia*: *AVMs = arteriovenous malformations* (lack of capillaries) near surface of skin --- lips --- mouth --- fingers --- nose . Frequent episodes of hemorrhage (+ complications) Types: Type 1: symptom onset earlier than type 2; more likely to have AV malformations in lung & brain; more common in F >> M Type 2: higher risk of liver involvement Type 3: higher risk of liver involvement Dx: 3+: Epistaxis Mucocutaneous telangiectasias Visceral AVMs Fhx of HHT Pathogenic mtn in ACVRL1, ENG, GDF2 Genetic test: . ****SMAD4 genetic test if juvenile polyps**** . ENG, ACVRL1 Pregnancy management: Maternal MRI to monitor for pulmonary/cerebral AVMs Management: Nosebleeds: humidifaction, nasal lubricants, hemostatic products, laser ablation, sclerotherapy GI bleeding: iron replacement therapy, surgical resection of bleeding sites Pulmonary AVMs: larger than 1mm require consideration of occlusion Cerebral AVMs: treated w surgery Liver AVMs: liver transplant may be recommended Anemia: iron replacement; transfusions may be required

Familial Thoracic Aortic Aneurysm and Dissection (FAA)

*AD* *TGFBR2* (some) *MYH11* (rare) TGFBR1 ACTA2 FBN1 MYLK SMAD3 AAT1 AAT2 Unkown gene (most) Symptoms of aortic dissection: Pain: severe, abrupt, sharp, shooting in chest, back, abdomen Pulselessness, paresthesia, stroke, acute myocardial infarction, paralysis May be sudden and often fatal *Aortic dissection rare in early childhood* Dx criteria (dx of exclusion) AD fhx of dilation / dissection of aortic root / ascending thoracic aorta (at sinuses level)/ descending thoracic aorta w/out additional criteria / major criteria for MFS / another connective tissue disorder *Dilation 2 SD above mean (usually > 4 cm in adults is concern)* Dissection of thoracic aorta involving either: Ascending Aorta (Stanford Type A) 60% DeBakey I 10-15% DeBakey II Descending Aorta (Stanford Type B) 25-30% DeBakey III Dx eval 1. Physical 2. Fhx 3. Echo 4. Dilated eye exam (to exclude MFS) 5. Consider gene seq 6. Imaging of vasculature, incl cerebral vasculature, for those w genetic mtn that predisposes to diffuse arteriopathy Patient Eval: Echo: for cardiac anatomy + aortic dilation MRA to assess vasculature Other features: skeletal, ocular Family Eval: Assess fm hx: ---aortic aneurysm ---sudden death, other features

Myotnic Dystrophy type 2

*AD* CNBP *Tetranucleotide expansion*: *CCTG* Repeat size 75-11,000 (does not correlate w age onset, *MILD anticipation*) Muscle: myotonia, slowly progressive weakness, proximal to distal Eye: early posterior subcapsular cataracts Heart: mainly arrhythmias, AV conduction block, CM rare Endocrine: DM, hypothyroid, decreased fertility in males CNS: LDs to ID

Van der Woude (vDW) *Microdeletion*

*AD* Haploinsufficiency: *IRF6* mtns *1q32-* ****Congenital bil LIP PITS**** (*think wood burnt his lips*) *CLP* Ankyloglassia Hypotonia CHD *Nl IQ, GROWTH*

Transient Neonatal Diabetes Mellitus (DMTN) *Imprinting*

*AD* Imprinted locus @ *6q24* caused by *overexpression of PLAGL1 + HYMA1* *mat copy normally off* (*think mom is off bcs baby is on*) 1. *upd(6)pat* (isodisomy of chr 6) (20%)(41% de novo) 2. *Pat 6q24 dup* (29%) (de novo, inherited, or rearrangement) 3. *6q24 hypomethylation* (hypomethylation of mat PLAG1, HYMAI) Differentially methylated region (DMR) (30%) . *SEVERE IUGR* (low birth weight) . *Hyperglycemia beginning in neonatal period in a term infant, resolves by 6 mos (between 3-18 mos)** [BOARDZ]* *Episodes of hyperglycemia can recur throughout childhood, especially during illness (or pregnancy) . *MACROGLOSSIA* [BOARDZ] . *UMBILICAL HERNIA* . Dehydration & absence of ketoacidosis Dx test: *UPD testing* [BOARDZ] Tx: Rehydration and IV insulin at dx *Episodes of hyperglycemia can recur throughout childhood, especially during illness (or preg)

Nail Patella Syndrome (NPS)

*AD* LMX1B . *Small nails* . *Small kneecap* . ****Iliac horn**** on x-ray (horn-like abn of crest of iliac bones of pelvis) [BOARDS]

Cleidocranial Dysplasia

*AD* RUNX2=CBFA1 (60-75%) - hapolinsufficiency . *Delayed closure of cranial sutures* . *HYPO/APLASTIC CLAVICLES* . *WORMIAN BONES* . Brachydactyly . Recurrent otitis media . HL . Short . Face: ---Eyes: hypertelorism ---Mouth: supernumerary teeth and other teeth abn *Nl IQ* Test: Seq+deldup (60-75% DR)

Von Hippel Lindau (VHL) *Cancer* *Childhood Cancer* - ABGC -

*AD* --- *DE NOVO (20%)* *VHL* @ 3p25 Tumor suppressor LoF Mtns: -*Point mtns* (80%) . Null . Truncated . Missense -dels (20%) *CHILDHOOD* 1. ****RENAL CLEAR CELL (RCC) ca**** (40%) - greatest cause of mortality 2. ****HEMANGIOBLASTOMA****: --- Retinal capillary: youngest onset (*start screening at 5y*) . CNS: cerebellar + spinal 3. *ENDOLYMPHATIC SAC* tumors (inner ear) 4. *PHEO* (w missense mtns) --- Secrete *NOREPINEPHRINE* ONLY in VHL (*vs. Metanephrine predominant in MEN2* *think M M*) 5. *EPIDIDYMAL CYSTS* in men 6. Pancreatic neuroendocrine tumors Types: 1: High HB + RCC risk; low pheo risk 2A: High HB + pheo risk; low RCC risk 2B: High HB, RCC, pheo risk 2C: High pheo risk, NO HB, RCC risk Refer if personal / FDR: . Bil / multifocal RCC . RCC <50 . RCC + FDR / SDR w RCC . CNS HB . Pheo . Endolymphatic sac tumor . Retinal capillary hemangioma Genetic test: seq + deldup Tx Brain+Spine: MRI start at 11y, every y Othal Exam: start before 5y, every y Abd MRI start at 5y, every 12 mo Biochem Screenfor pheo start at 5y Every y

Peutz Jeghers syndrome (PJS) *Cancer*

*AD* --- *de novo (20-50%)* ****STK11**** (think *"He put Jegher down on the ground w a stick"*) = LKB1 @ 19p13 (50% of cases) 40% have dels (higher than other tumor supressor syndromes) -*DARK BLUE/BROWN/BLACK FRECKLES AROUND MOUTH/LIPS (buccal mucosa) that CROSS VERMILION BORDER/ nose / eyes / genital / fingers / toes -> may fade after puberty* [BOARDS] -*<100 GI HAMARTOMA polyps*: . *Jejunum (small intestines)* (<100) . Glandular epithelium supported by smooth muscle cells contiguous w muscularis mucosa = *frond-like = broccoli stalks = BRANCHING TREE* -> . *CC* (39%): 15-64y . *Pancreatic ca* (36%) . Gastric ca (29%) . Small intestine (13%) . Small bowel ca (13%) -*INTUSSUSCEPTION = segment of intestine "telescopes" inside another -> obstruction / abn pain*; GI bleeding (beginning at 20 in 50%) -*BR ca* (54%) -*Ov ca (21%), sex cord (& mucinus) tumor (20%) w annular tubules ca* -*Testicular ca: sertroli cell tumors* (9-20%) -Uterine ca (9%) -Lung ca (15%) -Cervical adenoma malignum -Dental enamel pits Genetic test: *STK11 seq* Management: Upper endoscopy 10 Every y Small bowel barium study 10 Every y Colonoscopy 25 Every 1-3 y Testicular exam 10 Every y Pelvic exam 20 Every 12 mos BrCA ecreening 18 (as before) Refer if personal hx / FDR: . 2+ PJ GI polyps . 1+ PJ GI polyp & mucocutanous hyperpigments . Ov sex cord tumor w annular tubules . Adenoma malignum of cervix . Setroli cell tumor . Pancreatic ca & 1+ PJ GI polyp . Br ca & PJ GI polyp in person . 1+ PJ polyp & fhx of PJS

Treacher Collins *Craniofacial*

*AD* --- *de novo (50%)* .* TCOF1* (often) (*think TCO = Treacher COllins* . POLR1C . POLR1D Criteria: . Dysmorphic face --- *Malar (cheek bones) hypoplasia* --- *Zygomatic bone cleft* (some) --- *Downard slanting eyes* (downslanted palpebral fissures) --- No eyelashes medial to defect --- *Micrognathia* Other criteria: . Ear --- Conductive ****HL**** --- Microtia --- External ear abn . Lower lid *COLOBOMA* (eye abn) . Projection of scalp hair onto lateral cheek . Cleft palate . Obstructive apnea *Nl IQ*

Smith Magenis *Microdeletion*

*AD* --- *de novo* . *17p11.2-* (70%) [BOARDZ]: incl RAI1 . *RAI1* mtn . Dysmorphic face --- *Prominent lower jaw* --- Square face --- Deep set eyes --- Full cheeks . Behavior prob: --- Sweet but *SELF-HARM BEHAVIOR* --- *LICK & FLIP* BEHAVIOR (e.g. magazine) --- *Stick things in their butt [think "magnum"]* --- Self hugging . *ID* . Delayed speech . Sleep prob, sleepy during day . Scoliosis . Short . Less sensitivity to pain/temp Test: *Visible on karyotype but FISH / array to confirm*

Holt Oram

*AD* --- *de novo* (85%) *TBX5* (*think tea box good for heart*) ****Think Heart + Arm**** . *CHD* (75%) [BOARDZ] --- ASD --- VSD --- ****Cardiac CONDUCTION defects (of atrioventricular block) => arrythmia**** . *Upper limb / carpal bone abn* --- *Wrist* --- *Radius* --- Thumb: *NO THUMB* Exclude pts w other abn, incld: --- renal --- lower limb --- anus --- eye Management: *EKG + echo* to monitor heart

CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) *Neurologic*

*AD* --- Complete enetrance --- Variable expressivity *NOTCH3* --- Missense mtns (most) Onset: mid-*adulthood* (mid 40s) Criteria: . *Electron dense granular osmophilic material (GOM)* in media of arterioles + skin vessels => Cerebral arteriopathy: small artery occlusions => Recur schemic strokes (subcortical infarcts) / TIA (transient ischemic attack) . *MIGRAINES* w visual sensations / auras (blind spots w flickering, impaired vision) . *SEIZURES* . Progressive *DEMENTIA* . Mood disturbances . Apathy . Motor prob: gait impairment . Executive dysfunction Dx test: . Electron microscope eval of skin biopsy: *electron dense granules in media of arterioles* . Brain MRI --- Diffuse T2 white matter lesions (leukoencephalopathy): Electron dense granular osmophilic material (GOM) --- Subcortical infarcts: Ischemic Strokes/ TIA . NOTCH3 seq > deldup

Cowden Multiple Hamartoma = PTEN Hamartoma *Cancer*

*AD* --- DE NOVO (>50%) Tumor suppressor LoF: *PTEN* KLLN SDHB SDHD PIK3CA AKT1 associated w Cowden-like Major criteria [BOARDZ-KNOW EXACTLY WHICH ARE MAJOR AND WHICH ARE PATHOGNOMONIC]: PATHOGNOMONIC: 1. SKIN: mucocutaneous lesions: a . *Facial TRICHILEMMOMA* b . *Mucocutaneous mucosal neuroma* in mouth/lips c . *PAPILLOMATOUS PAPULES*: oral papilloma on tongue + *GINGIVAL KERATOSIS* d . *Acral keratoses* on hands / feet = *PALMOPLANTAR KETATOTIC PITS* / acral hyperkeratotic papules 2. Adult *LHERMITTE DUCLOS* (LDD) = dysplastic cerebellar gangliocytoma (slow growing, *BENIGN BRAIN hamartoma*) in 30s-40s MAJOR CRITERIA: 1. *MACROCEPHALY (84%)* (occipital frontal circumference≥97th percentile: 58cm for adult women, 60cm for adult men), dolichocephaly . *CA: in order of incidence* [BOARDZ] 2. ****Early onset BR ca (25-85%)**** (type: fibrocystic br disease) 3. ****epithelial (non-medullary) FOLLICULAR THYROID ca (10-38%)**** *PAPILLARY THYROID ca* (rare) 4. ****Epithelial ENDOMETRIAL ca**** *(25-30%)* Minor criteria: *GOITER* . *HAMARTOMATOUS polyps (40-50%)*: ganglioneuromas, not hyperplastic (NON-CA) . *PIGMENTED MACULES ON GLANS PENIS* .****AUTISM**** (5% of pts w autism+ macrocephaly (OFC>2.5 SD) have PTEN) . ID . *Melanoma* .*Lipoma* (fatty tissue lesion) . *CC* (9%) . Uterine ca (30%) . Uterine fibroids . Fibromas . Papillomatous papules . Vascular abn: multiple intracranial developmental venous abn . Testicular lipomatosis . Benign thyroid structural lesions: adenoma, nodular goiter . Papillary / follicular variant of papillary thyroid ca . Esophageal glycogenic acanthosis . Nonca thyroid lesions *NO OV ca* Allelic mtns -> other *PTEN hamartomata*: 1. *Bannayan Riley Ruvalcaba* (BRRS) . macrocephaly, DD . hamartomatous intestinal polyposis . lipomas . pigmented macules of glans penis: *SPECKLED PENIS LIKE A BANANA* [BOARDZ] . hemangiomas 2. *Proteus and Proteus-like* (not inherited, somatic mtns) *Overgrowth* Connective tissue nevi Hemihypertrophy Subcutaneous tumors Bone, cutaneous, vascular anomalies Genetic test: PTEN seq Refer if: *Br ca/CC + 2 Cowden criteria in person* Management CBE, 25, Every 6 mo Mammogram, 25, Every 12 mo Breast MRI, 25, Every 12 mo PEx (thyroid), 18, Every 12 mo Thyroid u/s, 18, Every 12 mo Colonoscopy, 35, Every 5-10 y Derm Exam, Every 12 mo Mastectomy (Consider) Hyerectomy After childbearing (Consider)

Williams = William Beuren *Microdeletion*

*AD* --- Most *de novo* ****7q11.23-**** [BOARDZ] --- Includes *ELN (elastin)*: involved w/ connective tissue Criteria: . CHD (75%): --- ****SUPRAVALVULAR AORTIC STENOSIS**** [BOARDZ] --- Peripheral pulmonic stenosis (due to ELN mtn) --- VSD --- ASD . Endocrine: --- ****SHORT**** --- Hypercalcemia --- Hypothyroidism --- Hypocalcenuria (FTT in infancy) . Renal: --- HTN --- Renal abn . *High-pitched hoarse voice* . Premature grey hair . Connective tissue abn: --- Joint hypermobility --- Contractures --- Scoliosis --- Lordosis . Feeding prob w frequent vomiting, constipation . DD, LD, ID --- Visuospatial prob --- Good at *spoken language, music, rote memorization (based on repetition)* . Outgoing, *friendly*, interest in others . Dysmorphic face: --- Eyes ------ Medial eyebrow flare ------ Periorbital fullness ------ Stellate iris --- Mouth ------ Full lips ------ Wide mouth w widely spaced teeth --- *Elf face* (*think willi wanka the elf*) --- Broad forehead --- Short nose w broad tip --- Full cheeks . ADD, anxiety, phobia are common . Dental prob . Other Prob --- Joint prob --- Soft/loose skin --- Hypercalcemia in infancy Test: Array / karyotype But usually ****FISH**** for WBSCR @ 7q11.23- (cheaper than array) > array (nl karyotype does NOT rule out dx) Dx: Clinical / genetic test Tx: . Development: --- Early intervention --- Special ed --- Vocational training, PT, OT, ST . Psych (esp. ADD) : --- Behavioral counseling --- Meds . Heart: surgery . Hypercalcemia: --- diet modification --- oral corticosteroids

Hypochondroplasia

*AD* --- de novo *FGFR3* @ 4p16.3 (*same gene as as achondroplasia but milder mtns*) GoF missense common mtns: *N540K* 70% C1620A 50% C1620G 21% other mtn 10% 1. Post-natal short 2. rhizo / *mesomelic* shortening - disproportionately short arms & legs, broad, short hands & feet (*Distinguish from Acondroplasia: mesomelic vs. rhizomelic limb shortening*) 3. Stocky build, limited elbow extension, brachydactyly, mild joint laxity, macrocephaly, nl face 4. Radiographic findings similar to achondroplasia but milder 5. *Seizures*, *DD* (ID rare) *Milder than achondroplasia but more seizures + DD* *Dx difficult in children <3y* *watch for spinal cord compression, central sleep apnea, seizures* Test: X ray features Targeted mtn (80% DR)

Sotos *Microdeletion* *Overgrowth*

*AD* --- de novo . *NSD1* --- mtn --- partial / whole gene del (del common in Japanese) . *5q-* (includes NSD1) Criteria: . Symmetric *OVERGROWTH* prenatal to puberty . CHD (20%) . Motor delay . Hypotonia . ID . Dysmorphic face . Teeth abn . Advanced bone age . HL Test: *NSD1 seq+deldup > array*

Pallister Killian syndrome (PKS) = 12p tetrasomy = Isochromosome 12p = 47,XY i(12)(p10)

*AD* --- de novo --- *MOSAIC* (often): ------ in *fibroblasts* only ------ *NOT in blood*: T-cells cannot survive w this ch abn => circulating lymphocytes contains T-cells w/out ch abn *12P TETRASOMY* (*think you need an army of people to kill so TETRASOMY MEANING 4 PEOPLE LOL*) Prenatal US: *diaphgragmatic hernia* ! . Congenital diaphragmatic hernia . *Hypothalamic hamartoma* . *HYPOTONIA* . *SPARSE anterior scalp HAIR* (localized alopecia) . Polydactyly . Syndactyly . Severe ID . Seizures . Abn pigments: hypo / hyper pigmented streaks . No speech . Dysmorphic face --- Coarse face --- Prominent forehead --- Flat occiput --- Short nose --- Flat nasal bridge --- Short neck Test: . *Karyotype of skin fibroblasts => detects mosaicism* . *Recently aCGH on interphase cells from blood sample can detect some mocaisim*

Crouzon *FGFR related Craniosynostosis*

*AD* --- de novo --- APA effect *FGFR2* exons 8/10 @ 10q26 ---GoF ---*A391E = Ala391Glu* *FGFR3* ---*Ala391Glu=> Crouzon w acanthosis nigrans* Allelic heterogeneity . *CRANIOSYNOSTOSIS* (brachycephaly) . Progressive hycrocephalus (30%) . Cervical spine abn . Dysmorphic: . Proptosis . Parrot beak nose . Mandibular prognathism . Mild shortening of humerus and femora; . Face: Eyes: prominent eyes, hypertelorism, strabismus Midface hypoplasia Nose: beaked Hypoplastic maxilla w relative prognathism *Nl IQ, hands/feet* (*Think smart cousins!*) Test: Seq FGFR2 exons 8+10

Albright Hereditary Osteodystrophy *Imprinting*

*AD* --- de novo GNAS --- mtn on mat allele (normally pat imprinted) --- *LoF* (*GoF => McCune Albright*) If mat inherited => fully expressed disease: pseudoparahypothyroidism w hi PTH (nl thyroid production but insensitivity to thyroid) If pat inherited => partially expressed; no parathyroid resistance: pseudopseudoparahyperthyroidism Resistance to parathyroid hormone: hypocalemia → Seizures, cataracts, muscle twitching DD/ID Brachymetaphalangy of 3-5 digits Short 4th metacarpal Brachydactyly Short Obese Round face

Pfeiffer *FGFR related Craniosynostosis*

*AD* --- de novo (*APA* effect) *FGFR2* @ 10q26 (common) exon 8/10 *FGFR1* (5% of type 1) *FGFR3* (5% of type 1) GoF . ****CLOVERLEAF SKULL**** (coronal craniosynostosis), midface hypoplasia . Broad, short *MEDIALLY DEVIATED (angulated) THUMBS, BIG (great) TOES syndactyly* . Vision + hearing pob . DD/ID . Exorbitism . Hydrocephalus . Seizures . Choanal atresia Types: Type 1 - rare, mild, nl IQ, similar to Crouzon Type 2: common, severe, (associated w MCA + early demise) Type 3: common, severe, *nl skull* (associated MCA + early demise) Test: Seq FGFR2 exons 8+10 > FGFR1/3

Multiple Endocrine Neoplasia Type 2A (MEN2A) *Childhood Cancer*

*AD* --- de novo (<5% ) --- *APA* effect *RET* @ 10q11.2 ---*GoF proto-ONCOGENE* ---mtns in several codons encoding cysteine ---exon 10 & 11 (95%) ---*allelic heterogeneity:LoF->Hirschprung* . *MEDULLARY THYROID CA (MTC)* (95%): Early *adulthood* (vs. 2B) *c cell hyperplasia* (MEN2A - 20-50% of MTC + 80% of hereditary MTC) . ****PARATHYROID adenoma / hyperplasia (20-30%) (vs. 2B)***-> HYPERPARATHYROIDISM (10-20%) . *Benign PHEO (50%)* [BOARDZ] (= adrenal medulla = above adrenal gland) . Cutaneous lichen amyloidosis: orange-colored skin lesion (rare) Management: [BOARDZ] 1. *Prophylactic thyroidectomy <6y* 2. *Pheo & PTH screening annually >6y*

Pallister Hall

*AD* --- de novo (some) --- inherited (some) *GLI3* (*zinc finger*) @ 7p13 --- 2023delG --- 2012delG . ****POLYDACTYLY**** . *HYPOTHALAMIC HAMARTOMA* . Tracheal/*LARYNGEAL CLEFT* (*think hall for cleft*) . Bifid epiglottis (flap of cartilage at roof of tongue) . Imperforate anus

Thanatophoric Dysplasia *FGFR related Craniosynostosis*

*AD* ---de novo ---*APA effect* ---no gonadal mosaicism *FGFR3* @ 4p16.3 GoF Arg248Cys (50% of type I) Lys650Glu=K650E (type II) Prenatal US: detected as early as 12-14wk . Severe nasal flattening . Distorted facial shape bcs of craniocynostosis . Trident shaped hands (bracydactyly) Perinatal lethal: . ****CLOVERLEAF SKULL**** (type II) . Micromelia . Bowed limbs (femurs) (type I) . Narrow thoracic chest (thorax) . Short ribs . Underdeveloped lungs-> most die of respiratory insufficiency . Macrocephaly . Redundant skin folds along arms Test: Targeted mtn > seq => detects Type I & II (single point mtn for type II)

Stickler *Hearing loss*

*AD* ---inherited / denovo --- highly variable AR (rare) *COL11A*1 (*think col in french means stick*) COL11A2 (*Think: stickler has sticky shit in ears, eyes, joints that causes prob*) 1. Ear: progressive ****SNHL****, hyperbombile ear systems 2. Eye: *retinal detachment*, *CATARACT*, myopia, cataract 3. *Arthropathy* (joint disease): spondyloepiphiseal dysplasia, precocious (early-onset) arthritis, hypermobility 4. Dysmorphic face: ****PIERRE ROBIN SEQUENCE**** (*think S in Stickler for Sequence*) Cleft palate, bifid uvula, micrognathia Flat face w prominent eyes, depressed nasal bridge 5. Marfanoid: marfanoid body joint hypermobility retrognathia high-grade myopia retinal detachment MVP *Nl IQ* Genetic test (<100% DR)

Multiple Exostoses = Hereditary Multiple Osteochondroma *Cancer*

*AD* 10% de novo 96% penetrant *EXT*1 (*think EXosToses*) EXT2 Onset: childhood 1. *MULTIPLE EXOSTOSES* (*cartilage growths on bone*) 2. *Osteochondromas* (benign cartilage-capped bone tumors at growth plate of long bones + surface of flat bones) 3. *Sarcomatous degeneration* (~5%) of *osteochondroma to => *osteochondrosarcoma* w age (ca *risk<1%*) which can be *fatal ca* 4. Short, limb length discrepancy and/or bowed long bones 5. Knee + ankle deformities 6. Compression of nerves or blood vessels Tx: surgical resection, recurrence w incomplete removal; surgical tx of bowing, limblength discrepancy Test: Seq EXT1&2 (70% DR) > deldup for del (20% DR)

Vascular Ehlers Danlos syndrome (EDS) (Type IV)

*AD* (50%) --- 50% de novo *COL3A1* Major criteria: . *Thin, translucent skin* . *Arterial (iliac artery), intestinal (bowel) or uterine fragility/rupture=> 12% risk of death for pregnant women* Minor criteria: . Fragility of blood vessels (surgery difficult), aneurysm or dissection . Extensive bruising . Hypermobility of small joints . Dysmorphic face (thin lips and philtrum, small chin, thin nose, large eyes) . Acrogeria (aged hands) . Keratoconus (cone-shaped distortion of the cornea) . Tendon/muscle ruptur Talipes equinovarus . Early-onset varicose veins . Arteriovenous sinus fistula . Pneumothorax . Gingival recession . Positive fx hm =>Median age of death 48 *Neonates* can have: *Joint dislocations* *Club feet* Congenital hip dislocation Inguinal hernias Pneumothorax Test: *collagen III biochem* (95%) Genetic test: seq (98-99% DR)

Polycystic Kidney Disease (PKD) *Microdeletion*

*AD* - *PKD1* (85%), *PKD2* (15%, *milder*), 5-10% de novo *AR* - *PKDH1* (rare) *AD - most common* (1-2/1000), *adult onset* *Bil RENAL CYSTS* → 2+loci *Mitral valve prolapse* Hypertension Renal pain Hematuria Renal insufficiency ESRD (PKD1 younger average age of ESRD than PKD2) Extrarenal cysts incl liver, pancreas, seminal vesicles Abd wall hernias Intracranial hemorrhage *AR* *Neonatal period* w enlarged echogenic kidneys Hepatic fibrosis, diverticula *Heart valve defects* Aneurysms Dilated collecting ducts HTN Variable renal dysfunction (>50% will have ESRD <10y and require renal transplant) Pulmonary hypoplasia from oligo hepatobiliary disease => 30% of infants die in 1st year of life due to respiratory complications Test: Many private mtns -> difficult to interpret Other: up to 39y and no renal cysts, and 40y or older w only one renal cyst has a NPV of 100% ****TSC (tuberous sclerosis)+PKD1 microdel (CGD) => TSC+ADPKD**** [BOARDZ]

Neurofibromatosis type 2 (NF2) *Cancer* *Hearing loss*

*AD*, ****50% DENOVO**** NF2 (MERLIN) (30% *MOSAIC*) Truncating mutations cause severe disease Missense/large dels cause more mild disease Mosaicism in 30% of pt (Recurrence difficult) (if neg and 1st affected person in family-> most likely MOSAICISM! better to test younger generation. -95% have *BIL VESTIBULAR SCHWANNOMA or ACOUSTIC NEUROMAS* (*EARLY ADULTHOOD*)-> *HL* [BOARDZ] -*balance dysfunction* -*tinnitus* (ear ringing) -SPINAL tumors -SHWANNOMA -MENINGIOMA (intracranial, less commonly spinal, lethal) -GLIOMA -Juvenile cortical CATARACT (60-80%); Juvenile posterior subcapsular lenticular opacity=>Rarely progress to visually significant cataract -*neurofibroma* (not common) -Neuropathy (e.g. facial palsy=facial droop) -Headaches -Skin schwannomas (70%) -CALs Dx: clinical, rather w genetic test Genetic Test: 60% DR (90% DR if familial) seq+deldup on PB > testing *on tumor* Management: Annual MRI at 10-12 y Opthal Exam, Infancy, Every 12 months Neuro Exam, Infancy, Every 12 months Audio Exam, Infancy, Every 12 months Cranial MRI, 10-12, Every 12 months Spinal MRI, 10-12, Every 1-3 years How to differentiate NF2: HAS schwannomas, meningiomas, and ependymomas (unlike NF1) HAS bilateral vestibular schwannomas which can cause progressive hearing loss Schwannomatosis: HAS multiple noncutaneous schwannomas DOES NOT HAVE bilateral vestibular schwannomas Legius : HAS CALS and skin fold freckling CAN HAVE behavioral issues, macrocephaly, vascular findings DOES NOT HAVE neurofibromas (looks like NF1, but doesn't act like NF1)

Zellweger *Peroxisomal* *Metabolic*

*AR* *12 PEX genes* => locus heterogenetiy --- PEX1 (68%) Enz def: *peroxins* =>*Defect in peroxisomal beta oxidation biogenesis* Onset: *PRENATAL* *DYSMORPHIC FACE* ---Forehead: enlarged anterior fontanelle, tall forehead ---Eyes: upslanted and narrow palpebral fissures ---Flat face *GROWTH* - poor suck *EYES* - cataracts, optic atrophy, RP *HEART* - congenital heart disease *LIVER* - Hepatomegaly, jaundice, fibrosis, cirrhosis, Liver cysts and dysfunction *KIDNEY* - renal cortical cysts *CNS* - severe neonatal hypotonia and hyporeflexia, seizures, poor suck, severe psychomotor retardation, brain malformations (e.g. neuronal migration defects), FTT, Developmental stagnation, Growth restriction HL Chondrodysplasia punctata of patella, long bones Limb contractures, clubfeet Epiphyseal stippling bony stippling (chondrodysplasia punctata Often fatal in first year or life; survivors w seizures/ ID Zellweger (*most severe, die by 1y*!) . *Neonatal adrenoleukodystrophy* Infantile Refsum (least severe) . FTT, DD . Dysmorphic face . Hypotonia . Cerebral atrophy . Seizures . Brain cysts . Liver cysts -> liver disease Dx: *Hi VLCFA* [BOARDZ], Hi branched chain FA *Low RBC plasmalogens* Hi plasma pipicolic acid Hi bile acid PEX multigene panel Tx: supportive, symptomatic Avoid phytanic acid (cow's milk)

Very Long Chain Acyl CoA Dehydrogenase (VLCAD) Deficiency *Metabolic* *Fatty Acid Oxidation*

*AR* *ACADVL* (*think VL CAD becomes A CAD VL Enz def: *very long chain acyl-coA dehydrogenase* => *body cannot break down VLCAD fat into energy* Criteria: . *Cardiomyopathy*: ventricular hypertrophy in chidldhood . *HSP* . Hypotonia . Hyperreflexia . Body myopathy throughout adulthood Infant: . *Hypoketotic hypoglycemia* . Liver failure . Myopathy . Cardiomyopathy Child: . Cardiomyopathy Late: . Exercise myopathy Biochem: . Blood test --- Metabolic acidosis --- Liver dysfunction --- Mildly hi CPK --- Mildly hi ammonia --- Low carnitine Dx: . Acyl Carnitine: --- *Hi C14:1* --- *Hi longer chain acyl carnitines* . ACADVL genetic test Tx: . *Medium chain fat supplemental diet (allows production of ketones as energy source during fasting)* . *Avoid fasting w frequent feeding + IV dextrose when ill* . Supplement: --- Cornstarch --- MCT oil --- Carnitine --- *High carb/low fat diet*

Wilson *Metabolic*

*AR* *ATP7B* Enz def: *COPPER-transporting ATPase 2* (*think Wilson Won the lottery and got a bunch of copper nickles and got ****ed over*) 1. *KAYSER FLEISHER RING* (copper in cornea) 2. *Liver* disease: liver dysfunction, jaundice, hepatitis-like illness, chronic liver disease 3. *Neuro* disease: movement disorders or rigid dystonia 4. *Psych*: depression, personality changes, sometimes intellectual deterioration 5. *Heart* prob Onset: *teens* Dx . Biochem: --- *Hi urine & liver copper* --- Hi serum non-ceruloplasmin bound copper --- *Low serum copper (bcs deposited in tissues)* --- Low serum ceruloplasmin . ATP7B genetic test Tx: . *Copper + zing chelating agents (penacillamine)*, blocking copper absorption, decrease copper intake . *Induce detoxification (zinc salts)* . ****LIVER TRANSPLANT****

Biotinidase Deficiency *Hearing loss* *Metabolic* *Organic Acidemia*

*AR* *BTD* --- Enz def: biotinidase -> affects function of multiple enz: ------ converts biocytin -> biotin (holocarboxylase->biocytin-> *biotin (biotin = co-enzyme for VOMIT + leucine + glucose metabolism*) => *enz def => biotin def => organic acidemia (so technically not real organic academia)* *Nl @ birth* Criteria: . Gradual, remitting onset *HYPOTONIA* . *SEIZURES* . *HL* . DD, ID . Eczema rash . Alopecia W age: . Retinal pigments => vision loss . Ataxia . Spastic paresis . Limb weakness Prenatal dx: amnio for metabolites / enz activity *NBS: enz activity ~0% (not by regular NBS)* Dx test: . Biochem: --- Low plasma + urine biotin --- Low plasma + serum enz activity --- Hi lactate --- uOA ------ 3-B-OH-isovaleric acid ------ 3-OH-propionic ------ methylcitric ------ 3-OH-butyric acids ------ acetoacetate ------ propionyl glycine ------ tiglylglycine --- Acyl Carnitine Profile: Hi C3 and C5-OH acylcarnitine . BTD genetic test Tx: . *Biotin* (type of B vit in eggs, milk, bananas): oral diet + supplemental (10-100mg/day)=>very effective/*cure*!!! . Avoid raw egg whites *"late onset" type of multiple carboxylase deficiency*

Smith Lemli Optiz Syndrome (SLOS) *Metabolic* *Cholesterol synthesis* *Sexual Development*

*AR* *DHCR7* Enz def: *7-dehydrocholesterol reductase* (*defect in cholesterol biosynthesis: enz in final step of cholesterol production: converts 7-dehydrocholesterol into cholesterol→ mtn→ low cholesterol and elevated 7-dehydrocholesterol → low androgen production*) *Prenatal onset*!! Variable expressivity from mild to lifethreatening pre/postnatal growth: FTT *MICROCEPHALY* with frontal narrowing *CHD*: *HLHS*, ASD, PDA, VSD Abn male genitalia (hypogonadism, *AMBIGUOUS genitalia*, *HYPOSPADIAS*, micropenis, cryptorchidism) Postaxial *POLYDACTYLY*, *2-3 Y-shaped TOE SYNDACTYLY* *HYPOTONIA* *Holoprosencephaly* *Severe ID* Behavioral problems| Feeding problems Malformations of the lungs, kidney, GI tract Cleft palate Dysmorphoc face CLP GR GU anomalies (Esp. hypospadius) Face: Eyes: ptosis Ears: abn Nose: anteverted nares => can lead to *stillbirth* Prenatal screen: Quad: ****very low uE3**** US: *IUGR + ambiguous genitalia*!!! Prenatal dx: *Hi amniotic serum 7-DHC* Dx test: Biochem: --- hi serum 7-DHC (dehydrocholesterol) + 7-OH cholesterol --- low cholesterol levels DHCR7 genetic test (96% DR) Tx: Cholesterol supplementation Treat w stress related doses of steroids during illness Supportive care

Cockayne Syndrome (CS)

*AR* *Defect in nucleotide excision repair*!!! *ERCC*6 ERCC8 *UV sensitivity-> DNA damage w/ pyrimidine dimers in a strand*: 1. *PHOTOSENSITIVITY* 2 *PREMATURE/RAPID AGING*-> *INFANT DEATH* <3y 3. Failure to thrive-> *short* 4. Neuro degeneration: HL, *Eye abn*, microcephaly *NO SKIN CA unless microdel CS+Xeroderma Pigmentosum* Classic (type 1): early childhood Congenital (type 2): death by 7 skeletal issues Type 3: most mild sx, later in life Test : . DNA repair assay on fibroblasts (non-molecular) . Seq+deldup *XP/CS microdel*: Dwarfism Microcephaly Neuro abn Premature aging

Krabbe = Globoid Cell Leukodystrophy *Metabolic* *Leukodystrophy* *Lysosomal storage*

*AR* *GALC* --- 30 kb del (infantile) --- G857A allele (late onset) Enz def: *B-galactocerebrosidase* *Lysosomal leukodystrophy* (demyelinating disease) *Infections (gram-negative sepsis)* => Stage I: irritability, spasticity, FTT, developmental arrest Stage II: neurodegeneration, hypertonia, neuropathy, seizures, optic atrophy Stage III: Blindness, deafness, unaware Infantile form: Onset < 6mos-1y ****IRRITABILE**** *"FEELING KRAPPY"* muscle weakness feeding problems fever without infection stiff posture DD seizures vision loss → death <13 mo-2y Atypical form (late onset): 6 mos-5th decade weakness vision loss intellectual regression *On NBS: Cannot predict prognosis bcs of variability of dx* Dx: *Enz activity* in blood / fibroblast: Low / none (for *AFFECTED*- not reliable carriers!) 30 kb del (if infantile) > seq > deldup (for affected + carriers) White matter disease on neuroimaging for infantile form Pathology: nervous system Tx: Preventative: *BMT in presymptomatic infants* Symptomatic: maximizing/prolonging function while minimizing discomfort/suffering

Alpha Thalassemia

*AR* *HBA1*, *HBA2* @ 16pter-p13.3 ****DEL (90%)**** 10% point mtns Mtn causes quantitative change in hemoglobin Mtns can be cis / trans (*Asians: ++/--, Africans: +-/+-*) *HbConstant Spring (HbCS, c.427T>C) - common missense mtn of the termination codon of HBA2* Carrier rates: Mediteranean 1/30-1/50 trans AA 1/30 trans Carribean, west indean 1/30 (trans) West african 1/30 (trans) Asian 1/20 cis SE asian >1/20 (*cis) Silent carrier: -a/aa - usually nl pheno CBC: *MCV slightly decreased* *MCH slightly decreased* *Hgb (amount of Hb) slightly decreased* *Hem elec: nl* HbA 96-98% HbF <1% HbA2 <3.5% Carrier: A-thal trait (2 working copies)(alpha thal minor): --/aa or -a/-a CBC: *MCV: 68-84 (low)* *MCH: 21-24 (low)* *Hgb (amount of Hb): slightly low (minor anemia)* Hemelec: nl *nl % HbA2, Hb F! (vs. beta thal trait)* HbA 96-98% HbF <1% HbA2 <3.5% mild microcystic hypochromic hemolytic anemia plenomegaly mild jaundice skeletal changes HB H: --/a- CBC: *Low MCV 57 (kids), 61 (adults)* *Low MCH 16-20* *Low Hgb: 8-12* Hemelec: *HbA 60-90%* *HbF <1%* *HbA2 <2%* *HbBart 2-5%* *HbH 1-40%* -mild to moderate microcytic hypochromic hemolytic anemia -mild jaundice -herpatosplenomegaly -thalassemia-like bone changes: Overgrowth of upper jaw and prominent forehead -live into adulthood Tx -Avoid sulfonamides, antimalarias (to prevent hemolysis) -Monitor for hemolysis during fever -Folate suppl'n -Intrauterine blood transfusion if needed during pregnancy -Rarely: BMT Hb Bart (0 working copy) = hydrops fetalis --/-- (*SE Asia ONLY!!!*) Alpha thal presents in utero (non-immune fetal hydrops) bcs alpha globin production occurs prenatally US 13-14 wk: Increased NT, thickened placenta, increased cerebral media artery velocity, increased cardio-thoracic ratio US 22-28 wk: hydrocephalus, generalized edema, ascites, pleural and pericardial effusions Pregnancy of affected fetus Preeclampsia Premature delivery Abn bleeding NBS: Hb Bart >15% at birth Newborn: Severe anemia Hepatosplenomegaly in fetus Diffuse edema CHD->Heart failure GU anomalies => Neonatal death CBC: Very hi MCV: >130 Nl MCH: 23-40 Very low Hgb: 3-8 Hem elec: Hb Bart only (no F, A, etc.) Labs: Microcytic hypochromic anemia in absence of ABO / Rh incompatibility Reticulocytosis Peripheral blood smear w anisopoikilocytosis and rare large hypochromic nucleated RBCs RBC supravital stain showing HbH inclusions Tx: RBC transfusions may be needed during hemolytic crisis w chelation therapy

Beta Thalassemia

*AR* *HBB = beta globin* @ 11p15.5: hemoglobin made up of 2 α-globin proteins + 2 β-globin proteins => reduce amount of beta globin and therefore hemoglobin (quantitative change) . Genetic heterogeneity - *15 mtn (90%) ---*missense, nonsense, frameshift* (often) ---del (rare) --- Some are promoter mtns --- Rare cases w nonsense mtn in third (which is last) exon-> shorter, non-functional protein -> Interferes w assembly of full-length β-globin + α-globin chains-> severe, anemia Carrier freq (ACMG) *Mediteranean - 1/20-1/30* (1/25) (Sardinia, Italy, Cyprus, Greece) Hispanic - 1/30-1/50 (1/40) *SE asian - 1/30* (~3%) Asian subcontinent (India, Pakistan) - 1/30 - 1/50 Black 1/65 Middle east 1/50 Freq of affected has decreased by 95% w carrier screening Major: *NL @ BIRTH* Onset: *6-12 mo* (dx <2y) *Less severe than alpha thal bcs there are other beta-like chains* Infant: Present few months after birth, bcs production of beta globin occurs after birth (gamma globin production occurs prenatally and stops within few mos of birth: *gamma to beta-globin switch is not complete until several mos after birth*) severe microcystic hypochromic hemolytic anemia postnatally pallor jaundice irritability FTT hepatosplenomegaly Iron overload by 10y Adult: Severe anemia w Heinz bodies Bone marrow hypoplasia Splenomegaly Growth retardation Skeletal changes Cardiac failure =>Death if untx CBC: *MCV: 50-70 (decreased)* *MCH: 12-20 (decreased)* *Hgb (amount of Hb): <7 (decreased)* Hemelec: *reduced HbA* *increased HbA2 and Hb F* Beta thal intermedia: clinical dx Onset: 2-7y Anemia Splenomegaly Moderate to severe hepatomegaly Bony changes Delayed puberty Thin, normal height At risk for iron overload due to increased intestinal absorption of excess iron from ineffective hematopoiesis Rarely need transfusion Hem elec: Increased Hb A2 (>4%) Increased Hb F (10-50%) beta-thal-0: beta-not: complete absence of beta globin genes; increased gamma globin chains Hem elec HbF 95-98% HbA2 2-5% HbA 0 beta-thal-+: beta-plus: variable reduction in beta globin chains: pheno: mild to severe Hem elec HbA2 2-5% HbA 10-30% HbF 70-90% beta-thal-minor/hets (carrier): Asymptomatic / mildly anemic CBC MCV <79 (reduced) MCH <27 (reduced) Hb <7 Hgb (amount of Hb) 14-15 minor RBC morphological changes Hemelec HbA 92-95% (reduced) HbF 0.5-4% (sometimes increased) HbA2 >3.5%** (increased) HbE: thalassemic structural beta chain variant that activates cryptic RNA splice site Hb E/beta-thal => severe, but can be mild or asymptoamtic HbE/HbE => unaffected HbFH/alpha-thal trait => make beta thal milder Genetic test: Not routinely performed, but may help to make dx Tx . *BMT* . Periodic RBC transfusions to maintain Hb at 100g/L by 1-2 yr -> iron overload and organ loading -> cardiac complications (account for 71% of deaths in thalassemia major) => secondary Fe chelation therapy: new forms of oral chelation, e.g. Deferasirox (Tridentate iron chelator) -> to reduce iron overload -> to prevent growth retard'n -> to prevent failure of sexual matur'n -> highly specific in targeting iron =>life expectancy at onset of heart failure 3 mos w/out chelation . Hb F stimulation

Familial Dysautonomia = Sensory Autonomic Neuropathy III = Riley Day *AJ*

*AR* *IKBKAP* *AJ* . *Carrier freq 1/31* . Founder mtns: *splicing mtn* --- *IVS20(+6→C) = 2507+6T→C* (99%) --- R696P (1%) *Almost exclusively in AJ* Criteria: . *SENSES DEFECT*: taste/perception/heat/cold-> autonomic neuropathy - less sensitivity to pain, temp => *POOR BODY TEMP MAINTENANCE*, absent fungiform sweating . *NO TEARS* . *LUNG INFECTIONS* . Poor blood pressure regulation . Progressive neuro degeneration=> hypotonia, no balance . DD, nl IQ . Recur pneumonia, vomiting, GI prob, Feeding prob . Poor growth . Scoliosis . Arrhythmia => cardiovascular instability, sleep apnea . Renal failure . Lung prob => Childhood death: lifespan 15y (60% reach 20y) Test: AJ mtns (99% DR)

Propionic Acidemia (PA) *Metabolic* *Organic Acidemia*

*AR* *PCC* Enz def: *propionyl-CoA Carboxylase (helps convert fats to sugars)* Pathway: ****VOMIT**** VOMIT AA V aline O dd chain FA M ethionine I soleucine T hreonine -> convert into -> Propionyl-CoA -> XXX Methylmalonyl-CoA -> Succinyl-CoA -> enters Krebs cycle -> energy metabolism Propionyl-CoA ends up converting to propionic acid-> toxic Nl @ birth Poor feeding, lethargy, vomiting, hypotonia Encephalopathy, seizures, coma, death Renal failure BM supression Basal ganglia infarcts ('metabolic strokes') Neutropenia -> predisposition to infection Later may present w pancreatitis, cardiomyopathy Dx: Hypoketotic hypoglycemia Acidosis pAA: Nonspecific elevation of and glutamine uOA: elevated 3-OH propionate (Propionic acid), methylcitrate (methylcitric acid), triglycine, propargylglycine, propionyl glycine Acyl-carnitine: elevated C3 acylcarnitine PCC genetic test Tx: Acute: hemodialysis, protein restriction, IV glucose/lipids, IV carnitine, IV ammonia scavengers, antibiotics, biotin Chronic: protein restriction + MTVi-free metabolic formulas; oral L-carnitine Reduce endogenous production of toxic compounds (antibiotics in propionic acidemia to clear the gut of propionate-producing bacteria) Liver transplant *NOT responsive to cofactor biotin*

Walker Warburg = Syndromic Congenital Muscular Dystrophy = Fukuyama, muscle-eye-brain = Congenital muscular dystrophy 1D *Muscular dystrophy*

*AR* *POMT1* (*think need a pomp to be alive*) Onset: *neonatal* . *Most SEVERE MUSCULAR DYSTROPHY* (*think need a "Walker bcs cannot WALK*!)-variable pogressive generalized hypotonia, elbow contractures; hi CK->INFANT DEATH (<3y) . *COBBLESTONE COMPLEX* enlarged lateral ventricles, SEVERE Type 2 *LISSENCEPHALY* (agyria), *CEREBELLAR HYPOPLASIA*, *DANDY WALKER cyst*, flat brainstem, polymicrogyria, hydrocephalus, encephalocele (other); seizure . Eye: *RETINAL DETACHMENT W DYSPLASIA*, infant glaucoma, microopthalmia . *MICROPHTHALMIA* (small eyes) Other criteria: *Enlarged lateral ventricles* => death by 10 d to 1-3 y (early infancy) Test (non-molecular): *High CK*

5 Alpha Reductase Deficiency (5-ARD) *Disorders of Sexual Development*

*AR* *SRD5A2* *46, XY* Enz def: *5-alpha-reductase -> converts testosterone to dihydrotestosterone (DHT) -> needed for external genitalia to masculinize + male sexual dev* => *Ambiguous / female external genitalia* *Internal testes* *"PENIS AT 12"*: masculinizing puberty (surge of testosterone during puberty-> develop penis+scrotum at 12y) Sparse facial/body hair Fertility tx: need ART

Methylmalonic Acidemia *Metabolic* *Organic Acidemia*

*AR* . *MUT* . *MMA*A . MMAB . MMADHC . MMEE Enz def: --- *Methylmalonyl-CoA mutase* --- Cobalamin --- Methylmalonyl-CoA epimerase ****Pathway: VOMIT**** Criteria: *Nl @ birth . Poor feeding, lethargy, vomiting, hypotonia . Bone marrow suppession=> neutropenia => recurr infection . Globus pallidus abn . Encephalopathy => seizures, coma, death Later on: . Pancreatitis . Progressive renal disease . Stroke-like episodes (metabolic strokes): basal ganglia infarcts . Cardiomyopathy Dx: -Biochem: . Hypoketotic hypoglycemia . Acidosis . uOA --- *Hi Methylmalonic acid (MMA)* + metabolites: ------ Propionic acid ------ 3-OH propionic acid (propionate) ------ Methylcitrate ------ Triglycine ------ Ropargylglycine . pAA --- Non specific hi glycine + alanine . Acylcarnitine profile: Hi C3 acylcarnitine - Brain MRI: . Bil infarcts (stroke-like episodes) of thalamus + basal ganglia - Multigene panel Tx: . Acute: --- Hemodialysis --- No protein --- IV glucose/lipids --- IV carnitine --- IV ammonia scavengers --- Antibiotics --- B12 injections Chronic: --- Diet: No AA (protein) --- MTVi-free metabolic formulas --- Oral L-carnitine --- Supplement B12 cofactor (cobalamin) --- Antibiotics --- Liver transplant

Sanfilippo = Mucopolysaccharidosis type III (MPS III) *Metabolic* *Lysosomal Storage*

*AR* 4 enz def (2 more common) involved in *degradation of heparan sulfate* (*think S for Sulfate*): 1. GNS: heparan-N sulfatase 2. HGSNAT: heparan-alpha-glucosaminide N-acetyltransferase 3. NAGLU: alpha-N-acetylglucosaminidase 4. SGSH: sulfamidase *GAG accumulates: heparan sulfate* Onset: 2-6 y (early childhood) CNS disease: behavior changes, cognitive plateau and progressive neurodegeneration ---*ADHD* ---*Aggression* ---Speech delay ---Autism ---DD Face: ---Mildly coarse face ---Coarse hair Insomnia Mild HSM Mild joint stiffness / diarrhea *No skeletal dysplasia, corneal clouding, cardiac prob => teen death (<20y) Dx: MPS spot +/- Enz assay *Urine GAG: hi heparan sulfate* (no dermatan sulfate in the urine) GNS, HGSNAT, NAGLU, SGSH genetic test Tx: None (no cure; symptomatic) Substrate reduction (in trials)

Maroteaux Lamy = Mucopolysaccharidosis type VI (MPS VI) *Metabolic*

*AR* ARSB Enz def: N-acetylgalactosamine-4-sulfatase = arylsulfatase B Substance Stored (GAG): Dermatan sulfate Onset: birth w/ macrocephaly and chest wall anomalies Decelerated growth after 1 y Skeletal: Short in mid-childhood, claw hands, joint restriction, dysostosis multiplex, spinal cord compression Progressive: Face: sometimes coarse, corneal opacities Hernias Carpal tunnel HSM Cardiac valve disease Dysostosis multiplex *Nl IQ => Death in teens (severe cases) Dx: Urine GAG: elevated dermatan sulfate Arylsulfatase B enzyme activity ARSB genetic test Tx: ERT: Galsulfase

CPT2 and CACT Deficiency *Fatty Acid Oxidation*

*AR* CPT2 CACT Enz def: carnitine palmitoyl transferase II carnitine acylcarnitine translocase *Myoglobinuria* & *hi serum creatine kinase (CK) after prolonged exercise, exposure to cold, or other stress* In utero: Dysmorphic features Renal disease or cysts Neonatal: Hypoketotic hypoglycemia Liver failure CM Late: exercise induced myopathy Dx: Acyl carnitine: hi C16 and/or C18 CPT2, CACT genetic test Tx: Avoid fasting w frequent feeding and IV dextrose when ill Supplement: cornstarch, MCT oil, carnitine, high carb/low fat diet

MPS type IV = Morquio *Metabolic* *Lysosomal*

*AR* GALNS, GLB1 (MPS) Enz def: N-acetylgalctosamine-6-sulfatase / B-galactosidase Substance stored (GAG): *keratan sulfate&, chondroitin-6-sulfate Onset: 1-3 y Skeletal: *Short trunk dwarfism* Spinal stenosis Ligamentous laxity Dysostosis multiplex Cervical spine compression Atlantoaxial instability (compression of spinal cord - weakness) Dislocation of hips Chest, joint abn => Abn gait Non-Skeletal: *Corneal clouding* Valvular heart disease HL Restrictive lung disease=> Respiratory insufficiency Dental abnormalities Sleep apnea Ligamentous laxity Arthritis Face: macrocephaly, coarse facial features *nl IQ* Dx: Urine GAG: elevated keratin and chondroitin-6-sulfate N-acetylgalactosamine-6-sulfatase enzyme activity Radiographic Findings: anterior beaking of vertebral bodies GALNS genetic test Tx: no established tx ERT: Elosulfase alfa: ERT experimental Also: C-spine fusion, PT/OT, annual cardio, lung, eye, genetics eval

Nonketotic Hyperglycemia (NKH) *Metabolic* *Amino Acid*

*AR* GLDC, AMT, GCSH Enz def: *glycine cleavage system* 4 components to system => NH4, CO2, etc* defect => *hi glycine* Nl @ birth 1. *Neonatal hypotonia* 2. *Intractable neonatal seizures, encephalopathy* 3. Apnea 4. Hiccups 5. Burst suppression EEG 6. PFLCSz Dx: Lumbar puncture + pAA Analysis (respiratory acidosis): abn CSF to plasma glycine ratio (hi gly csf - v. high gly) MRI: elevated glycine peak in brain; severe white matter changes GLDC, AMT, GCSH genetic testing Tx: *Sodium benzoate* NMDA channel blockers *Dextromethorphan*

Maple Syrup Urine Disease (MSUD) *Metabolic* *Organic Acidemia* *Amino Acid*

*AR* Many genes: *BCKDH*A BCKDHB DBT Enz def: *branch chain keto-acid dehydrogenase* Pathway - defect in second step in *breakdown of branched AA*: *leucine* (main toxin) *isoleucine* *valine* *Nl @ birth* Criteria: *Maple syrup odor in urine + EAR WAX (if untx)*! Poor feeding Vomiting Lethargy Progressive irritability Encephalopathy White matter changes Cerebral edema Coma Seizures Respiratory failure High mat leucine => teratogen ****NBS - tandem mass spec: Hi leucine**** Dx [BOARDZ] Biochem: *pAA - hi BCAA: lue, ile, val, alloisoleucine; low ala* *uOA - hi branch chain keto acids (ketosis) & hydroxyacids* *NO acidosis* Genetic: *seq+deldup* Tx: - acute/severe: restrict branch chain AA (no LEU, ILE, VAL) may require hemodialysis/hemofiltration -chronic: diet restriction of branch chain aa, avoid deficiency of isoleucine + valine => supplement isoleucine + valine (formulas w ile/val an BCAA free) Supplement thiamine cofactor

Oculocutaneous Albanism = Tyrosinase negative

*AR* Melanin production defect: *TYR* => *TYROSINASE* enz: melanocytes -> melanin (if defect -> nomelanin) (type 1) OCA2 (type 2) TYRP1 (type 3) MATP = SLC45A2 (type 4) Type 1 . Caucasian . Criteria: Pigment does not develop=> --- White hair --- Very pale skin --- Light blue/pink irides --- Severe photophobia (light sensitivity) --- Poor visual acuity Type 2 . African . Criteria: less severe, most prevalent --- Light-blond / yellow / light-brown hair --- Pale creamy white skin with nevi --- Light eyes --- Poor visual acuity Type 3 . South African , pts w darker skin . Criteria: --- No vision abn --- Reddish-brown skin --- Ginger / red hair --- Hazel / light brown irises Type 4 Asian . Criteria: same as type 2, less severe --- Creamy white skin --- Light-blonde / yellow / light-brown hair *Nl lifespan, nl fertility* Test: Suspected gene seq + deldup Tx: . Skin ca-> sun protective clothes . Eyes: Dark, corrective lenses or surgery if severe

Achondrogenesis

*AR* *AD* Type IB: *HITCHHIKER THUMBS* Types IA, IB, II: Prenatal US: . *Undermineralized bones* . Micromelia . Flattened nasal bone *Nl face shape* *Similar to OI*

SCAD Deficiency *Organic Acidemia* *Metabolic*

*AR* --- *Incomplete penetrance (most nl)* *ACADS* Enz def: short chain acyl-coA dehydrogenase *Later onset & only starts after an acute crisis!* Dx: *Acyl Carnitine: Hi C4* ACADS genetic test ****NBS - tandem mass spec**** Tx: Avoid fasting w frequent high-carb feeding and IV dextrose when ill

Familial Mediterranean Fever (FMF) *Metabolic*

*AR* AD (rare) *MEFV-> encodes pyrin* = marenostrin (*in WBC*): help regulate inflammation in immune system Type 1: . *Recurrent short episodes of inflammation* w chest/abd pain, fever, arthritis for 2-3d . *Amyloidosis -> renal failure* Type 2: Nl then amyloidosis Dx: clinical Hi erythrocyte sedimentation rate (ESR) Hi leukocytosis Hi serum fibrinogen Genetic test: . MEFV (90% DR) --- Targeted mtn analysis for Med/Middle Eastern

Glutaric Acidemia = Glutaric Acidemia type I *Metabolic* *Organic* *Mitochondrial*

*AR* *GCDH* Enz def: *glutaryl-CoA dehydrogenase* (*mt enz* involved in *metabolism of lysine, hydroxylysine and tryptophan*) Pathway: Lysine, hydroxylysine, tryptophan Criteria: Nl @ birth (or just microcephaly) => neurologic decompensation: *Macrocephaly* due to accumulation of fluid at frontal + temporal lobes even before symptom starts Acute *encephalopathy*: basal ganglia injury -> ataxia epilepsy myoclonus extrapyramidal symptoms stroke-like episodes -> followed by *choreoathetosis (involuntary movements)*, dystonia Dx Metabolic acidosis: *high ammonia during episode* (otherwise, no ketosis, no acidosis) pAA: nl uOA: w / without 3-OH glutaric acid + glutaric acid Blood Acyl Carnitine Profile: w / without elevated C5-DC acylcarnitine. *Glutarylcarnitine suggests possible dx of glutaric acidemia types I or II (obtain when patient sick)* CT/MRI: cerebellar and cerebral (frontal lobe) atrophy + basal ganglia infarct and hemorrhage GCDH genetic test Type I: Macrocephaly Fluid collections pre-frontal and temporale lobes "Metabolic stroke-like features" Type II: caused by disturbed mitochondrial beta oxidation (mitochondrial electron transport flavoprotein) or multiple acyl-CoA dehydrogenase mtn Prenatal onset! Malformations Renal cysts Tx Crisis --- fluids --- glucose --- carinitie Chronic ---riboflavin ---dietary restriction of Lysine and tryptophan --- Lys/Trp-free formula --- riboflavin B2 cofactor --- carnitine

Sickle Cell Anemia

*AR* *HBB* on 11p15.5 (*abn hemoglobin structure*) Usually *POINT* mtn: *GAG -> GUG*: ****MISSENSE**** mtn ****Glu6Val**** [BOARDZ] (most common) 60-70% S/S variant 30% S/___ other variant: S/C, S/beta thal, etc Carrier freq: African Am 1/12 Non-hispanic carribbean, west indean 1/12 (1/9) West african 1/6 Med 1/40 Mexican: low 1/67-1/104-carrier screening not indicated (recommended for hispanics if carribean ancestry) HbC carrier freq African Am: 1/50 Non-Hispanic Caribbean, W. Indian: 1/30 West african 1/25 Criteria: First manifestation is dactylitis (digit inflammation) Hemolytic anemia (by 4-5 mo, normocytic, normochromic) Painful abd and bone aplastic crises, especially due to hypoxia Delayed growth Acute pain Vaso-occlusive disease (50% by 1y, most by 6y) ---painful bone/joint crises (ER complaint) ---pulmonary crises (50%, hospital admission) ---painful abdominal crises Infarcts of internal organs and joints=> organ damage Fever Infection (most common compl'n, prevent with penicillin prophylaxis early on) Other: cardiac, CNS, pripaism, ocular disease renal prob Hem elec: costs less than DNA analysis for screening in high-risk populations, but need RBCs Presence of HbS, HbC, HbE Hb SS MCH: nl Hgb: moderately decreased (anemia) Hb: HbA2 <3.5% HbS 80-90% HbF 2-20% S-trait MCV: nl MCH: nl Hgb: nl Hb: HbA 60% (reduced) HbS 34-42% HbF <1% HbA2 1-2% Hb SC - milder than Hb SS, but can be as severe MCV: nl MCH; nl Hgb: mod decreased (anemia) Hb: HbA2 <3.5% HbS 45-55% HbC 45-55% HbF 1-8% C-trait: MCV: nl MCH: nl Hgb: nl Hb: HbA 50-60% (reduced) HbC 40-50% HbF 1% Tx Crises: oxygen, IV fluids, pain killers Long Term: chronic RBC transfusion to keep HbS <30% Surgeries Hydroxynurea to induce HbF Penicllin prophylaxis Vaccination Oral hydration Folate supplements Avoid hypoxia/exhaustion/temp extremes

Constitutional Mismatch Repair (C-MMR) deficiency (CMMRD) = Homozygous MMR *Childhood cancer*

*AR* LYNCH GENES: *MLH1* ****MSH2* (incl *methylation due to EPCAM del*)*** [BOARDZ - REMEMBER EPCAM] *MSH6**PMS2* *Lynch+BBE+NF* 1. *Childhood ca*: . *Lynch ca* (childhood CC), duodenal ca . *Brain ca* <18 (childhood) . *Blood ca*: leukemia or lymphoma . *Embryonic tumors* 2. *NF1-like*: . CAL spots . Hypopigmented skin lesions . Skinfold freckling . Lisch nodules . Neurofibromas . Tibial pseudoarthosis (rare) Genetic test: seq

Bloom *Cancer* *AJ* *Breakage*

*AR* (*carriers at-risk for CC*) *Nucleotide excision repair defect* *BLM* @ 15q26.1 *AJ* --- *Carrier freq: 1%* (1/107) --- *Founder mtn: 2281del6ins7* (>99% DR) Criteria: . Short . ****ABNL FAT DISTRIBUTION**** . *MICROCEPHALY* . *PORPORTIONATE IUGR* . Skin --- Sun-induced *BUTTERFLY FACE RASH* of reddened skin across nose + cheeks / other body parts --- Telangiectasias on rash --- CAL + hypo/hyperpigmentation . Ca: (av. age of dx 26) --- *LEUKIEMIA*, *LYMPHOMA* --- Wilms tumor --- Br ca --- Cervix --- CC --- Esophagus --- Skin --- Larynx --- Lung --- Stomach Other criteria: . LD w *NL IQ* . High-pitched voice . Diabetes . COPD . Mild immune def --- Recur infection of upper respiratory tract, ears, lungs . Imfertility --- Male: infertility --- Females: ------ Reduced fertility ------ Earlier menopause Dysmorphic face --- Long, narrow face --- Small jaw --- Prominent nose + ears --- Malar hypoplasia --- Dolichocephalic skull Life expectancy 40y Dx . *Ch breakage/instability studies & increased rate of sister chromatid exchange (SCE)* = hyper-recombination . BLM AJ founder mtn / seq+deldup Tx: . *BMT* . *Avoid UV/sun, x-ray* . For growth: supplemental feedings . Diabetes: treated normally . Ca: sensitivity to ionizing radiation + DNA damaging chemicals; use lower dose

Ataxia Telangiectasia (AT) *Cancer*

*AR* (*think AT AR*) ---- *incomplete dominance* (carriers-> *br + lung ca*: F carriers 2x *br ca* risk) *Ch breakage*: double strand break repair (cell cycle checkpoint regulator): loss of signal that double strand breaks are present + need repair *ATM* @ 11q22.3 ------ null mtn (often) ------ del (rare) *Amish founder mtn* Onset: 1-4 y (childhood) → *wheelchair by 10 y* Neuro criteria: . *Progressive cerebellar ataxia* . Eye: --- *Oculomotor apraxia* (>3y): difficulty moving eyes side-to-side, may turn head instead --- Vision prob . Choreoathetosis: chorea (irregular migrating contractions)+ athetosis (twisting+writhing) . Dystonia Other criteria: . *Immunodeficiency => recur infection* . Telangiectasias: of conjuctivae + scleral vessles . Endocrine dysf . Inc radiation sensitivity . Vitiligo . Premature greying + aging . Slurred speech . CAL . Ca (30-40%) --- Leukemia + NHL (often) --- Br --- Medulloblastoma --- Glioma --- Gastric --- Uterine *Nl IQ* Dx: . *Immunoglobin/immunoblotting test for ATM protein (more sensivite than genetic test)*: intracellular *ATM protein depleted* --- *Hi serum AFP (in >95%)* . Radiation sensitivity . 7;14 transl . MRI - dystrophic cerebellum . *Seq > rarely, look for dels (95% DR)* Management: *Avoid radiation exposure* Tx: None

Antley Bixler = Trapezoidocephaly synostosis = POR deficiency *Craniosynostosis* *Steroid*

*AR* (*think Andy was dating Simone both carriers*) (maybe AD too) . *POR* @ 7q11.2 (*think POOR Andy was dumped by Simone*) --- Enz def: *Cytochrome* P450 Oxidoreductase --- *biallelic mtns in POR => Antley Bixler + urogenital abn . *FGFR2* highly variable range of allelic disorders of *STEROID GENESIS* . *CRANIOSYNOSTOSIS* . *BRACHYCEPHALY* = prominent forehead, frontal bossing . *Fusion of adjacent bones*-> *RADIOHUMERAL/RADIOULNAR SYNOSTOSIS* . *INFANT DEATH* . Dysmorphic face --- midface hypoplasia --- proptosis --- lowset dysplastic ears --- hydrocephaly . Choanal stenosis / atresia . Arthrogryposis . Stenotic auditory canals . Endocrine: --- *Ambiguous genitalia (both sexes)* --- Cortisol deficiency --- Mat virilization in pregnancy w affected fetus . Join contractures . Bowing of thighs, long bones . Neonatal fractions . Arachnodactyly . Renal abn . HL . CHD . ID Prenatal test: --- *Low uE3 on Quad* *NBS* Dx: . Urine + blood Sseroid: --- Hi ------ Pregnenolone ------ Progesterone ------ 17-OH-pregnenolone ------ 17-OH-progesterone . *POR genetic test + FGFR2 seq* Tx . Adrenal corticosteroids . Cortisol replacement

Pyruvate Carboxylase Deficiency *Mitochondrial*

*AR* (*vs. PDHC XLD*) -severe lactic acidosis -hi ammonia -nl lactatse/pyruvate ratio -hi citrulline -hi lysine -nl glecemia *Similar to PDHC def*

Meckel Gruber = Meckel *Ciliopathy* *Metabolic*

*AR* (like AR PKD) *>8 genes: MKS* genes Onset: ****prenatal dx by US**** (*think ate too many burgers that you got round burgers in kidneys and brain and grew extra fingers then died*) 1. ****POLYCYSTIC KIDNEY**** [BOARDZ] 2. Occipital ****ENCEPHALOCELE**** (NTD IN BRAIN) 3. *Postaxial POLYDACTYLY* (not unique to this dx) Other criteria: *LIVER FIBROSIS* Potter-like facies Short webbed neck Dandy-walker malformation Arnold-chiari abn => *perinatal death*

Diastrophic Dysplasia

*AR* (unlike other skeletal dysplasia!) SLC26A2 = DTDST @ 5q32-q33.1 5 common mtn: R279W IVS1+2T>C delV340 R178X C653S 1. Short w short limbs 2. Spinal abn 3. *HITCHHIKER THUMB* 4. *CONTRACTURES of large joints* 5. Club feet 6. Dislocation of radius 7. *CYSTIC EARS = ear cysts = cauliflower ears = swelling in NEONATE* 8. Cleft palate 9. Early onset osteoarthritis *Nl IQ & nl skull Test: . Targeted mtn (65% DR) > seq (>90% DR) > sulfate transporter mtn . Biochem test on skin fibroblasts . X rays Dx on prenatal US

Alpha 1 Antitrypsin Deficiency

*AR/codominant*: M, S, X alleles *SERPINA* @ 14 (*think trip Sin for ser pina*) Enz def: *alpha1 antitrypsin produced in liver: inhibitor of neutrophil elastase-> normally coats lungs to protect against damage* Criteria: *COPD* Shortness of breath w mild activity Reduced ability to exercise Wheezing worse w smoking Pulmonary emphysema (hets and homozygotes) Hepatocellular ca Jaundice Hepatic cirrhosis (homozygotes) ZZ => disease SZ => emphysema MZ => impaired liver & lung function Test: *Low serum protein AAT* & functionally deficient AAT protein by protease inhibitor type Dx by electrophoresis . M allele normal - 95% of whites . Z allele very reduced (glu342lys) - 10-15% activity, impaired release from hepatocyts (liver toxicity) --- protein has multiple N-linked glycosylation sites (contribute to heterogeneity of bands on IEF) --- Z allele likely had a single origin ------ null alleles - only lung disease, no liver disease . S allele reduced Genetic test: SERPINA biallelic mtn Tx *Liver transplant* No smoking Antioxidant Alpha-1-at augmentation

XXY = Klinefelter

*As common as XYY* Sporadic - *Extra X*: nondisj --- ****Pat (45%)****→ m I --- Mat (55%)→ m I, II *RR 1%* Criteria: . *HYPOGONADS*: small testes that don't produce enough testosterone, sperm [BOARDZ] . *MICROPENIS* . *TALL* [BOARDZ] . *LD, delayed speech / language development* [BOARDZ] . Gynecomastia . Less body hair . Infertility (most common cause of nonobstructive azoospermia) . Cryptorchidism . Hypospadias . Br ca . Systemic lupus erythematosus . Behavior prob . Personality: --- Quiet --- Sensitive --- Unassertive Dx Karyotype Tx: Testosterone for sexual dev

Codeine

*Codeine while breastfeeding* Genetics: *ultrarapid metabolizers of cytochrome (CYP2D6) are at higher risk* 1/100-28/100 in population ****If mom UM CYP2D6****: -> Newborn exposed to toxic doses of morphine Complications in baby: excessive *sleepiness* *feeding and respiratory difficulties*

Hidrotic Ectodermal Dysplasia = Clouston

*Common in French Canadian* AD --- 100% penetrant GJB6 --- 4 common mtn (~100% DR) . SKIN --- *SWEAT* --- Palmoplantar hyperkeratosis = thick skin on palms of hands/feet soles --- Hyperpigments . HAIR --- Sparse/absent --- Broken . NAILS dystrophy --- Thick --- Misshapen . Clubbed fingers

WAGR *Microdeletion* *Cancer*

*De novo (sporadic)* *11p13-* (*think 1 for W*) --- *PAX6: eye findings* --- *WT1: Wilms tumor* W *WILMS* tumor! (40-50%) A *ANIRIDIA* (reduced visual acuity, photophobia), cataracts, glaucoma G *GU* abn (M >> F) --- M: cryptorchidism --- F: streak gonad, bicornate uterus R *RETARDED* --- ID --- Psych prob --- Behavioral prob Other features: . *Obese (WAGRO)* . Pancreatitis . Renal failure Dx test: FISH 11p13 / array Management: . *Monitor for Wilm's tumor in childhood*

Supernumary Chromosome = Marker Chromosome

*If found on CVS/amnio*: => *parental karyotype* *50% from ch15* > *UPD* test (regardless if familial / de novo) Lab characterizes marker: . Unable to characterize - 13% . i(18)p - 100% risk . idic(22) - 100% risk . i(12)p - 100% risk . der (X) w/out XIST - 100% risk . No coding material (small, bisatellited) - no inc risk

CHARGE Association = CHARGE Syndrome

*It has become clear that CHARGE is a SYNDROME!* . *AD* --- *de novo* (1-2% empiric RR bcs gonadal mosaicism) . Unknown (some) *CHD7* @ 8q12.1 (60%) *haploinsufficiency of proteins important in early embryonal dev* Critera: [BOARDZ] C: *Coloboma* (80-90%) (iris and retina) H: *Heart defects* in 75% --- *ToF* (most common)[BOARDZ] --- Conotruncal --- Truncus arteriosus --- ASD --- VSD A: *Atresia choanae* = choanal atresia: nasal passage blocked (50-60%), endocardial cushion R: *Retardation of growth* & dev G: *GU abn* (males) E: *Ear abn (90-100%) -> SNHL* Other criteria: . Cranial nerve abn => CNS dysfunction --- *Facial palsy* (70-90%) --- Swallowing prob --- Hyposmia/anosmia . CLP . TE fistula . Dysmorphic face: --- Square face w broad --- Broad / prominent forehead --- Prominent nasal bridge and columella --- Flat midface Dx: . Clinical: temporal bone imaging (e.g. Mondini defect) . Genetic test: ⅓ will not have identifiable mtn *CHD7 seq* > *del/dup* (rare) > *array (to rule out 22q11del)*

Muir Torre *Cancer*

*Lynch variant* *MSH2* (common) MLH1 Lynch + . ****SEBACEOUS CA**** [BOARDZ]: sweat gland tumors, e.g. on scalp . *Keratoacanthomas* (skin tumors)

Friedreich Ataxia (FA) *Triple repeat expansion* *Mitochondrial* *Metabolic* *Mitochondrial*

*MITOCHONDRIAL DISEASE* ****AR: only AR triple repeat****! --- *Mat anticipation* (*Think Freddy is mama's boy so mat ant., but also loves his dad so AR*) *FXN = frataxin* --- nu gene => *frataxin (mt iron chaperone)* => mt iron metabolism ------ Shields iron from reactive oxygen species & makes it bioavail ------ Participates in synthesis + maintenance of iron-sulfur clusters in respiratory electron-transport chain complexes I-III & aconitate in Krebs cycle --- ****GAA repeat**** in *INTRON 1* [BOARDZ] ("AA for Ataxia") => gene silencing => insufficient frataxin => mt iron overload => mt dysfunction --- Point/deldup mtn + GAA (some) Repeats: *5-33: nl* *34-65: premutation (44-65: reduced penetrance)* *66-1,700: dx (most 100/600-1,200)* Onset: 1-15 (range 4-40y) => wheelchair dependant by 10y after onset Criteria: Progressive neuro --- No balance / limb coordination --- Slurred speach --- Apraxia --- Neuropathy --- Loss of lower limb / deep tendon reflexes --- Muscle weakness --- Sensory loss --- Upper limb ataxia --- Abn eye movements --- Optic nerve atrophy --- SNHL --- Bladder dysfuction --- Vibration and position senses Other criteria: . ****HCM**** (most)!!! . Scoliosis . TIID (some) . Foot abn: --- Pes cavus --- Extensor plantars Test: *PCR*, *SOUTHERN BLOT* (if 1 expansion detected) > seq > deldup

Monosomy 1p36 = Monosomy 1p = 1p36 Deletion *Microdeletion*

*MOST COMMON TERMINAL DEL* (1/10,000) *1p36.3-* [BOARDZ] --- 52% de novo --- Parental balanced transl (some) Criteria: . *Hypotonia* . DD, *severe ID* . CLP . Microcephaly . Brain abn, seizures . CHD . Dysmorphic Face: --- Straight flat eyebrows --- Deep-set eyes --- Midface hypoplasia --- Long philtrum --- Pointed chin --- Posteriorly-rotated, low-set ears . Behavior Problems --- Tantrums --- Bite self --- Dysphagia Other criteria: . Vision prob . HL . Skeletal abn . GI abn . Genital abn *Pheno similar to Prader Willi* Dx test: Clinical > FISH / karyotype / array to confirm Tx . DD: rehab / educational programs to help w speech/communication . Seizures: antiepileptic drugs . GI: GI tube . Standard care for other prob

Infantile Refsum *Metabolic* *Peroxisomal* *Hearing loss* *Zellweger*

*Mild type of Zellweger* *AR* *13+ genes for peroxins* (PEX) = peroxisomal assembly / import of enz into peroxisome: . *PEX1* (60%) (*think ref pex*) --- no geno-pheno correl Enz def: *phytanoyl-CoA hydroxylase* => no peroxisomes in hepatocytes => defect in all peroxisomal enz activities Criteria: . *RP* . Progressive *SNHL* . CNS --- *Anosmia* --- ID --- Hypotonia . *DYSMORPHIC* face --- Epicanthal folds --- Low set ears --- Broad nasal bridge . *Short fingers/toes* . Cerebellar ataxi . Polyneuropathy . Elevated CSF . Liver --- Early enlarged liver --- Jaundice Dx: 1) Biochem: -Blood + fibroblasts: --- Hi phytanic acid --- *Hi VLCFA* --- Hi pipecolic acid --- Hi bile acid intermediates -RBCs + fibroblasts --- Low plasmalogens synthesis -Urine: --- Hi bile acid intermediates --- Hi pipecolic acid 2) Genetic test Prenatal dx: . *Peroxisomal function in cultured CVS/amnio* . Mtn analysis if familial mtn Tx: symptomatic . Treatable: no phytanic acid in diet . Drugs improving biochem: in trials

XXX = Triple X

*More common than 45,X* *Sporadic* --- *mat meiotic nondisjunction* (*AMA* effect) --- *RR < 1%* Nl pheno *75% fertile (usually nl offspring)* [BOARDZ] 15-25% mild LDs (severity increases w number of X ch) Tx Not usually required

Waardenburg *Hearing loss*

*Most common AD syndromic HL* *AD* --- de novo (rare) --- variable expressivity Many genes: *PAX3* @ 2q35 (type I) (pax of cigarettes make you get old w grey hair) SOX 10 (type II) MITF (type II) EDN3, EDNRB, SNAI1 point mtn (90%), dels (6%) 1. *SNHL*: 20-50% 2. *PIGMENT ABN* of hair/iris/skin (neural crest migration defect) 3. *WHITE FORELOCK* (partial albinism), *EARLY GRAYING* (*think wearing a wig*) 4. FACE: Eye: *HETEROCHROMIA* of irides, sapphire-blue eyes, dystopia canthorum, synophrys Nose: hypoplasia of alae nasae, straight nose 5. GI prob highly variable (all features) type I - congenital SNHL, pigmentary abnl (heterochormic irides, white forelock, premature gray, leukoderma), telecanthus, NTD type II - same, no telecanthus type III - 1 + skeletal abn (limb hypoplasia or contracture, carpal bone fusion, syndactyly) type IV - 1 + hirschprung *Nl IQ* Test: *eval for HL + Hirschsprungs* Genetic test: PAX3 seq / multigene panel

Usher *Hearing Loss*

*Most common AR HL syndrome* *AR* 11 genes: MYO7A USH2A USH1C CDH23 PCDH15 SANS Type I: *MY07A* (50%) USH1C CDH23 PCDH15 SANS Type II: *USH2A* (80%) Others 1. Congenital *SNHL* 2. *Vestibular prob* => *balance prob* 3. *Retinitis pigmentosa* (RP) Type I congenital profound bilateral SNHL congenital balance problems RP onset pre-puberty Type II congenital mild-severe bilateral SNHL nl balance RP onset teens-20s Type III progressive later onset HL progressive balance prob variable onset RP Test: Hearing test Electroretinography (ERG) Eye exam for pigment changes Genetic test: multigene panel

Achondroplasia *FGFR related Craniosynostosis*

*Most common form of dwarfism* 1 in 26,000 ****AD**** --- *de novo* (80%) ---*APA* effect ---*GONADAL MOSAICISM* ****FGFR3**** (*normally inhibits bone growth*) @ 4p16.3 ---*missense* mtns (most) *GoF* -> constitutive activation of receptor --> inhibits chondrocyte proliferation at growth plate (*think counterintuitive*) >97% due to identifiable Gly380Arg mtn (one of most mutable nucleotides): ---1138G>A (98%) ---1138G>C (2%) Homozygous mtns -> lethal Prenatal onset: . detectable by US >24 wk (usually 3rd tri) . detectable by x-ray sooner ****Criteria**** [BOARDZ]: *Short-limb dwarfism*: . *Rhizomelic short stature (short long bones)->bowed legs* . Midface hypoplasia (mild flattened) & frontal bossing . Limited elbow extension . Trident hands . Megalencephaly . Macrocephaly . Spinal cord compression (Head CT to rule out spinal cord compression, if abn sleep, brisk reflexes, abd neuro exam) *Nl IQ*, except delayed motor dev bcs macrocephaly, hypotonia Sleep apnea (central apnea, obstructive apnea) *nl lifespan except 3-7% die in infancy bcs of central or obstructive sleep apnea* Lumbar spinal stenosis Otitis media (ear infections) Sudden death Failure of widening of the distal lumbar interpedicular distance Flat acetabula w narrow sacrosciatic notch Radiographic Findings: metaphyseal dysplasia abn foramen magnum on CT Test: *Targeted: 2 common mtns* Management: Surgery Bracing Pain meds BMN11 C-type natriuretic Peptide analog Sleep study for children *Incidence of homozygotes rising*

X linked Adrenoleukodystrophy (ALD) *Metabolic* *Peroxisomal*

*Most common peroxisomal dx* --- 1/10,000-50,000 --- Panethnic *XLR* --- Carrier females: 20% neurologic features similar to x-AMN (mild spastic paraparesis) in midlife (after 3rd decade) *ABCD1* @ Xq28 (*think A for Alphabet*) --- Many mtns ------ point mtns (most) ------ del (rare) --- no geno-pheno correl Enz def: *adrenoleukodystrophy protein* => *required to transport VLCFAs into peroxisome (VLCFAs undergo beta-oxidation in peroxisomes)* => *defective VLCFAs metabolism* => accumulation of abn cholesterol esters (C24:0 + C26:0) => damages adrenal gland => CNS effects (but NO correlation btw blood levels & neuro severity) Prognosis . Untx: asymptomatic to severe in early/mid childhood . Tx: depends on tx + tx time of onset 3 Types: 1. Childhood cerebral (classic) Nl @ birth Onset 3-10 y (3-5y)→ Childhood Cerebral Leukodystrophy . *BEHAVIOR*/attention changes→ school failure --- starts w ADHD-like behavior --- rapid progression to loss of language + motor function . Progressive dementia . Incoordination→ vision loss . *RAPID neurodegeneration* to spasticity + unresponsiveness . Adrenocortical insufficiency (common) ! => *Death within 2 y of symptoms* -Adrenomyelopathy (x-AMN): adult form of x-ALD Nl development for 20-40 y (midlife)→ Slow progression (over decades) . Progressive leg weakness + stiffness . Bowel/bladder dysfunction: poor sphincter control . Sexual dysfunction . Adrenocortical insufficiency (66%) . Behavioral impairment . Spastic paraparesis (partial paralysis of lower limbs) . Dementia -Addison's only adrenocortical insufficiency . Adrenocortical insufficiency . Adrenomyeloneuropathy (AMN) in midlife . Bronze skin . Progressive weakness + stiffness in legs / poor sphincter control / sexual dysfunction . Vomiting Dx . ****Hi plasma (serum) VLCFA (enough for dx)**** [BOARDZ] . Hi blood LCFA / fibroblasts . Low plasmalogens . Hi plasma ACTH + low cortisol (bcs ACTH not converted to cortisol) . White matter lesions on brain MRI: posterior to anterior progression (present well before disease manifestations!) . *ABCD1 genetic test (rarely needed for dx)* Carrier test . Plasma VLCFA (85% DR) . Genetic test if familial mtn Prenatal dx . VLCFAs (CVS/amnio) . Genetic test if familial mtn Tx- All experimental . Presymptomatic --- *VLCFA-free diet may help prevent symptoms, but NOT helpful once neuro disease ongoing* --- Supplement of erucic + oleic FA (e.g. "*Lorenzo's oil*")*, but probably does not cross blood-brain barrier --- BMT ------ May help in males w brain MRI abn + before neuro exam changes --- Lovastatin (lowers VLCFA levels) + 4-phenylbutyrate: efficacy not proven --- Anti-inflammatory med: interferon trial did not appear to be that helpful to protect brain --- Corticosteroid steroid replacement: for adrenal insufficiency . Symptomatic --- Maximizing / prolonging function while minimizing discomfort / suffering

Wilms Tumor *Cancer*

*Most common renal tumor in children* Pos fhx (1-2%) => may be associated w syndrmoe *FWT*1 (*think familial wilms tumor*) FWT2 Associated w: *BWS* *Isolated hemihypertrophy* *WAGR* *Li Fraumeni* Denys Drash Perlman of renal hamartomas Nephroblastomatosis, and fetal gigantism

Molar Pregnancy = Mole

*Non-viable* *Complete mole: 46 pat ch* . *Empty egg + 1 sperm (90%) => sperm reduplicates* . Empty egg + 2 sperms (10%) => highest *choriocarcinoma* risk (*think bad in man*) *Partial mole*: *69 ch (triploid) - 23 mat + 46 pat ch / 92 ch (tetraploid)* . Egg + 2 sperm . Egg + 1 sperm that reduplicates => *no choriocarcinoma risk*

Fanconi Anemia (FA) *Cancer* *Blood* *Bleeding* *AJ*

*Remember Hera's recent pt at FRE* *Most common of rare inherited BMF syndromes* . *AR* . 2% XLR (FANCB) *Risk w ART:* 1/4,000 (9x gen pop) Carrier freq: *AJ: 1/90* *gen pop 1/300* 13 complementation groups. *Many genes*: *FancA* (65% of cases) *FancB* *FancC*: AJ* mtn *456+4A>T* = IVS4+4A>T - 1/89 (1/80) carriers FancD1: *BRCA*! FancG FancN: *PALB2* (*br ca, male br ca, panc ca, possibly ov ca*) Onset: childhood -****BLOOD DISORDER**** [BOARDZ]: *Progressive BM failure (90%) - evident at 6y: ---fatigue* ---*frequent infections due to decreased WBC* ---*easy bruising* ---*bleeding* (clotting problems due to decreased platelets) ---myelodysplastic syndrome ---*aplastic anemia* -Ca - *AML*!!!, other blood ca, solid tumors of head, neck, skin, GI (esophageal), genital tract (females) -Abn forearms, radial ray and thumb: ---*BIFID THUMB* ---****MISSING THUMBS**** [BOARDZ] -*Cryptorchidism* -*Hypopigmented* skin + *CAL* spots -*Short* -Rrenal abn -HL -DD -Pancytopenia in 1st decade -VATER-like *Ov ca NOT CHARACTERISTIC (only in BRCA2 hetero)* Dx test ****Can only detect homozygotes = affected**** 1. *Radical formation* + *ch breakage studies (increased sensitivity to crosslinking agents)* by DEB/MMC (Mitocycin C Chromosome) stress test on cultured lymphocytes -> Rslt can be nl bcs of mosaicism due to gene conversion events > testing on *cultured fibroblasts* *Genetic test: 99% DR* *If AJ-> FANCC founder mtn* *If not AJ-> multigene seq+deldup* Tx *Avoid x-rays* *BMT*

McCune Albright *Endocrine*

*SPORADIC* (vertical transmission never seen) --- *post-somatic mtn* (germline mtn lethal) *GNAS GoF* (LoF=> Albright Hereditary Osteodystrophy) Triad: due to endocrine system overworking 1. *POLYOSTOTIC (BONE) FIBROUS DYSPLASIA*-> fibrous tissue in bones, often confined to one side of body => ---*FRACTURES* ---Face *asymmetry* ---Uneven growth ---Deformity 2. *CAL spots w irregular borders like "COAST OF MAINE* 3. Endocrine: ---*PRECOCIOUS PUBERTY in girls, as early as 2y due to excess estrogen from ovarian cysts* ---Goiter, hyperthyroidism Test: Targeted mtn Tx: Drugs to block estrogen + testosterone production can help Bisphosphonate for fibrous dysplasia Treat hormone abn

Spinal Muscular Atrophy (SMA) - ACMG 2008 -

*Second most common fatal AR disease after CF* *AR* --- *2% de novo* exon 7 del (usually *pat*) - high compared to other AR 2 survival *motor neurons* @ 5q13: 5 bp changes btw SMN1 & SMN2 (none of them change AA) *SMN1* produces predominately *fulllength transcript* *SMN2* produces predominately an *alternatively transcript (exon 7 del)* --- bcs of C to T change at 6 in SMN2 exon 7 => ------ does not change AA ------ but disrupt exonic splicing enhancer ****SMN1**** (9 exons) --- ****EXON 7 DEL****(95%) [BOARDZ] => pheno-geno correl rare (since most exon 7 del) SMN2 copy number (0,1,2,3) => *extra SMN2 can improve pheno (NOT applicable for carrier screening)* --- 2-5% point mtn in one allele + del in other (15% of nl people have no SMN2) --- *2% de novo del in affected (BUT does not mean 2% de novo rate of del in non-carriers!)* . Reduced Carrier Risk: don't know if in cis / trans --- 3 SMN1 copies (4% general pop; 5% in Caucasian; 30% of AA) --- 2 SMN2 copies (most) . Carrier: 1 SMN1 copy - *Carrier freq in USA: 1/50* (1/40-1/60, ACMG 2008) . Affected: 0 SMN1 copies Carrier test: . ****SMN1 dosage analysis (93-95% DR): detects copy number (cannot detect cis / trans) **** ------ Residual risk of being silent carrier if 2 copies: 4% in cis (30% in AA to 5% in Caucasian) . SMA Enhance: ****T27134G SNP in intron 7 of SMN1**** can be present on duplicated allele (most useful for AJ and Asian). Only reported if 2 SMN1 copies --- if pos: inc risk of being silent carrier (reported as carriers per Counsyl if AA / Asian) --- if neg: dec risk of being silent carrier Population carrier screening guidelines: *ACMG 2008: SMA carrier screening should be offered to all precon/preg women* *ACOG 2017: SMA carrier screening should be offered to all precon/preg women* *Not specifically associated w AJ (NOT on AJ panel) Criteria: . Progressive degeneration of anterior horn cells (lower motor neurons) in spinal cord + brainstem *Nl IQ* SMA0: onset prenatal, death < 6 mo SMA1=Werdnig-Hoffmann (60-70%): onset 0-6 mo; die <2 y *most common* . Severe, symmetric hypotonia . Muscle wasting of limbs, respiratory, bulbar and brainstem muscles-> "floppy baby": *NO sitting, but alert facial expressions* . *TONGUE FASCICULATIONS (muscle twitch)*; sucking + swallowing prob . Postural termor of the fingers (occasional) . Mild knee contractures . No deep tendon reflexes . No motor dev . Spared facial muscles . Ocular muscles + diaphragm involved in later stage . No sensory loss . NCV (Nerve Conduction Velocity) *Nl IQ + cerebral function* =>Death by 2 y from respiratory failure SMA2: onset 6-12/18 mo; live past 4 y, death by teens-20-30 y . Sitting independently, no walking (may walk w support) . Hypotonia at birth . Slow gain of motor milestones: sitting but no walking (ability to sit independently lost by teenage) . General flaccidity . Postural fine finger tremor . No deep tendon reflex . Rrespiratory issues . Scoliosis SMA3: onset > 12 mo (infancy/adolescent); nl lifespan . Walking unaided, some may need whealchair . Difficulty ascending/descending stairs at 2-3 y . Proximal muscle weakness (lower extremities more severely affected than upper) . Depressed/no deep tendon reflex . Delayed but attained motor milestones SMA4: onset >30 (30-40); nl lifespan - Nl milestone - onset of weakness > 30 y . Tongue fasciculations . Muscle atrophy . Depressed deep tendon reflex . Very slow progression Dx: . *Genetic test (first-line)* Clinical test for affected: prenatally (amnio) / postnatally Targeted analysis of SMN1: for exon 7 del > SMN1 seq: for point mtns => rec risk assessment . EMG --- Denervation --- Diminished motor action potential amplitude --- Regular spontaneous motor unit activity . Muscle Bx --- Denervation w no other structural abn / storage material / dystrophic changes Tx: None Inc SMN expression (in research): e.g. valproic acid

Pearson *Mitochondrial*

*Sporadic (somatic mtDNA mtns)* *Large 4.9kb mtDNA del heteroplasmy*!!! PEAR P Pancytopenia + neutropenia bcs of BM failure w low blood count => frequent infections Thrombocytopenia: easy bruising and bleeding E Exocrine pancreatic insufficiency Reduced pancreatic enz secretion with high level of fat in the liver, malabsorption, FTT, lactic acidosis Sometimes reduced insulin causing DM Fibrosis of pancreas A Anemia of sideroblastic type => : paleness, weakness, fatigue R Renal tubular acidosis 4. Also causes KSS (Kearns-Sayre syndrome) if in other organs or / in 2nd decade (later in life)

VACTERL Association = VATER Association

*Sporadic* Dx of exclusion: 3+ [BOARDZ] V *Vertebral abn* A *Anal atresia* C *CHD* T *Tracheo esophageal fistula* E *Esophageal atresia* R *Renal abn* L *Limb abn - POLYDACTYLY* *Differential*: Holt oram Fanconi anemia Townes Brocks Infant of mat diabetes Feingold Management: . Spine x-ray . Echo . Renal US . Limb x-ray *VACTERLH seprate dx* --- *incl hydrocephalus* (likely XL / AR)

46, XX Testicular Disorder of Sexual Development

*Sporadic* *46, XX* *SRY recombination* *Ambiguous genitalia* ****Small testes**** *Infertility*

Congenital Hypothyroidism (CH) *Endocrine*

*Sporadic* (most) *Genetic (15-20%)* ---Inherited (2-5%): *AR* / *AD* ------PAX8 (AD) ------TSHR (AD) ------DUOX2 (AD) On ****NBS**** *Hi TSH* or low T4 +/- high TSH if untx => ID Slow growth Dwarf Big abd Tx: *Thyroid supplement*: if started in infancy => usually *nl development*

Tuberous Sclerosis Complex (TSC) *Cancer*

*Think of Yemeni family at Kaiser SF* *AD* Variable expressivity men more severe > women *TSC1*, ****2/3 DE NOVO**** *TSC2, 98% de novo, large deldup* --- de novo TSC2 mtns => more severe Tumor supressor gene-LoF ****TSC2+PKD1 microdel => TSC+ADPKD**** Prenatal - childhood onset Major criteria: 1 . Heart: . *CARDIAC RHABDOMYOMA* prenatal/newborn (regress in adulthood -> echo not needed) 2 . Skin: 100% . *HYPOMELANOTIC ASHLEAF MACULES (spots)* . *FACIAL ANGIOFIBROMAS / forehead plaque* . *SHAGREEN PATCH (connective tissue nevus)* . *Nontraumatic ungual / periungal fibroma* 3. KIDNEYS: in childhood . *RENAL ANGIOMYOLIPOMAS* (26-80%) . *RENAL CYSTS*/ca (TSC2) *Renal ca (controversial) 4 . Lungs: . *Lymphangiomyomatosis* = ****LAM****: smooth muscle growth only in women in 3rd/4th (estrogen) 5 . Brain: features usually detected on MRI . Subependymal Giant Cell Astrocytoma (SEGA) (10%) . *Subependymal glial nodule* (90%) . *Cortical hamartoma tubers* . Cortical hypoplasia . Cortical dysplasia & white matter migration lines . Focal cortical hypoplasia . Heterotopic grey matter . *SEIZURES* & *SEVERE ID-> EARLY DEATH* (better chances of outcome w seizure control, but no guarantee. 50% or more of pts w TSC have nl IQ) 6. Retinal lesions (87%) = retinal (optic nerve) nodular hamartoma *difficult to dx w/out pupil dilation & indirect ophthalmoscopy Minor criteria: 1. Bone cysts 2. Dental enamel pits 3. Hamartomatous rectal polyps 4. Confetti skin lesions 5. Renal cysts (histologic) 6. Non-renal hamartomas 7. Cerebral white matter radial migration lines 8. Gingival fibromas 9. Retinal achromic patch Definite dx . 2 major . 1 major + 2 minor Probable dx: . One major + one minor Possible dx: . 1 major / 2 minor Dx: Clinical skin exam opthal exam kidney brain imaging Genetic test: *Seq > deldup* (80-85% DR) Parental eval: Skin exam Brain MRI Fundoscopic (eye) exam Renal imaging Management: . *Nephrology eval: renal US (and CT/MRI)* in childhood to detect masses and cysts . *Chest CT* in adult women if lung symptoms or every 5-10y . Yearly derm Exam start in childhood; Skin bumps: Rapamycin . Yearly brain MRI childhood-25; Brain tumors: surgical resection . Seizures: antiepileptic drugs . LAM: BSO for women w LAM to reduce estrogen exposure . Heart Echo/ EKG . Yearly opthal exam start in childhood Refer if personal hx / FDR: . 2 criteria (major / minor) . SEGA + another criteria in person

X Linked Agammaglobulinemia (XLA) = Bruton Agammaglobulinemia

*Think recent blond couple at LG who is preg w their 2nd child and 1st son has XLA which they knew abt from pt's mat affected uncles and son is treated at Stanford and doing great*) *XLR* *BTK (Think B for B cell!)*: important in development of B cells gammaglobulinemia to prevent bacterial infection Nl @ birth (due to residual mat gammaglobulin)- => *Life threatening BACTERIAL/VIRAL INFECTIONS in first 2y*(some do not show symptoms until teen / adult): . pneumonia . emphysema . meningitis . sepsis . cellulitis Dx test . Low serum immunoglobins (all classes): no B cells . BTK genetic test (90% DR) Tx: *Antibiotics* *AVOID live vaccines!*

Russell Silver Syndrome (RSS) *Imprinting* *Dwarfism*

*Under-expression of genes (opposite of BWS) - normally expressed in pat* . Ch 11 imprinting defects: ---****Hypomethylation of pat imprinting center 1 (IC1)**** H19/IGF2 region on 11p15.5 (35-50%) [BOARDZ] ---*mat dup* . Ch 7 imprinting defects: ---*upd(7)mat* (10%): incl imprinted gene GRB10 (involved in growth regulation) ---*GRB10* mtn [BOARDZ] Prenatal US: ****IUGR**** !!! Postnatal -*PROPORTIONATE DWARFISM*: . *GR (especially limbs), FTT, SHORT (up to 5ft)! . *BODY/FACE ASYMMETRY* . CAL . Face: --- Small *TRANGLE FACE* --- Downturned mouth --- Micrognathia . 5th finger clinodactyly (curved)!!! . 2-3 toe syndactyly *Nl head size, nl IQ*

Familial Colorectal Cancer Type X = Hereditary Colon Cancer Syndrome X *Cancer*

*Unknown gene* . Onset: later age . Rate of 2nd tumor: lower Dx: *Amsterdam* criteria + *CC only* (no other HNPCC ca) + *No Lynch gene mtn (nl MSI + IHC)*

Fryns

*Unknown inheritance / gene* Criteria: . *CONGENITAL DIAPHRAGMATIC HERNIA* => pulmonary hypoplasia => usually neonatal death . *Distal digital (nails, phalanges) hypoplasia*! --- Short/stubby fingers/toes --- Hypoplastic nails --- Hypoplastic right fifth digit . Dysmorphic face --- *COARSE* --- Ocular hypertelorism --- Broad + flat nasal bridge --- CLP --- Thick nasal tip --- Long philtrum --- Low-set + poorly formed ears --- Tented upper lip --- Macrosomia --- Micrognathia --- Abn nares --- Protuberant tongue . ID . Big mouth Other criteria: . Polyhydramnios . Cloudy corneas . Micropthalmia . Facial clefting . Renal dysplasia / renal cortical cysts / enlarges kidneys . Hypoplastic lungs . Hypoplastic corpus callosum Prenatal US: . Diaphragmatic hernia Dx: clinical (no genetic test)

Rubella = German Measles *Teratogen*

*Virus* --- Common *HL cause in Western countries in 1960s* => now rare bcs successful MMR immunization programs against influenza (*Think Rube was German*) *1st tri*: 8-10 wk => *SAB* 1 . *HL* 2 . Eye --- *Cataract* --- *"Salt and pepper" (hypo+hyper pigments) retinopathy* --- Microphthalmia 3 . *CHD* --- Pulmonary artery stenosis --- Patent ductus arteriosus 4 . Thrombocytopenia purpura w petechiae + ****"blueberry muffin"**** skin lesions (focal areas of erythropoiesis) Other criteria: . IUGR . Hepatosplenomegaly (HSM) . LD, ID . Diabetes . Swollen lymphs . Hepatitis . Jaundice . Hemolytic anemia . Pneumonitis . Meningoencephalophalitis . Corneal clouding . Metaphyseal radiolucencies . Diarrhea 1st tri . MCA . Cataract . CHD 2nd tri: . HL . Retinopathy

Androgen Insensitivity = Testicular Feminization

*XL* --- ⅓ de novo (-> mother has 2/3 chance to be carrier) *46, XY* *Androgen Receptor (AR)* [BOARDZ] (*same as Kennedy*!) Mullerian ducts regress + Wolffian ducts don't develop→ *pheno female / ambiguous genitalia w undescended testes (streak gonads) => which *need to be removed to reduce ca risk* [BOARDZ]; infertility, amenorrhea* Types: 1. *Complete AIS → does NOT respond to androgens → nl female external genitalia) 2. Partial AIS ambiguous, male, or female genitalia 3. Mild AIS typical male genitalia Dx test: clinical (*ambiguous to nl female genitalia*) + 46,XY . Karyotype for undermasculination of genitalia . Impaired spermatogenesis w nl testes, absent . Mullerian (ovaries) structures, nl/increased testosterone w nl conversion to dihydrotestosterone . Nl / hi LH Genetic test: (for confirmation) AR genetic test

Oro Facio Digital = Oral Facial Digital *Ciliopathy* *Metabolic*

*XLD (lethal in males)* *OFD1* ORO- Oral cavity defects (*clefting*), ****TONGUE- lobulated, hamartoma**** FACIAL - *Dysmorphic face* DIGITAL - *Digit defects* Brain abn->ID

Incontinentia Pigmenti

*XLD* --- *LETHAL in males* *IKBKG* = NEMO @ Xq28 [think I for I] . del in gene . mtn *BLISTERS + SKIN COLOR CHANGES* 4 stages --- Variable onset, from infancy 1. Birth - Vesicular erythema: skin *BLISTERING* skin rash 2. Infancy - Verrucous: *Wart-like skin rash* 3. Childhood - *Swirled macular HYPERPIGMENTATION* (grey/brown) 4. Adulthood: Atrophic skin patches: *linear HYPOPIGMENTATION* Other criteria: . Teeth --- *SMALL/FEW TEETH* --- ****Delayed teeth eruption**** [BOARDZ] . Hair --- Hair loss --- Woolly hair . Nail --- Ridging / pitting . CNS --- Seizures --- ID (rare) . Eye --- Retinal neovascularization=> detached retina . Eosinophilia (inc in type of white blood cells) *Nl life expectancy!* Test: . *Hyperpigmnted streak bx: free melanin granules* . Genetic test: --- *Southern blot for common exon 4-10 del* (80%) > *IKBKG seq + deldup* > *X inactivation / skin bx*

Coffin Lowry

*XLD* --- 80% de novo *RPS6KA3* Severe in M >> F Onset: neonatal (most) Criteria: . *Soft, broad hands w soft stubby tapering fingers* (*think fingers got cut when coffin closed*) . ****Stimulus induced drop episodes (SIDES)****: sensory induced drop attack, collapse when excited/startled (*think got scared in haloween and dropped in coffin*) . *SELF-HARM BEHAVIOR* . ID, DD --- In males --- Fem may be nl . Dysmorphic face --- Microcephaly --- Prominent forehead --- Hypertelorism --- Short nose w wide tip, wide mouth w full lips (more prominent w age) . Kyphosis . Short Test: *RPS6KA3 seq*

Steroid Sulfatase (STS) deficiency = X-linked Ichthyosis *Microdeletion*

*XLR bcs gene escapes X inactivation* (=> females nl) . *STS* del (90%) / mtn . *Xp22.32-* (incl *STS+KAL*) => --- X-linked ichthyosis --- Kallmann --- Short --- Chondrodysplasia punctata --- ID --- Ocular albinism Prenatal screen: *VERY LOW uE3* on Quad Labor: failed / prolonged in mother of affected son Onset: 2-6 wks (<6 mos) . Hypertrophic ichthyosis: brown, firm adherent *DRY SCALY SKIN* on scalp, ears, neck . *Comma-shaped corneal opacities w nl vision* . Hyperkeratosis . Cryptorchidism

Becker Muscular Dystrophy (BMD)

*XLR* *DMD* @ Xp21.2 --- 10% de novo --- manifesting carriers (esp DCM) *In-frame* mtns* => reduce gene function, but out of frame del more severe . ****large dels (85%)**** . dups (6-10%) . point / small mtn (5-10%) . unknown (5-10%) . *Proximal muscle weakness* . Ambulatory -> wheelchair bound @ 20y . DCM . Activity-induced cramping . Flexion contractures of elbows . Retains neck flexor muscle strength (vs. more severe allelic disorder) Dx test: *Hi blood (serum) CK* Muscle bx - *SOME DYSTROPHIN PROTEIN PRESENT (vs NO protein in severe DMD)* [BOARDZ]

Lesch Nyhan *Metabolic*

*XLR* *HGRPT1* (*think H for HURT yourself*) Enz def: *hypoxanthine-guanine phosphoribosyltransferase* . *SELF-INJURY*, pain insensitivity . *DD, LD, ID* . *Cerebral palsy, motor dysfunction* . *Hyperuricemia* => --- kidney stones --- renal failure --- *gout* . *Anemia* . Seizures Biochem: ****hi uric acid**** Dx: . HGPRT1 enz analysis . HGPRT1 genetic test Tx: . Physical restraint to protect from self injury . Allopurinolz . Carbidopa/levodopa . Haloperidol

Duchenne Muscular Dystrophy (DMD)

*XLR* --- DE NOVO (1/3) - equally from males and females => so mother has 2/3 chance of being carrier* ****APPLIES TO ALL ISOLATED CASES OF XL LETHAL / SEVERE (unlikely to have children e.g. DMD, Hunter) CONDITIONS*** --- *Gonadal mosaicism* - If mother not carrier, still 7% recurrence risk (i.e. 14% risk to pass on DMD del due to GONADAL MOSAICISM) *DMD* @ Xp21.2 ****LoF mtn**** Dystrophin: ****largest known gene 2.4 Mbp on X**** ****hi new mtn rate (10^-4 = 1/10,000)**** dystrophin recombination rate: 10-12% (v. hi, important for linkage) . *null mtns*: nearly all identifiable by genetic test - multiplex PCR, (formerly southern), MLPA, seq) *usually out of frame*! ---*Large dels - one or more exons* (60-70%) ---*Large dups* (5-10%)(hot spot: exon 2-19, 45-55)=>may lead to in-frame or out-of-frame transcripts (dups may be slightly more common in BMD): ------*Out-of-frame dels: DMD (del 46-49)* ------*In-frame dels: BMD (del 45-49)* ---Small dels ---*Single nucleotide variants* (25-30% of DMD and 10-20% of BMD) ------Dels ------Insertions ------Substitutions Nonsense in DMD > BMD Splice site in DMD = BMD Missense rare in DMD & BMD Onset 2-5y Proximal weakness then distal, *gower maneuver (sign of proximal muscle weakness)*, wheelchair by 12-13y ID in 1/3 Muscle weakness + muscle wasting (effects hips, pelvis, thighs first) (some have NL tone) 1stpresenting sign: difficulty climbing stairs, Gower's maneuver Proximal to distal progression; face usually spared Scoliosis develops after loss of ambulation Eventually heart and lungs are affected (DCM 100%) Hypertrophy of calf Lifespan into 4th decade Some degree of static cognitive impairment in 25-50% (deficits in short-term/working memory; deficits in executive function) Symptomatic female carriers (skewed X inactivation-> majority of active x-ch carry mtn): *Greatest risk muscle weakness*, but not as severe as boys -2/3 have CK levels >95th % -15-20% have left ventricular dilatation, 5-8% DCM! -15% have muscle weakness -5% have cramps and myalgia -calf pseudohypertrophy is rare Dx test: 1. *Clinical pheno + hi blood CK confirm dx* (skeletal bx not routine) if pos-> 2. Genetic test: Tier 1: *exonic del* > Tier 2: *DMD seq > deldup > seq* 3. *Skeletal muscle bx (LAST RESORT)* to look for Western blot and IHC studies of dystrophin only if you can't find a mtn: little to no dystrophin protein [BOARDZ]-> would show fiber size variability *Note: some doctors may order genetic test for LGMD to rule that out before doing a muscle bx* Carrier test: for known mtn / linkage (but huge gene so recombination may occur) / by CK (50% penetrant, decreases w age) Tx: Mostly supportive Can give oral corticosteroid-> expect prolonged independence of ambuation in pt (used clinically) Gene therapy via exon skipping & stop-codon read through (only in trials for males)

Aarskog Scott

*XLR* AR (rare) AD (rare) *FGD1* = Facio Genital Dysplasia @ Xp11.2 (7-20%) . *SHAWL SCROTUM*, cryptorchidism . Dysmorphic face: --- *Hypertelorism* --- Small nose --- Long philtrum --- Widow's peak . Short . *Hand abn* --- *Brachydactyly* --- 5th finger clinodactyly --- Syndactyly --- Mild interdigital webbing . Single palmar (simian) crease . CHD . Cervical vertebral abn . Pectus excavatum . Hyperextensible . ID (30%) Test: FGD1 genetic test (DR 20%)

Kallman (KAL) *Disorders of Sexual Development* *Microdeletion*

*XLR* - ANOS1 (KAL1) AD - FGFR1 LoF (KAL2) Can have *Xp22.3 microdel* => --- Kallmann+ *X-linked ichthyosis*+*Chondrodysplasia punctata* --- *Ocular albinism* --- *Short* --- *ID* MALE W: 1. *DELAYED/ABSENT PUBERTY*: hypogonadotrophic *hypogonadism* 2. *ANOSMIA*= loss of sense of smell (call a man to clean up the mess because he cannot smell) Type 1: Mirror hand mvt (bimanual synkinesis) Ataxia GU abn High palate Type 2: ID CLP Cryptorchidism, micropenis CHD SNHL Choanal atresia Abn tooth dev Genetic test: seq (low DR)

MELAS (Mitochondrial myopathy, Encephalopathy, Lactic Acidosis and Stroke-like episodes) = CPEO (Chronic Progressive External Opthalmoplegia) *Mitochondrial* *Metabolic*

*mtDNA* --- Variable expressivity: may be mild => only diabetes +/- deafness (usually adult-onset) --- *HETEROPLASMY* --- Single-base mtns in tRNA gene: ------ if point mtn => maternal inheritance; if del=> sporadic *Point mtns* (rarely, dels & nDNA mtns): . *MT-TL1* = *tRNA*leu(UUR) = transfer RNA leucine: "hot-spot" gene: ---- ****A3243G**** (80%) => causes: ------- *MELAS* (****ENCEPHALOPATHY****) - NOT most common presentation of this mtn ------- 1% of isolated ****DIABETES**** ------- ***CARDIOMYOAPTHY*** . 2 other MT-TL1 mtns . 1 MT-ND5 mtn . 8 other mtDNA genes . Large 5kb *KSS (Kearns Sayre syndrome) del* (sporadic) Onset: 2-10y (or delayed 10-40y) 1 . Initially --- *MIGRAINES* --- Proximal limb muscle weakness + pain --- No appetite --- Vomiting --- Seizures 2. Then → --- Progressive atrophy of extraocular muscles --- Cortical blindness --- HL (usually adult-onset) --- Transient hemiparesis = weakness of one side of body 3. W time => neurodevelopment prob: - Generalized tonic-clonic seizures + - *Seizures + strokes / stroke-like episodes* (<40y) => progressively damage brain (mt encephalopathy) => --- Impaired motor abilities --- Dementia --- Seizures --- Transient hemiparesis cortical blindness Other criteria: . Mt myopathy . *CARDIOMYOAPTHY* . Lactic acidosis . Diabetes . Short . Exercise intolerance Labs: -*Lactic acidosis* -*Ragged red fibers on muscle bx* -Hypoglycemia (rare) Dx test: -*Targeted test for 4 common mtns > multigene panel / seq of mtDNA* ---- Tissues to test ------ Start w blood (mtn may not be detectable) ------ > buccal mucosa / urine sediment / muscle bx (most reliable)

Myoclonic Epilepsy with Ragged Red Fibers (MERRF) *Mitochondrial* *Metabolic*

*mtDNA* ---Heteroplasmy ---Single-base mtns in tRNA gene . MT-TK = tRNAlys (transfer RNA lysine) ---Point mtns ------ ****8A344G**** (80% of MERRF) [BOARDZ] ------ *T8356C* & *G8363A* (10%) [BOARDZ] => defective protein synthesis for all mtDNA-encoded polypeptides . MT-TL1, MT-TH, MT-TS1 (rare) Onset: late childhood - adulthood Criteria: *PROGRESSIVE myoclonic EPILEPSY* Biopsied muscle cells look abn under microscope (*ragged-red fibers*) *DEMENTIA* Myopathy Spasticity Muscle twitches Peripheral neuropathy Ataxia SNHL Short Optic atrophy Symmetrical lipomatosis (large subcutaneous fat masses, usually around neck HCM Dx: Lactic Acidosis in blood Elevated CSF protein Brain MRI Muscle Bx Genetic test

Canavan *Leukodystrophy* *Metabolic* *AJ*

*think asparagus in a big shaking can* ****AR**** ****ASPA**** (aspartoacylase) @ 17pter --- Common mtn: p.Ala305Glu AJ: *Carrier freq: 1/41* . 2 founder mtns (98% of AJ mtns) --- A285E (83%) --- Y231X (14%) Nl @ birth *Onset: 3-5 MOS* (<1-2y) ****Criteria**** [BOARDZ]: . *LEUKODYSTROPHY* (degeneration of myelin) => Neonatal form (most): --- ****MACROCEPHALY w poor head control**** (head lag) --- Seizures --- DD --- Hypotonia --- Irritabile --- Feeding/swallowing prob => *CHILDHOOD DEATH*: <10y - early teen Mild form: . DD . Hi urine NAA *Nl head size* Dx test: . ****Hi urine Nacetyl Aspartic Acid (NAA) (enough for dx!)**** . MRI: Diffuse white matter disease/neurodegeneration . MRS: Hi NAA . Com mtns > seq > deldup (97% DR) Prenatal dx: . Hi NAA in amniotic fluid Tx: suportive No cure

Menkes *Metabolic* *Mitochondrial*

*think of Trishna's pt* ****XLR**** *ATP7A* Enz def: *ATPase COPPER transporting alpha* *Defect of copper transport in electron transport chain* assembly factors, co-factors *Inadequate copper* => *cytochrome oxidase (complex IV of electron transport chain) cannot function* (other body systems require copper=>other manifestations not related to mt: e.g. connective tissue disease bcs need copper in collagen metabolism Onset: Neonatal / 2 mo - 3 y . Derm: trichorrhexis nodosa = pili torti (****kinky hair****), short/sparse/coarse/brittle hair; lax skin, puffy cheeks, hernias, vascular tortuosity, hypopigmentation . Neurologic: lose developmental milestones, hypotonia, seizures, . Severe DD, ID . Wormian bones . Bladder diverticuli . Temperature instability . Hypotension . FTT => death by 1y *Pheno similar to mt dx bcs cytochrome C oxidase has copper atom as cofactor* Dx: -Biochem: low serum ceruloplasmin and copper levels low hepatic copper concentration abn plasma catecholamine levels copper transport studies in fibroblasts -ATP7A genetic test Tx: Copper histidine / copper chloride subcutaneous injections Supportive care

Herpes *Teratogen*

- *HL* (*Think H for HL*) - *SEM*: --- Skin: *BLISTERS* --- Eyes: *BLIND* --- Mouth - ID - Cerebral palsy - Liver - Lungs - CNS disease *Similar pheno to Epidermolysis Bullosa*

Aicardi

---****XLD**** (*LETHAL in males, unless XXY*) ------ denovo (most) --- Variable expressivity Onset: mean age 8y (*think Ai Cardi for A C*) . A *ACC* => *INFANTILE SPASMS/seizures* => ID . C *CHORIORETINAL LACUNAE*!!! [*pathognomonic*] Other criteria: . Scoliosis . Tumors

Complex Conditions = Multifactorial conditions

---Locus heterogeneity = many genes at different loci cause same/similar dx/pheno/traits ---Incomplete penetrance ---Phenocopy *Prevalence is not a characteristic Polygenic Inheritance: Locus heterogeneity All have small additive effect *Enviro/behavior does not contribute Multifactorial Inheritance: Locus heterogeneity All have a small additive effect Env + other triggers contribute Aggregate in families, but don't segregate Etiology of exclusion Etiology of most medical conditions and human traits Multifactorial Threshold Model Assumes there is susceptibility to specific dx Assumes there is threshold of liability→ people who exceed this threshold will have trait Different populations have different threshold (must meet threshold to get trait) Different distributions among populations (genetic liability different for different populations) Jar w different color jellybeans: blue represents environmental contributes red represents genetic contributions → become more vulnerable to disease overtime as jar fills up Heterogeneity: environment sometimes contributes more to risk than genetics and vise versaFor complex disorders: In absence of any other family history: Chance for FDR = square root of the frequency of the condition in the population. The chance for a third degree relative approaches that of the general population. RR (in absence of any other fhx) Based on empiric data FDR = square root of general pop risk TDR = minimal => approaches that of general pop => can be ignored Limits of Empiric Data: Represent average probabilities Pt's risk includes: . Characteristics of affected relative ---Higher RR if: ------earlier age of onset ------less frequently affected sex ------more severe illness . Characteristics of individual for whom probability is being calculated ---Higher RR if: ------age ------more commonly affected sex ------med hx . Characteristics of Fm Hx Association of a marker allele with a disease: *Association is about an allele not a marker *Association is not causal Higher heritability for a trait would imply that monozygotic twins are more likely to both be affected than would dizygotic twins e.g. Multifactorial inheritance can explain why siblings in a family may or may not be affected by a particular trait, such as cleft lipv

Techniques for detecting specific small mutations (small deletions, missense, etc.)

-Dot blots (pt dna on blot, hybridize probes) -Reverse dot blots (used more) (mtn and wt probes on blot, hybridize pt dna) -OLA - oligo ligation assay (olgos matching mtn and wt, if anneals will be ligated and product produced) -ARMS - allele-specific PCR - only runs if primers match (one primer for WT, one for mtn) -Sequencing! especially if don't need high throughput parallel testing (i.e. family mtn vs. carrier screening)

Fetal Alcohol

-Face: *Flat smooth philtrum* Thin upper vermillion border Short palpebral fissures Midface hypoplasia Microphthalmia, ptosis Microcephaly Flat nasal bridge -Skeletal: Radioulnar synostosis Flexion contractures Aberrant palmar creases Clinodactyly Klippel-Feil anomaly Hemivertebrae Scoliosis Small distal phalanges (finger bones) -IUGR, GR -microcephaly -CNS: microcephaly, *ID, ASD, seizures, irritability, ADHD, brain malformations, behavior prob* -Hypoplastic finger nails -CHD -Cleft palate -Renal abn

Techniques for detecting deletions and duplications

-MLPA - mutiplex ligation probe amplication; PCR in log phase to allow for quantification (better for dups and carriers than southern and PCR) - may need to confirm or check if SNP at probe binding site is cause of apparent del -Array (better for dups and carriers than southern and PCR) -PCR - multiplex (ex. DMD) - dups difficult ot detect, easier if done in log phase; need to confirm dups with another method -rtPCR for quantitiy (better for heterozygotes than straight PCR) -Southern blot

Limb Girdle Muscular Dystrophy (LGMD)

. ****AR**** (often): --- *LGMD2* [BOARDZ] (****type 2 meaning AR****) --- others . *AD* (rare) --- *LGMD1* (type 1 meaning AD) Many genes: . *CAPN3* (LGMD2A) . *SGC*A: milder --- Cardiomyopathy (rare) . SGCB: more severe --- Cardiomyopathy (30%) . SGCG: --- Cardiomyopathy (30%) . SGCD: more severe --- Cardiomyopathy (30%) No geno-pheo correl => do muscle bx . *Onset: 2-15y* --- *Wheelchair dependence: 15y after onset* (some remain ambulatory) Criteria: . *Progressive weakness* --- *Begins in proximal limb muscles* ------ Shoulders ------ Upper arms ------ Pelvis ------ Thighs --- *Early unusual gait* ------ Waddling ------ Walking on balls of feet --- *Cardiomyopathy* --- Scolisos --- Contractures --- Respiratory prob . No bulbar symptoms *Nl IQ* Dx . *Hi serum CK* . *Sarcoglycan protein staining* . Dystrophic changes on muscle bx Test: Multigene panel Tx . Monitor respiratory + cardio prob

Charcot Marie Tooth (CMT) *Duplication* *Microduplication*

. *AD* (*PMP22*) [*Think Pimps have grills on their teeth*] --- 25-33% de novo . AR . XL --- Complete penetrance --- Variable expressivity Many genes: *PMP22* @ 1711.2p (often) --- dup (*17p dup*) / *GoF* mtn (70-80%) (*think cMT MiroTuplication*) (*del / LoF => Hereditary neuropathy w liability to pressure palsies (HNLPP)* - allelic dx) CMT1: AD --- Demyelinating --- Conduction velocities <38 m/s CMT2: AD --- Axonal --- Conduction velocities >38 m/s --- Reduced amplitude CMT4: AR --- Axonal / demyelinating CMTX: XL --- Axonal / demyelination Onset: <30y (1st-3rd decade) Criteria: Abn peripheral myelination Slowly progressive distal muscle atrophy + weakness (feet, legs, to hands) => . Distal weakeness -> --- *"Foot drop" gait* --- Gait abn --- Thinning below knee --- Foot deformities: ------ Pes cavus ------ Hammer toe ------ High arch . Abn sensation --- Parasthesias --- Loss --- Proprioception --- Burning --- Tingling --- Shooting pain Test: . Slow nerve conduction (by 5y, even if asymptomatic) . Nerve bx . Genetic test to confirm dx: --- *If Type 1/2 -> PMP22 (17p) dup* --- *If uncertain type-> multigene panel* *Nl life expectancy

Cornelia de Lange

. *AD* (common) . XLR (SMC1A) - rare --- de novo . *NIPBL* (>50%) (*think Corelia has nice niples*) . *SMC*1A . SMC3 . HDAC8 . RAD21 . Dysmorphic face: (*think corelia looks like a cat*) --- Eyebrows ------ *UNIBROW = synophyrs* (think one long unibow*) ------ Arched ------ Bushy --- Small nose --- Long curly eyelashes --- Nose ------ Depressed nasal bridge ------ Inteverted nares --- Mouth ------ Thin upper lip ------ Long/flat philtrum ------ Downturned mouth . *HYPERTRICHOSIS = werewolf* (*think Corelia is like a cat*) . *Upper limb abn* (*think Corelia is a car w no thumb bcs of fight) --- *ABSENT THUMB* --- *Micromelia* --- Oligodactyly --- 5th finger clinodactyly --- Flexion contracture of elbow . Microcephaly,*ID* . Hypoplastic genitalia . Small widely spaced teeth . Cleft palate . IURG, Growth retardation . Skin --- Hirsuitism --- Cutis marmarota . HL . CHD --- Cardiac septal defect . Lower limb abn: --- Micromelia --- Syndactyly of 2nd-3rd toes . GI/GU abn Dx test: . Clinical dx . Genetic test: --- Sequential single gene / multigene panel

Bardet Biedl *Ciliopathy* *Metabolic*

. *AR* . *Triallelic* (10%) ****14 KNOWN GENES**** [BOARDZ] (*think bard a papa is old and has many generations of kids*) . *BBS*1 (18-32%) . BBS10: 91fsX95 (10%) . BBS (8%) . BBS6 (6%) Criteria: . *RETINALCONE ROD DYSTROPHY-> BLIND by 15y* (*think bad a pappa cannot see*) . Postaxial ****POLYDACTYLY****, brachydactyly (*think bad a pappa growing digits*) . *RENAL DISEASE* . Truncal *OBESITY* nl prenatal growth . *ID* . Female GU abn . Male hypogonadism Test: . Atypical pigmentary retinal dystrophy . Renal abn on US . Multigene panel . Mouth: --- Small mouth --- Dental crowding --- High palate

Joubert = Oro Facio Digital (OFD) *Ciliopathy* *Metabolic*

. *AR* . XLR: rare (OFD1) *30+ genes* (affecting primary *cilia*) . FACIO - *Dysmorphic face* --- Triangle mouth --- Broad forehead --- Arched eyebrows --- Ptosis --- Wide nose w broad nasal bridge --- Hypertelorism=widely spaced eyes --- Lowset ears ORO - Mouth --- *Cleft tongue* --- CLP --- Lobulated tongue --- Tongue hamartomas --- Hyperplastic frenulum --- Absent/extra/dysplastic teeth DIGIAL - Digits --- *Polydactyly* --- Syndactyly --- Brachydactyly --- Clinodactyly . Cerebellar vermis agenesis => *MOLAR TOOTH SIGN* on brain MRI Renal: . *Renal cysts* => failure *Type 1 similar to AR PKD* . Hypotonia => ataxia . ID . Ptosis Test: Multigene panel: seq+delup (50% DR)

Amyotrophic Lateral Sclerosis (ALS) = Lou Gehrig

. *Sporadic ALS* (90%) --- de novo AD (rare) . Familial ALS (5-10%) --- *AD* (often) --- AR / XL (rare) . ****SOD1**** (20%) [BOARDS] (*think alS for Sod*) . ****C9orf72**** (23-30%) (ALS, FTD) [BOARDS] (*think or*) . *FUS* (4%) (ALS, FTD) [BOARDS] . *TARDB* (1-4%) (ALS, FTD) [BOARDS] . VCP (ALS, FTD, Paget's, inclusion body myopathy) . UBQLN2 . ALSIN M >> F Onset: --- Sporadic ALS: 55y (40-70y range) --- Familial ALS: 46y --- Juvenile (rare) Criteria: Rapidly progressive neurodegeneration => Attacks nerve cells controlling *voluntary muscles* . Affects upper + lower motor neurons . Muscles weaken, twitch, cramp, stiff, atrophy . Loss of voluntary movement . Slurred peach . Difficulty chewing / swallowing . Frontotemporal dementia (FTD) (20%): affects personality, behavior, language => *Death from respiratory failure 2-5 y from onset* (10% survive > 10 y) Test: . SOD1 / multigene panel --- 2/3 DR if familial --- low DR if sporadic

Cat Eye *Marker chromosome* *Ring chromosome*

. *Sporadic* (often) . Inherited - from balanced transl (rare) *4x 22q11.2 (partial tetrasomy)*: . *Bisatellited supernumerary marker ch* (often) . Ring supernumerary marker ch Criteria: (*think defected cat w defected eyes + fur*) . *COLOBOMA of iris (CAT EYE-like)* . *SPARSE HAIR* . *HYPOTONIA* . Anal atresia/fistula . Ear pits/tags . Micropthalmia . Cleft . CHD . Renal abn . Mild ID (some) . Downslanting palpebral fissures . *Nl dev* Test: *Karyotype*

Hypohidrotic Ectodermal Dysplasia & Anhidrotic Ectodermal Dysplasia) *Ectodermal dysplasia*

. *XL* --- *EDA* (60%): mild in carrier females . AD/AR --- EDAR (20%) --- EDARADD (12%) *both can be either . *Hypohidrosis/anhidrosis (reduced/absent sweat glands)=> hyperthermia* . Ectodermal dysplasia=> . *HAIR* --- Hypotrichosis (*sparse hair*) on body + scalp + eyebrows + eyelashes --- Brittle hair . *SKIN*: --- *Less sweat* --- Thin --- Less pigments . *NAILS* . *TEETH* --- Hypodontia . Eyes --- Periorbital wrinkling --- Hyperpigmentation . Mouth --- Conical teeth --- Oligodontia --- Papular changes on face Dx test: . Clinical: chronic skin prob (eczema) . Multigene panel Management: ****Stay out of heat!****

Emery Dreifuss Muscular Dystrophy *Nuclear Membrane* *Laminopathy* *Cardiovarcular*

. *XL* --- *EMD* (*think Emery Muscular Dystrophy*) --- FHL1 . AD/AR (LMNA) Triad: 1. Childhood joint *CONTRACTURES* --- XL: precede muscle weakness --- AD: after muscle weakness 2. Humeroperoneal (*UPPER ARM*) muscle *WEAKNESS* + wasting 3. HEART --- *CARDIAC CONDUCTION DEFECTS=>ARRYTHMIA* --- *DILATED CARDIOMYOPATHY* Test: Multigene panel / serial single gene test based on emerin protein status + inheritance

Dyskeratosis Congenita

. AD . AR *Telomerase* defect . Pigement abn . Fingernail abn . Premature graying . BM failure . Liver cirrhosis . Lung scarring . Somewhat shorter lifespan (median age @ death >50)

Argininosuccinic Aciduria (ASA) = Argininosuccinic Acid Lyase Deficiency *Metabolic* *Urea Cycle*

1 in 218,750 *AR* *ASL* --- Enz def: *argininosuccinate lyase def* Nl @ birth . Progressive hi ammonia => encephalopathy => lethal encephalopathy Chronic: . Progressive liver fibrosis => failure . Hepatomegaly . Recur headaches . Neuropsych prob . HTN . Hi transaminases . Trichorrhexis nodosa: thickened / weak points (nodes) along hair shaft => hair breaks off easily => kinky /brittle hair Dx . Hi plasma ammonia . pAA --- Hi ------ ASA ------ Citrulline ------ Glutamine ------ Alanine ------ Arginine-succinate --- Low ------ Arginine ------ Ornithine uOA: --- Nl (often) / mildly hi orotic acid . ASL genetic test Tx: . Acute: --- Hemodialysis --- Stop protein --- IV glucose/lipids --- IV ammonia scavengers . Chronic: --- No protein --- Formulas --- Oral arginine/ammonia scavengers

Citrullinemia Type I deficiency = Arginosuccinic Acid (ASA) Synthase deficiency *Metabolic* *Urea Cycle*

1 in 250,000 AR ASS1 --- Enz def: Argininosuccinic Acid (ASA) Synthetase I def - AS is step after OTC: converts citrulline (substrate) -> ASA Nl @ birth . Liver failure . Progressive hyperammonemia . Encephalopathy→ lethal encephalopathy . Recurrent headaches . Neuropsych prob Dx: . Metabolic panel: - uOA: hi orotic acid - Hi ammonia (1000-3000 µmol/L) - pAA: --- Hi citrulline (>1000), glutamine, alanine --- No arginino succinate --- Low ASA, orginine, ornithine . ASS1 genetic test NBS: citrulline Tx: . Acute: --- hemodialysis --- no protein --- IV glucose/lipids --- IV ammonia scavengers . Chronic: --- low protein diet + formula --- oral arginine/ammonia scavengers

Translocations

1 in 500 individuals are translocation carriers Rearranged ch called derivative ch and defined by its centromere (translocation is unbalanced when one of der chromosomes is inherited)

Arginase Deficiency (ARG deficiency) *Metabolic* *Urea Cycle*

1 in 950,000 *AR* *ARG1* Enz def: *arginase def* Criteria: . Onset: 1-3y (nl @ birth) --- Growth slows --- Developmental regression --- Spastic: Spastic diplegia! --- Seizures Mildest: . nl @ birth + childhood . Episodic hyperammonemia - rarely severe but enough to be life threatening . Progressive spasticity . Seizures . Loss of developmental milestones . Chronic neurologic presentation: --- DD --- Spastic diplegia . Adult: --- Severe ID --- Short --- Spastic --- Joint contractures --- No ambulation/bladder control Biochem: - Usually nl plasma ammonia in non-crisis ---- Rarely neonatal hi ammonia ---- *Hi plasma ammonia in acute crisis*: >=150 umol/L w nl anion gap & nl plasma glucose - uOA: Nl / slightly hi orotic acid - pAA: *Hi arginine* (3-4x nl)

ICSI

1% risk of sex ch abn May be due to underlying sex ch aneuploidy in father or ICSI itself

X Linked Chondrodysplasia Punctata *Microdeletion*

1) Type 1: XLR *ARSE* . *Contractures* . *Infant death* . DD . Cataracts . Stippling in epiphyses & paravertebral areas 2) Type 2: milder XLD (lethal in males!) EBP Enz def: sterol isomerase . Craniofacial: frontal bossing, flat nasal bridge, sparse eyebrows/lashes . Skeletal: chondrodysplasia punctata, rhizomelic limb shortening, scoliosis, short Ectodermal: newborn ichthyosis, coarse hair/scarring alopecia, dystrophic nails Ocular: *CATARACTS*, microphthalmia, microcornea Screening: *Hi VLCFA* Dx: . Sterol Analysis: increased 8(9) cholesterol + 8-dehydrocholesterol . EBP genetic test Test: *Microdel ARSE+STS+KAL* (*think of pt at LG whose son had STS and wanted to go to Stanford for array*) Tx Supportive

Teratogen Resources

1. *Reprotox*: https://reprotox.org/ 2. *TERIS (Teratogen Information System)*: Teratogen database by University of Washington (Seattle) depts.washington.edu/terisdb 3. *OTISpregnancy* (good for patients)

Human genome

1.5-2% protein-coding genes 26% introns 12% miscellaneous unique sequences 8% miscellaneous 50% repeats ---20% LINEs ---13% SINEs

Cartilage Hair Hypoplasia (CHH) *Skeletal Dysplasia*

1/1,300 *Amish and Finnish* *AR* (unlike other skeletal dysplasia!) *RMRP: RNA gene in nuDNA* (most RNA genes are coded by mtDNA) --- g.70A>G => no protein product Type: *Short trunk dwarfism* 1. Short w short limbs 2. *Blond, fine, sparse hair* 3. Defective T-cell immunity (no live vaccines) =>*Immune deficiency* =>skin ca, leukemia, lymphoma 4. *Hypopigmented skin* 5. Nail and teeh abn 6. GI abn: ****Hirschsprung****, malabsorption, *megacolon* 7. Radiographic Findings: metaphyseal dysplasia Test: If Amish/Finnish-> founder mtn If not: Seq > deldup Tx: Surgical

Fabry *Metabolic* *Lysosomal Storage* *Cardiovascular* *Cardiomyopathy* - NSGC -

1/1,600-1/3,000 *Panethnic!* ****XL**** (NOT XLR: ****~100% penetrance in males + females****, BUT variable expressivity) (unlike other metabolic dx) *GLA* @ Xq22.1 *431 mtns (most private; no geno-pheno correl)* Enz def: *α-galactosidase A (α-gal A): lysosomal enz* - breaks down glycosphingolypids (complex sugar-fat) Defect in fat breakdown => *accumulation of glycolipid globotriaosylceramide (GB3 / GL3) in lysosomes* Disease pathology: vascular endothelial cells Onset: childhood . M: 6-8y . F 9y ****Criteria**** [BOARDZ] *PROGRESSIVE*: . Chronic acute neurpathic ****PAIN CRISIS IN HANDS + FEET**** beginning in childhood (painful neuropathy), painful burning episodes . *Angiokeratomas* (Red-purple cutaneous spots) . Acroparesthesias (*NUMBENESS/TINGLING*) provoked by exercise + temp changes . *HEAT/COLD INTOLERANCE* (hypohidrosis= excessive sweating), pain w heat . *CARDIOMYOPATHY*: Left ventricular hypertrophy, HCM . *Corneal whorls (=ocular opacities), CORNEAL CLOUDING* . Renal insufficiency-> renal failure . Tinnitus . HL . Vertigo . Transient ischemic attacks . Strokes . Arrhythmia: atrial fibrillation . Cardiac valve insufficiency GI dysfunction: ---chronic alternating diarrhea+ constipation ---obstructive pulmonary disease ---proteinuria . Panic attacks . Depression . Adaptive function disorders . Dyshidrosis (eczema) . Cerebrovascular disease *Male life expectancy 41 if untx* Test if: 1. Fhx of Fabry OR 2. Corneal verticillata (whorls) on slit lamp exam OR 2 of below: 1. Decreased sweating (anhidrosis / hypohidrosis) 2. Angiokeratomas = reddish-purple skin rash in bathing trunk area 3. Personal / fhx renal failure 4. Personal / fhx "burning"/"hot" pain in hands + feet, particularly during fevers (acroparesthesias) 5. Personal / fhx of exercise/heat/cold intolerance 6. Pt w sporadic / non-autosomal dominant (no male-to-male) transmission of unexplained cardiac hypertrophy Dx test (biochem+genetic test both needed for dx in males *common pseudodeficiency allele, D313Y, also results in low plasma and slightly low blood α-gal A enz): 1. Biochem test (for males ONLY, not reliable for females): --Deficient leukocyte (blood) and plasma α-gal A enz activity (females nl to decreased levels. Also: *enz levels do not correlate w severity) . Biomarkers in plasma/fibroblasts/urine to aid in tx monitoring: --Lobotriaosylceramide (GB3/GL3) --Lysoglobotriaosylceramide (LysoGL3) *GL3 & LysoGL3 levels difficult to correlate w prognosis in females and individuals w non-classic Fabry + 2. GLA genetic test to confirm dx (for males + females): Seq GLA (and flanking regions)*Standard seq does not detect some intronic mtns & mtns in promoter/other regulatory regions > array-based deldup (for large del + dup) (Targeted mtn analysis if Taiwanese) . Storage patterns on renal / heart biopsy->suggest Fabry BUT not required for dx Prenatal dx: CVS + amnio if familial mtn Enz + genetic test (for prenatal, U.S. labs only do genetic test) PGD avail NBS - enz analysis (->mainly for males) in: . Taiwan . Missouri . Washington State . Illinois After dx: 1. Refer to metabolic specialist and GC (see National Fabry Disease Foundation) 2. Baseline eval: - CBC, platelet count, serum creatinine, BUN + GL3 + Thyroid studies + Thrombophilic blood coagulation disorders + Basic biochem panel - Routine urinalysis - 24 h urine w creatinine, glomerular filtration rate, and protein clearance - First morning urine measuring total protein and creatinine levels - EKG - 24 h Holter monitor - Echo and/or Cardiac MRI - Brain MRI or Head CT - Hearing exam - Ophthalmologic exam - Pulmonary function test - Depression/Anxiety assessment 3. ERT discussion Tx: . Pain meds . ACE inhibitors . Preventative ERT: ---agalsidase beta (Fabrazyme®, Genzyme, Inc.)-US approved-human form of natural enzyme produced by recombinant DNA=>Reduces lipid GL3 accumulation in plasma + kidneys (earlier the better, but NOT cure) ---agalsidase alfa (Replagal®, Shire Human Genetic Therapies, Inc.) - similar to agalsidase beta . for certain alleles - galactose . Dialysis/Renal transplant (test kidney donors, especially relatives, for Fabry prior to trsplt) . Pharmacologic chaperones . Experimental tx: ---substrate reduction therapy ---residual enz activators ---chemical chaperone therapy ---GLA promoter activation ---protein homeostasis regulation ---next generation ERT ---gene therapy ---chaperone therapy (Amicus, AT1001) in trials-> stabilize naturally occurring enz Pregnancy management: 1. *Ween off teratogen meds*: . Dilantin . Carbamazepine (Tegretol) . ACE Inhibitors 2. Monitor proteinuria 3. Consider MFM consult 4. ERT discussion (continue or stop) Management: Yearly eval Support grps: 1. Fabry Support and Info: fabry.org 2. National Fabry Disease: fabrydisease.org 3. NORD—National Organization for Rare Disorders

Rubenstein Taybi *Microdeletion* *Cancer*

1/125,000 *AD* --- *de novo* (most) . *CREBBP* mtn (often) . *16p13.3-* --- *TERMINAL DEL* --- includes CREBBP Criteria: [digits ktir "taybin", that he sucked on them so much and they got inflamed and big and bent) . *BROAD THUMBS* . *BIG TOES* *Some w deviation* Other criteria: . Ca: --- *LEUKEMIA* --- Tumors . Dysmorphic face --- *HYPOPLASITC MAXILLA* (upper jaw) --- *NARROW PALATE* --- *GRIMACING* smile --- *TALON CUSPS* (teeth) --- Nose ------ Prominent *BEAK NOSE* ------ Septum extending below alae nasi --- Eyes ------ Downslanted palpebral fissures ------ Heavy/arched eyebrows ------ Long eyelashes . Hirsuitism . Short . ID (moderate) . CHD Test: CREBBP > FISH / array

Glycogenosis type IV = Glycogen Storage disease IV (GSD IV) = Andersen disease

1/20,000 AR GBE1 Abn glycogen-branching enzyme (GBE) Abn accumulation in liver, muscle, and other tissue Hepatosplenomegaly FTT

*Peroxisomal Disorders* *Metabolic*

1/25,000 - 1/50,000 Peroxisomes bound by a single (not double) membrane several hundred per cell many peroxismal proteins show minimal posttranslational processing ubiquitous in mammalian cells except RBC Peroxisome functions: -very long branch-chain fatty acids and long chain fatty acids, straight and branched undergo beta-oxidation in peroxisomes -peroxidase-based respiration -plasmalogen and bile acid synthesis -glyoxylate transamination -some steps of bile acid metabolism occur here DISORDERS OF PEROXISOMAL BIOGENESIS: *Zellweger* *Neonatal adrenoleukodystrophy* *Infantile Refsum* Dysfunction of all peroxisomal enzymes although to different degrees of *severity* (*highest=Zellweger, lowest=infantile Refsum*) PEX genes responsible for assembly of peroxisomes or import of proteins into peroxisome Liver problems Kidney problems ****High VLCFA**** Low RBC plasmalogen

Ichthyosis Vulgaris

1/250 (most common form of ichthyosis) AD FLG Onset: 2 mo - 1y Dry, scaly skin Prominent white scales Hyperlinear palms

Pompe = Glycogen Storage Disease (GSD) II *Metabolic* *Lysosomal storage* *Glycogen storage* - ACMG -

1/40,000 (common in AA + Taiwanese) *AR* *GAA* Enz def: *hydrolase glucosidase acid alpha (GAA)*, acid maltase deficiency (AMD) Pathology: cardiac/skeletal muscle Classic Infantile: Onset: 1.6-2 mo; Death: 6-8 mo . Progressive muscle breakdown/weakness => Hypotonia + *cardiomyopathy (HCM) in infantile cases*, cardiomegaly . HSM . Respiratory failure . Skeletal . Smooth muscle involvement . Myopathy in all cases . Macroglossia Types: 1. Infantile onset: <1% GAA enz activity . Hypotonia of distal muscles . Cardiomyopathy, aneurysm . Respiratory accumulation-> failure, G-tube (risk of aspiration) . Death by 1-2y 2. Late (adult) onset: 2-40% = skeletal and respiratory muscles . Myopathy . Respiratory failure . PT to improve strength and physical ability-> eventually may need wheelchair *No cardiomyopathy* . *GAA assay on skin fibroblasts (preferred tissue) or muscle biopsy is dx "gold standard"*, can render definitive dx when combined w clinical and lab data (muscle histology when available). ● GAA assay in blood collected on filter paper (dried blood spots) is poised to become a reliable, relatively noninvasive and specific assay ● Dried blood spot/lymphocyte assay and peripheral blood mononuclear cell assay, when done with appropriate inhibitors to inhibit the interfering MGA activity, perhaps in combination with the urine glucose tetrasaccharides (Glc4) assay, are useful adjuncts in the diagnostic work up ● Laboratory testing to help in the initial eval, regardless of the type, should include serum creatine kinase (CK), AST, ALT, LDH, and urine for Glc4 may also be useful ● Analysis of leukocyte vacuoles for glycogen by PAS staining is an inexpensive, quick and reliable test used in some centers Prenatal dx: If known familial mtn-> genetic test. Ideal method of prenatal dx! Otherwise: enz activity in uncultured CVS Can also be done on amnio but enz activity lower than in CVS Genetic test: helpful in some cases Determination of common late-onset splice site mtnn is useful in Caucasians ---GAA common mtn / seq Tx: . ERT: ---Myozyme for infantile onset ---Lumizyme for adult onset ---Issue: Neutralizing antibodies (e.g. CRM negativity in Pompe)-> inhibit efficacy of ERT ---Cardiology fwp ---Pulmonary fwp ---GI fwp ---Musculoskeletal, functional, neurology fwp GENERAL MEDICAL CARE RECOMMENDATIONS ● There should be strict hand washing and aggressive management of infections. ● Routine immunizations, including pneumococcal vaccination, should be used. ● There should be influenza vaccination for patients and other household contacts and use of palivizumab when indicated. ● There should be careful use of over-the-counter meds and concomitant medications. SURGERY/ANESTHESIA RECOMMENDATIONS ● Anesthetic procedure only when absolutely necessary ● Consolidation of procedures requiring anesthesia, to reduce risk of repeated anesthetic exposures ● Judicious use of anesthetics, with precautions followed due to underlying cardiomyopathy ● Procedures at centers with experience anesthetizing pts w Pompe disease or consulting w experts ● Avoidance of intubation

Potter Sequence

1/4000 live births Primary anomaly: obstruction of urinary tract -> renal disease/agenesis, polycystic kidney, and obstructive uropathy during middle gestational weeks ->*OLIGOHYDRAMNIOS* and compression => potter's facies: flat nasal bridge, retrognathia club feet contractors due to deformation (from oligo) a lung hypoplasia => neonatal lethal

Fragile X Syndrome (FXS) = FX = FraX *Imprinting* - NSGC and ACMG -

1/4000 male births, 2nd most common heritable (genetic) form of ID (Down syn is #1) Always considered in differential dx of ID,DD,Autism Most common form of inherited ID XLR, mat anticipation only 1 / 4,000 M (moderate ID) 1 / 8,000 F (1/2 - 1/3 of females w full mtns have symptoms, but ID milder than males! Some completely unaffected) FMR1 = FraX Mental Retardation-1 @ Xq27.3 Abundant in neurons: plays role in synapses-> encodes for FMRP (P=protein) is part of family of interactive proteins that regulate metabotropic glutamate receptor (mGluR) pathway => neuronal function Expansion of ****CGG**** repeat => methylation of CpG islands in promoter => Methylation shuts off transcription => Findings in FraX are due to loss of FMRP => absence of FMRP => abn synaptic signaling and dendritic development => ID . CGG repeats at 5' CGG UTR (in PROMOTER REGION which is NON CODING REGION, unlike HD) . Point mtn / del (2%) AGG Interruptions can Modify Risk: More AGGs→ more stable locus→ lower risk for expansion (once there are 90 repeats, AGGs do not modify) No/Less AGGs→ higher risk of expansion Prenatal dx: Offer to women w premutation or full mutation (males w premutation alleles should get GC) . CVS: usually accurate & reliable (although FMR1 methylation is incomplete in placental tissue at 10 to 12 weeks, methylation patterns can usually be interpreted and used to distinguish between pre- and full mutations. ) Rarely, rslt may be inconclusive if: 1. FMRI methylation status not yet established=Incomplete methylation of FMR1 alleles 2. Expansion of abn allele to borderline size ---fwp amnio may be required if male fetus w 100-250 CGG repeats -> to confirm presence or absence of unmethylated full mutation . if CVS inconclusive, fwp w amnio: cultured amniocytes ideal specimen -PGD: using PCR & linked polymorphic markers ---By detection of nl parental alleles, therefore parents must have different # ---POF or irregular period in pre mtn females ---Amplification of CGG repeat gets harder as it gets larger ---Distinguishing FMR1 alleles may be tricky since carrier rate of intermediate alleles high Dx: southern blot and PCR determine repeat number and methylation status of gene 1. PCR: best for smaller repeats (large repeats are harder to amplify-> full mtn can be missed), short TAT, not affected by skewed X-inactivation & / OR SOUTHERN BLOT (less accurate for repeat size, than PCR) + Methylation Carrier test: Combination of PCR + Southern blot Southern blot analysis is more labor intensive than PCR and requires larger quantities of genomic DNA. Southern blot analysis accurately detects alleles in all size ranges, but precise sizing is not possible. Furthermore, highly skewed inactivation of the X-chromosome harboring the premutation could lead to the lack of resolution of the premutation allele. Laboratories should have both methods available. PCR testing could identify premutation, but not full mutation. (99% DR-> misses rare individuals w pt mtn pr del outside CCC region): intermediate alleles common-> so rule out if pt carries a premutation (or full mtn in cases of females) *allele size may vary by ±1-4 repeats for alleles less than ~120 repeats For larger alleles, accuracy ±10% Old test: Karyotype (less resolution than PCR/Southern blot) e.g. If pt desires FraX carrier testing based on a family history determined by karyotype, affected person is recommended to get molecular test first. Remember: intermediate alleles are common in the general pop(1 in 37 in F, 1 in 57 in M) Population screening: ****ACMG & ACOG**** (2010): . ****If woman has fhx of FMR1-related disorders**** (including FXPOI) . ****If requested by pt**** => offer test (w counseling), regardless of fhx ACOG Opinion: Women with fm hx of fraX should be offered screening Women with POI before 40 w/out known cause should be offered screening Woman who request fraX screening should get it Prenatal testing for FraX should be offered, if mom is carrier Offer FMR1 mtn test if: . Pt w ID / DD / autism . Pt or relative w FX diagnosed w cytogenetic test . Pts seen for reproductive GC if: --- Fhx of FraX or ID (with no specific dx) --- Fhx of FMR1-related disorders (including FXPOI, unexplained infertility, early menopause!) --- Requested by pt, even if no fhx . Woman w reproductive / fertility problems associated w elevated levels of follicle stimulating hormone (FSH) . Pts (especially men) with late (adult) onset tremor / cerebellar ataxia of unknown origin NBS: being evaluated in research studies 1. Nl: 5-44 Stable normal alleles have an AGG triplet every nine or ten CGGs Probably helps prevent slippage. 2. Intermediate = grey zone: 45-54 Carrier freq in females: 1/35-1/57 Small risk to expand to premutation, BUT most are stable: Sometimes expands minimally (1-5 CGG, largest reported expansion 10 CGG). NO reports of expansion to full mtn in single generation-> prenatal dx NOT medically indicated. Despite this, some pts still request prenatal dx * no evidence for significant inc risk for FXPOI or FXTAS 3. Premutation carrier = 55-200 (unmethylated) Risk of expansion to full mtn when maternally transmitted (Nolin, AJMG 2003): 55-59 -> 3.70 % 60-69 -> 5.30 % 70-79 -> 31.10 % 80-89 -> 57.80 % 90-99 -> 80.10 % 100-200 -> 94-100 % Premutation size usually stable when paternally transmitted Premutation carrier freq: F 1/151-1/259 (0.3% per ACMG 2004); M 1-468-1/813 ~1/755) FMR1 premutations produce nl FMRP but high mRNA -> FXTAS and FXPOI due to mRNA toxicity a. FXPOI = FraX premature ovarian insufficiency = diminished ov reserve -> irregular period, elevated FSH, reduced fertility, POF (cessation of menses <40) early menopause 15-20% risk (vs. 1% backg risk) and correlated with repeat size: Highest risk if 55-95 repeats, plateau at 100, declines after as it approaches 200 repeats -- affected Pt w soradic POI: 2-7% have premutation -- affected Pt w familial POI: 10-15% have premutation b. FXTAS = FraX associated Tremor/Ataxia Syndrome Onset >50y Dx: . Clinical features: ---neuro: progressive cerebellar ataxia, intention tremor, peripheral neuropathy, atypical parkinsonism, dementia ---cognitive: declines in intellect, short-term memory, executive functioning ---psychiatric: personality or mood changes, increased irritability, impulsive behavior + . Premutation allele *Hyperintensities of middle cerebellar peduncles often seen on brain MRI in pts w FXTAS and may be a useful dx sign -Sex (males higher risk) & age-related penetrance: After 50y: 46% (20-40% risk per ACMG 2004) risk in males; 17% risk in females (more common in males) ---50-59y - 20% ---60-69y - 38% ---70-79y - 47% --->80y - 75% -short-term memory loss, executive fxn deficits, cognitive decline -late-onset, progressive cerebellar ataxia and intention tremor, parkinsonism, peripheral neuropathy, lower-lim proximal muscle weakness, autonomic dysfxn If mother has >100 repeats-> 94-100% chance of expansion to full mtn in offpsring 4. Full mutation = >200 (hypermethylated) (freq females 1/200 females->1/3-1/2 severely affected (50-60% penetrance); males 1/1,250) 1. ID (mild-severe IQ 30-50 but can be above 70), ADHD, Autism (1-5% of autism due to FraX. 20% of FraX boys have autism), delayed milestones (esp. speech) 2. Hyperactive 3. Post-puberty: . Dysmorphic face - long face, big ears, prominent chin&forehead (may not be apparent until after puberty) . Macroorchidism (testicles of more than 25 ml in size) may not be apparent until after puverty . Cleft palate . Connective tissue: hyperflexible, flat feet, mitral valve prolapse, soft velvety skin, joint laxity, strabismus Severity depends on: . Repeat # in full mtn allele . Methylation status: "Methylation mosaicism" in some males (some alleles unmethylated->gene product (FMRP) made) . Mosaicism (males w milder pheno) . X inactivation (in females only)-> females show more variable clinical expressivity than males ****NOT associated w FXTAS / FXPOI**** *Sperm in affected males w full mtn contain only permutation alleles! Affected Male (Full Mutation) Variable degrees of intellectual disability ASD, poor eye contact, hand flipping Attention deficits, anxiety, speech difficulty Physical: long face, prominent ears, enlarged testicles IF mosaic: symptoms may be milder at may be at risk for FXTAS/FXPOI Affected Female (Full Mutation) Often less severe intellectual impairment than in males Mild-moderate ID, ASD, learning disabilities and psychiatric disorders Poor eye contact, attention problems, shyness, social anxiety Face: long face, prominent ears (more subtle than males) Tx: Targeted tx: Regulation of mGluR pathway through drugs that mimic effect of FMRP. Studies of mGluR antagonists in FXS knockout mice have shown a positive effects - some of these meds in clinical trials

Marfan Syndrome (MFS) *Connective Tissue*

1/5-10,000 *AD* ---25% de novo *FBN1* (fibrillin) on ch 15 ---Truncating mtns=>milder dx ---Missense mtn in center=>severe dx Skeletal: Tall=>skin striae (stretch marks) Scoliosis (progressive) Kyphosis Spondylolisthesis ****Dural ectasia**** [BOARDS]=widening or ballooning of dural sac surrounding spinal cord (usually in lumbosacral region, where cerebrospinal fluid pressure is greatest) Pneumothorax (chest pain and breathlessness) Dural ectasia (local and radicular pain; leg and sphincter weakness, confusion w other possible pelvic masses) Pectus Reduced upper:lower segment ratio Increased arm span:height ratio Arachnodactyly Flexibility Flat feet Positive wrist sign; positive thumb sign Contractures Muscle/fat hypoplasia Face: Mouth: high arched palate, crowded teeth, overbite, malar hypoplasia Eyes: deep-set, downslanting palpebral fissures Ocular Major: ectopia lentis Minor: high myopia, increased axial globe length, corneal flatness Cardiac: Aortic root dilation Aortic Regurgitation: CHF, sudden death Aortic Dissection: sudden death, MI, organ ischemia (stroke), late rupture ---More likely to dissect in colder mo, daylight): ---Associated w medial degeneration (associated w age; not specific to Marfan) Mitral valve prolapse ACMG systemic score: . Reduced upper-to-lower segment ratio AND increased arm/height AND no severe scoliosis = 1 . Scoliosis / thoracolumbar kyphosis = 1 . Reduced elbow extension = 1 . Facial features (3 of 5: incldolichocephaly, enophthalmos, downslanting palpebral fissures, malar hypoplasia, retrognathia) = 1 . Skin striae = 1 . Myopia >3 diopters = 1 . Mitral valve prolapse (all types) = 1 . Wrist AND thumb sign = 3 (wrist OR thumb sign = 1) . Pectus carinatum deformity = 2 (pectus excavatum or chest asymmetry = 1) . Hindfoot deformity = 2 (plain pes planus = 1) . Pneumothorax = 2 . Dural ectasia = 2 . Protrusio acetabuli = 2 =>Score 7+ => systemic involvement (max total: 20 points) Dx eval 1. Physical 2. Fhx 3. Echocardiogram 4. Dilated eye exam 5. Consider CT or MRI for evidence of lumbosacral dural ectasia and protrusion acetabulae 6. Consider FBN1 seq (90-95% DR)=>NOT necessary to make dx (very few geno-pheno correl) *Ghent criteria: clinical dx* (Z = SD from mean, e.g. 2+ => 2 SD above mean) -W neg fhx: 1+ of: . Aortic root dilation Z score >2 + ectopia lentis . Aortic root dilation Z score >2 + FBN1 mtn . Aortic root dilation Z score >2 + systemic score >7 . Ectopia lentis + FBN1 mtn w known aortic root dilation -W pos fhx: 1+ of: . Ectopia lentis . Systemic score >7 . Aortic root dilation: Z score >2 if >20 y, >3 if <20 y Tx: Cardio: (cardiologist) A. Aortic root dilation and/or diagnostic criteria met for Marfan . Annual echo for root diameter <4.5 cm in adult and rate of increase <0.5 cm/y . Echo every 6 mo if diameter >2 SD in adult or rate of increase in size >0.5 cm/y . Med: B-blockers=B-andrenergic blockers, ACE inhibitors: Current trial of Cozaar=Losartan (HTN med) vs Tenormin=atenolol (beta blocker) . Surgical repair for measurements >4.5-5 cm, rate of increase in size >1 cm/y, or progressive aortic regurgitation ---Older method: Aortic Root Surgery at dissection or severe CHF ---Current method: Prophylactic Composite Graft Repair . Magnetic resonance angiography / CT of entire aorta starting in young adulthood. Repeat annually if hx of aortic root replacement or dissection, less frequently if not . Avoid: competitive/contact sports B. Nl aortic root size w systemic involvement of another system w positive family/genetic history: . Annual echocardiogram C. Nl aortic root size w systemic involvement w neg family/genetic history: . Repeat echo every 2 to 3 y until adult height reached . Then repeat if symptomatic or when major increase in physical activity planned *Diameter of aortic root slightly larger in men than women. Increases very slightly and gradually w age is nl, but should not exceed upper limit of nl of 40-42 mm, even in tall individuals During Pregnancy: Meds continued and echos done in all trimesters! --Risk of aortic dissection low in women w nl aorta size --If aorta slightly enlarged-> risk of dissection higher during pregnancy + postpartum

Cri du Chat *Microdeletion*

1/50,000 *AD* --- *90% de novo* --- 10-15% parental balanced transl *5p15- (TERMINAL DEL)* [BOARDZ] Criteria: . *HIGH PITCHED (cat-like) CRY* . *Microcephaly, ID, DD* . Low birth weight . Slow growth . Hypotonia . Hypotonia . Strabismus . Dysmorphic face --- Hypertelorism --- Low set ears --- Small jaw --- Round face --- Epicanthal folds --- Micrognathia Other criteria: . CHD . Neuro abn . Renal abn Dx: Clinical dx > G-banding karyotype / FISH / array Tx: Treat other problems w standard tx

Wolf Hirschorn = Pitt Rogers Danks *Microdeletion* *Ring chromosome*

1/50,000 *AD* --- *de novo (>50%)* --- *unbalanced transl inherited from balaned parent (~50%)* . ****4p16.3- TERMINAL DEL**** [BOARDZ] . *Ring chrom* / transl (some) Criteria: *think G. G. for Greek + GU defect* . Dysmorphic face: --- *Greek warrior helmet* face [BOARDZ] --- High forehead --- Short philtrum --- Small ears w pits/tags --- Microcephaly --- Broad, flat nasal bridge --- Hypertelorism; protruding eyes --- Micrognathia --- Asymmetrical face . *GU abn* . DD, ID . Seizures: usually disappear w age . CHD: ASD . Conductive HL . Eye abn . FTT . Hypotonia→ delayed motor skills . Short . Strong socialization; poor communication/language Other criteria: . Mottled, dry skin . Scoliosis, Kyphosis . Dental prob . CLP Dx test: *FISH / array* (karyotype 50% DR) Tx . Communication, ID --- ST, OT, PT --- Sign language . Seizures → neurology --- Antiepileptic drugs . FTT → gastroenterology --- Special feeding techniques --- Gastrostomy . CHDs → cardiology . Eye abn → ophthalmologist . Skeletal prob → orthopedics . Antibody def → immunologist . HL → audiologist . Urinary tract abn → urologist

Familial Hypercholesterolemia *Dyslipidemias*

1/500 . *AD* (homozygotes have earlier onset/more severe disease) --- *reduced penetrance* --- CAD onset 30s+ (chol > 300mg/dL, avg 250-400) . AR (rare): --- childhood onset, severe (chol > 600mg/dL) . *LDLR* @ 19p13.2 (most common) --- Enz def: *LDL receptor* . *APOB-100* . PCSK9 *20-40% unknown gene* . Private mtns, some founder mtns . Some promoter mtns Criteria: *Hi total serum LDL ("bad") cholesterol + cholesterol = hypercholesterolemia early in life (onset at birth)* > . *Atheromas* (collections of cholesterol in artery walls): Atherosclerosclerosis = artherosclerotic plaque deposition in arteries and increased risk of CAD (heart attack at young age) . *XANTHOMAS = deposits in tendons* . *XANTHELASMAS* = arcus corneae = deposits around eyes* (if in <40y = arcus juvenilis) . Angina . MI . Strokes Genetic test: *LDLR seq* APOB & PCSK9 targeted analysis Benefits of genetic test: Early screening for elevated cholesterol levels Risk-factor modification before onset of disease Tx: . *Restrict cholesterol intake* . Statins . Oral lomitapide . SQ Mipomersen injection . Plasmapheresis/exchange transfusions . *Cardiac/liver transplant*

Hypertrophic Cardiomyopathy (HCM) *Cardiovascular* *Cardiomyopathy*

1/500 pts w unexplained LVH *Genetic (60-70%)* Types 1) Adult onset: -*AD* --- *Reduced penetrance* --- Variable expressivity -*Sarcomere* mtns: geno-pheno correl ---****MYH7**** (*think MY Heart*) [BOARDZ] (40%): onset 2nd decade ------ Arg663His (G1988A) on exon 18: Class 1 ------ R403Q - inc sudden death risk --- MYBPC3 (30%): onset 3rd-4th decade --- TNNT2 (25%): mild LVH + inc risk sudden death risk --- TNNI3 (5%) Onset: 1-90y (*usuall adolescence 15-25y*) Criteria: . *LVH* (non-dilated): asymmetric (2/3) - in absence of predisposing heart condition: --- Aortic stenosis --- HTN --- Athlete's heart => outflow obstruction . *Disarray / disorganized heart muscle cells* => *arrhythmia* . Syncope . Exercise fatigue . Chest pain/palpitations . Short-breath . Orthostatic hypotension . Arrhythmias . Sudden cardiac death (10-20%) . Heart failure 2) Infant / early child onset + severe (3-5%) - AR (most) -Sarcomere mtns ---Noonan Spectrum ------RAF1 ------KRAS ------BRAF Non-genetic / unknown cause (30-40%) Dx . *Echo* / cardiac MRI --- LVH w/out dilated ventricle --- Intracavity hypertrophy --- Outflow obstruction . *Hi heart weight* (e.g. 600 grams) . Ventricles hypertrophy . *Myocardial disarray* . HCM . *Syncope* . EKG --- *Inc QT* --- Prominent Q waves in inferior and lateral leads --- Diffuse T wave inversions --- Pattern consistent w LVH w HCM --- Pattern consistent w LA enlargement . Heart pathology --- Cellular/myocyte disarray --- inc fibrosis/scarring --- No infiltrative disease . Physical exam: ---4th heart sound ---Prominent left ventricular apical impulse / lift Test if: . Clinical dx of HCM or . Fhx of sudden cardiac death < 45 or . Unexplained cardiovascular prob: --- Chest pain --- Syncope --- Short breath Test on: Youngest + most symptomatic relative (first) Genetic test: . *Multigene panel (DR 60-70%)* => Distinguishes different HCM types (*geno-pheno correl*) *Tx (only if SYMPTOMATIC)*: . No competitive endurance sports / burst activities: sprinting, intense isometric exercise (heavy weight lifting, etc) => use moderate exercise . Meds --- *Beta blockers*, and other antiarrhythmics --- *Calcium channel blockers* --- Disopyramide . Catheter-based ablation . Surgical myectomy (removal of section of muscle from IVS) . ICD . Pacemaker . Heart transplant Screening: echo, HOLTER, exercise <12y if fhx if early HCM-related death 12-25/30y EKG + echo yearly >25/30y -ECG + echogardiography every 3-5y if asymptomatic Family testing . Proband pos: cascade family test . Proband neg: cascade family EKG/echo screening every 3y (*nl echo does NOT rule out HCM bcs low penetrance*)

Pendred *Hearing loss*

10% of hereditary HL *2nd most common AR HL* *AR* *SLC26A4* @ 7q31 (50%) => encode pendrin (*in thyroid and inner ear*) FOX1I (1%) Allelic: DFNB4 - no thyroid defects 1. Temporal bone abn on CT scan: . ****Bil ENLARGED VESTIBULAR AQUEDUCT**** +/- cochlear hypoplasia . *MONDINI* defect => *CONGENITAL & PROGRESSIVE SNHL* => gets worse if you fall and hit your head & => *Balance prob* 2. Thyroid: euthyroid ****GOITER**** [BOARDZ] (75%), *HYPOTHYROIDISM*, or perchlorate discharge test (in late childhood to early adulthood); block in thyroxin synthesis; or nl thyroid 3. *ID* Other criteria: Hi serum thyroglobulin Dx test: *Clinical: hearing test + temporal lobe CT/MRI* *SLC26A4 common mtn > seq*

Carbamyl Phosphate Synthetase (CPS) Deficiency (CPSD) *Metabolic* *Urea Cycle*

1:1,300,000 *AR* *CPS1* *Step before OTC -> product: CAP* Biochem: *Hi ammonia* *uOA: nl / low orotic acid (vs OTC) (bcs no CAP made to go to orotic acid)* pAA: ---Low citrulline (like OTC) (bcs no CAP --> citrullne, i.e. downstream of enz defect) ---Low arginine Severe Rapid hyperammonemia in newborn Children who successfully rescued from crisis are chronically at-risk for repeated hyperammonemia bouts

Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) *Arrhythmia*

1:10,000 *AD* *RYR2* (50-55%) > 60 known mtns 83% penetrance AR (rare) CASQ2 (1-2%) Age of onset: 7-9 y *1st symptom may be sudden death: fhx of SCD <40 in 30% of pts w CVPT* Associated w *SIDS* Episodic dizziness/palpitations/syncope during exercise or acute emotion *No structural cardiac abn* Dx test: Stress/exercise EKG: induced polymorphic ventricular ectopy/arrhythmia (80% DR) -Bidirectional VT -Irregular polymorphic VT w/out a stable QRS vector *Nl resting EKG Genetic test (DR 65-75%) Family testing: Proband pos→ cascade family testing Proband neg→ cascade family EKG screening Tx: Beta-blockers (50% of pts w CPVT will continue to experience arrhythmias) ICD (mortality 30% by age 30 w/out tx) Surveillance Semi-annual or annual -Resting EKG -Holter monitoring -Exercise stress test, performed at maximal age-predicted heart rate

Ornithine Transcarbamylase (OTC) Deficiency *Metabolic* *Urea Cycle*

1:56,500 *Most common UCD* ****XLR**** (only XL UCD) *OTC* Enz def: *ornithine transcarbamylase* =>* hi ammonia* Onset: --- M ------Neonatal (severe deficiency) ------Later/adult onset (partial def) ---F (15% of carriers show symptoms): later/adult onset *NL @ BIRTH* - become symptomatic after starting to ingest *protein* (e.g. human milk / formula given to newborn) => Progressive *HYPERAMMONEMIA* Criteria: [BOARDZ] *Neonatal onset* form: *ENCEPHALOPATHY* --- Poor feeding -> *ANOREXIA* --- *LETHARGY* --- *VOMITING* --- Seizures --- Poor body temp control --- Heavy/rapid breathing --- Progressive liver damage --- ID => progress to lethal (*NEONATAL COMA*, respiratory failure, death) ===> *Late-onset* form: chronic - symptoms worse w illness / protein ---*HEADACHES*, vomiting ---*NEUROPSYCH* prob: *POST-PARTUM DELIRIUM*, erratic behavior, less conscious, disoriented ---*PROTEIN AVERSION* (can east sugar just fine) ---*COMA DURING FLU-LIKE ILLNESS* ---*REYE-SYNDROME LIKE ILLNESS* ---abn pain ---liver damage ---brittle hair ---seizures Pregnancy: ------*MAT HYERMAMMONEMIA if pregnant woman is a carrier* => at-risk of becoming catabolic during preg + postpartum (esp at delivery bcs stressful); protein aversion => watch for symptoms for hyperammonemia Dx . Biochem: - v hi ammonia (>2000) - uOA: ****hi orotic acid**** (*only UCD w this*) bcs CAP (OTC substrate) builds up and gets converted to orotic acid - pAA: ---hi glutamine (w ammonia) ---hi alanine ---Low citrulline ---Low ASA ---Low arginine . OTC genetic test Prenatal dx: *Genetic test (not enz / biochem bcs OTC expressed only in liver)* Tx -Neonate: If pos prenatal dx=>prospective IV w *ammonia scavengers* within few hours of birth can prevent hyperammonemic crisis -Acute: ---hemodialysis ---protein cessation ---IV glucose/lipids ---IV ammonia scavengers -Chronic: ---protein restriction ---metabolic formula ---oral citrulline/ammonia scavengers ---Liver transplant *Unexpected death of adolescent in 1999 during gene therapy trial*

Aneuploidy

20-25% of eggs 10-30% of conceptions 0.3% (1/333 of newborns) Trisomies: 16 (31% of prenatal trisomies) 22 (10%) 21 (9%) 15 (8%) 18 (6%) 13 (5%) Aneuploidy risk: Hydrocephaly/ventriculomegaly: 10% - 21,13,18,triploidy CHD - 10% (17%) - 21,18,13,22-,8,9 Meningomyeloceles - 7% - 18 Anencephaly - 2% Encephalocele - 10% Limb reduction - 8% - 18 Clubfoot - 6% - 47,XXY, 47,XXX,18, 21 CLP - 1% - 13,18,22q Cystic hygroma - 60% (>50%, 45,X) Hydrops - >50% - 13,21,18,45,X Holoprosencephaly - 50% (47%)13,18,18p AV canal - 40%, 21 Omphalocele - 30%, 13,18 Duodenal atresia - 30%, 21 !!!!! Bladder outlet obstruction - 20%, 13,18 VSD - 38% TE fistula - 40% MCA - 29%

Arrhythmogenic Right Ventricular Dysplasia / Cardiomyopathy (ARVD/C)

30-50% of pts have pos fhx *AD* --- 50-80% penetrance 8 genes: PKP2, DSG2, DSP, DSC2 (RYR2, TGFB3, JUP) => Part of *desmosome* complex => Keep myocytes aligned Variable expressivity + broad spectrum of symptoms -Incidence: 1/1,250 - 1/5,000 ---Greater in certain regions: Italy and Greece ---M >> F -Avg age of dx = 31y Fibro-fatty replacement of right/left ventricular myocardium: myocytes (heart cells) separate or deteriorate and replaced w fat => Loss of muscle leads to thinning of ventricle wall => Disrupts cell-to-cell electrical signaling => Arrhythmias: monomorphic ventricular tachyarrhythmia w left bundle branch block => May have arrhythmias before changes in heart seen => Affects dilation of right/left ventricle => Causing poor contractions of heart => Often 1st symptom death (30 y) Heart palpitations Ventricular tachycardia (fast heart rhythm) Ventricular fibrillation (uncoordinated beating) Fainting (syncope) Chest pain Breathlessness (shortness of breath) Intolerance to exercise Heart failure/Cardiac Arrest Dx test: Combination of noninvasive and invasive dx tests to detect changes in heart structure and rhythm: ECG Exercise stress test Cardiac MRI to assess RV heart function or biopsy of RV (can't always detect by Echo/EKG) Dx 2 major / 1 major + 2 minor / 4 minor criteria *Some individuals may not meet strict criteria Major -*Severe right ventricular dilation and reduction of right ventricular function w no (or only mild) left ventricular impairment. Fibrofatty replacement of myocardium observed on endomyocardial bx* -Localized right ventricular aneurysms -Severe segmental dilation of right ventricle Epsilon waves or localized prolongation (>110 ms) of the QRS complex in right precordial leads (V1-V3) Familial disease confirmed at necropsy / surgery Minor Mild global right ventricular dilation and/or ejection fraction reduction with normal left ventricle Mild segmental dilation of the right ventricle Late potential (signal averaged ECG) Regional right ventricular hypokinesis e.g.Familial history of premature sudden death (<35 years) suspected to be caused by right ventricular dysplasia Fhx (clinical diagnosis based on present criteria) Left bundle branch block-type ventricular tachycardia on ECG, Holter, or exercise testing Inverted T waves in right precordial leads (V2 and V3) (age >12 years, in absence of right bundle branch block) Tx Serial echo EKG Stress echo Cardiac MRI B-blockers ICD Heart transplant No competitive sports Screening: MRI, EKG Known mtn: yearly from 10-50y FDR: every 3-5 y > 10y

Advanced Paternal Age (APA) - ACMG -

40+ / 45+ (av pat age 27) De novo mtns: 0.3-0.5% risk of AD dx if FOP 40+ AD single gene disorders: *Many detectable w US but some not until 3rd tri* [BOARDZ] 1. FGFR2 craniosynostoses: . Crouzon . Apert . Pfeiffer 2. FGFR3 skeletal dysplasias: . *Achondroplasia* [BOARDZ] . Thanatophoric dysplasia 3. RET mtns: . MEN2A . MEN2B Less strongly associated AD conditions: 1. NF1 2. OI Also: Multifactorial conditions [BOARDZ]: ---*Autism* [BOARDZ] ---Schizophrenia Association w aneuploidy: Pretty much NO (mayyyyybe inc risk for T21 + XXY based on some new studies but not conclusive) Test: NO screening / dx test specific for APA. No "APA panel" Recommend det US can detect some AD dx associated w APA (e.g. skeletal dysplasia, but most not detected by US especially since most adult onset) =>if you see a couple and male is APA=> still offer same prenatal testing

Hereditary Breast and Ovarian Cancer (HBOC) *Cancer* - ACMG -

5-10% of br ca hereditary Risk Factors for br ca: Age Fm Hx Early Menarche (<12) Late Menopause (>52) Nulliparity Estrogen/ Progesterone use after menopause > 2-3 alcoholic beverages/wk Protective Factors: 4 or more h/wk of exercise Breastfeeding Maintaining ideal body weight (Esp. after menopause) Having children prior to age 30 *Lobular carcinoma in situ (LCIS): lesions characterised: --- 25-30% ca risk --- not premalignant --- multi-centric --- bil *Atypical hyperplasia (atypia)*: ductal / lubular -> ****MODERATE INC RISK**** [BOARDZ] --- w/out br ca fhx-> 20-25% risk --- w br ca fhx-> up to 40% risk AD -BRCA1 @ 17q21 -BRCA2 @ 3q12.3 (ov ca cluster exon 11) -PALB2 (interacts w BRCA2): ---br ca, male br ca ---*pancreatic ca* ---ov ca (rare) -ATM: ---Br ca ---CC ---Pancreatic ca (rare) -CHEK2: common mtn c.1100delC (genetic test CHEK2 seq) ---Br ca ---CC Homologous recombination DNA repair 5-10% del/dup/rearrang *AJ: 1/40* *General pop: 1/400* . BRCA1: 1/300 . BRCA2 1/800 AJ mtn: *BRCA 1 185delAG* (1% carrier rate in AJ) *BRCA1 5382insC* (0.4% carrier rate in AJ) *BRCA2 6174delT* (1.2% carrier rate in AJ) Founder mtns: Dutch: 3 large BRCA1 dels Iceland: 999del5 Hispanic BRCA1: mainly br+ov 20-40% of all hereditary br ca 70-90% of all hereditary ov ca BRCA2: br+ov+others 10-30% of all hereditary br ca 20% of all hereditary ov ca *BR* ca (path: BRCA1: ductal (often) or medullary (rare); triple neg. BRCA2: ductal (often), lobular (some-more common in BRCA2), medullary (rare); nothing unique) (40-87% in BRCA1 >> 28-84% in BRCA2)(40-60% risk for 2nd primary br ca) *Ov* ca - epithelial (15-60% risk in BRCA1 >> 10-27% risk in BRCA2 >> 2% general pop) *PROSTATE* ca (16% risk in BRCA1, 5-25% risk in BRCA2) ****PANCREATIC**** ca (2-3% risk in BRCA1, 3-10% risk in BRCA2) *MALE BR ca* (1-5% risk in BRCA1, 5-14% risk in BRCA2) *Melanoma* ca (1% risk in BRCA1, 3-5% risk in BRCA2) Fallopian tube ca Primary peritoneal ca Refer if: Personal hx / FDR: . Br ca ≤50 . Triple-neg br ca ≤60 . 2 primary br ca in person . Ov/fallopian tube/prim peritoneal ca . AJ & br / pancreatic ca . Male br ca . 3 cases of br / ov / pancreatic / aggressive prostate ca in close relatives (exclude if all 3 aggressive prostate ca) HCCN criteria: -Br ca pathology (BRCA1): *Triple neg* = . Estrogen receptor neg . Progesterone receptor neg . HER2/neu neg -*AJ* -*Br ca w sister w ov ca* -Fallopian tube ca Ca models that include breast bx: BCRAT: Breast Cancer Risk Assessment Tool Tyer-Cuzik (IBIS) Cancer risk models for unaffected people: GAIL Claus Models of Numeric Risk Assessment: br ca risk for women w no known mtn *Gail Model*: Provide 2 risk estimates: Absolute lifetime risk of br ca to age 90 5 y br ca risk Not used in women w LCIS/DCIS -Incorporates: Age *REPRODUCTIVE HX* Benign br disease hx Br ca in mother or sisters -Does Not Incorporate: Other ca SDR Pat hx Age at dx in relatives -Limitations: underestimate hereditary risk of br ca *Claus Model*: Statistical model to calculate cumulative br ca risk based on fhx Fhx of br ca in FDR + SDR (incl. age at dx in relatives) is only risk factor considered -Limitations: can't input certain relationships, so need to use different people w same degree of relationship *BRCA1/2 Prior Probability Models* Uses: Determine pre-test chance that individual will test pos for BRCA1/2 mtn Helpful in determining who to offer testing in research + clinical setting Many programs consider 5-10% reasonable prior probability to offer test -Examples: Cancer Gene Connect: *BRCAPro* [BOARDZ], MMRPro, PANCPro, MelaPro *Myriad Prevalence Tables* [BOARDZ] *Penn II Model* *BOADICEA* *Tyrer-Cuzick* Male Breast Cancer models: *BOADICEA* *BRCAPRO* Genetic test: BRCA1 & 2 seq > deldup In AJ: Test for founder mtns, even in familial mtn BRCA1/2 seq > deldup (12%) *BRCA 1/2 VUS* Many are missense mtns Variant tracking can help Check to see if reported w a deleterious mtn: 1-*BIC Database - through National Ca Institute* 2-*Polyphen* 3-*Protein Blast* Management: Clinical/Self Breast Exam 20-25 Every 6 mo Mammogram 20-25 Every 12 mo Breast MRI 20-25 Every 12 mo CA-125 30-35 Every 6-12 mo Transvaginal u/s 30-35 Every 6-12 mo Prophylactic Bil Mastectomy (consider) (>90% risk reduction) Prophylactic Oophorectomy After childbearing Recommended (80-96% Ov, 50% Br risk reduction) Chemoprevention: Tamoxifen reduces the risk of second br ca in BRCA pos women Raloxifene has similar risk reduction as Tamoxifen (w/out uterine ca risk) Aromatase inhibitors used exclusively in postmenopausal women PARP Inhibitors BRCA1/2 deficient tumors have base excision repair; if PARP is blocked- both repair mechanisms are knocked out→ cell dies This spares normal cells but kills ca cells Avoid: Meds that inc br ca risk: hormonal contraceptives (incld. estrogen)

Skeletal Dysplasias = Osteochondrodysplasias - ACMG 2009 -

> 350 dx => many types and prenatal dx difficult Most AD If homozygote / compound heterozygote-> usually lethal Ossification @ early GA: . Clavicle + mandible @ 8 wk . Appendicular skeleton + ileum + scapula by 12 wk . Metacarpal + metatarsal by 12-16 wk Fetal skeleton visualized by 2D US by 14 wk: measurements of femora + humeri part of basic midtrimester US Evaluate for skeletal dysplasia (evaluate whole skeleton and GC) if: . Long bones (femora / humeri) > 2 SD below mean (<24wks) in 2nd tri (<24 weeks) ---If 5th centile / 3 SD below mean-> skeletal dysplasia strongly suspected, especially if head circumference >75th centile US measurements to eval: 1. Cranium (BPD, head circumference) 2. Face profile 3. Chest circumference 4. Long bones 5. Hands + feet 6. Vertebral bodies 7. Mandible, clavicle, scapula Prenatal dx: . US DIAGNOSTIC (even if genetic test neg) . GC based on US findings . Routine US accuracy: 40% . CONFIRM dx postdelivery/postmortem by: - Clinical - Radiologic eval: ---anterior-posterior radiographs of appendicular skeleton (incl hands+feet) ---anterior-posterior+lateral radiographs of cranium+spine *Pathologists collect cartilage+bone (ideally femora+humeri) for histomorphic analysis - Autopsy . Consider genetic test to confirm US findings ---Tissue (fibroblasts+cartilage+bone) / DNA banking for genetic analysis (bcs many skeletal dx have significant rec risk) 3D US: Helps distinguish face abn Prenatal dx can identify many lethal (and non-lethal) skeletal dysplasias Identified in 1st tri: lethal Identified in 2nd tri: may be lethal Identified in 3rd tri: usually less profound Lethality in most skeletal dysplasias bcs: short ribs-> small chest circumference -> pulmonary hypoplasia (chest circumference: good predictor of lethality) Perinatal lethality strongly suggested if: . Chest to abd circumf ratio <0.6 and/or . Femur length to abd circumf ratio <0.16 Management: Surgical Options: scoliosis, spinal stenosis, joint replacement; limb lengthening Growth meds: GH, BMN-11, statins, meclozine Maternal skeletal dysplasia management: . Consult w OB, MFM, anesthesiologist . Pregnancy safe w minimal complications (often w C-section): eval whether mother affected by long-trunk vs short trunk skeletal dysplasia->need for operative delivery, regional vs general anesthesia, optimal delivery time Resources: 1. Little People of America 2. Osteogenesis Imperfecta Foundation 3. International Skeletal Dysplasia Registry: csmc.edu/skeletaldysplasia 4. European Skeletal Dysplasia Network

Angelman syndrome (AS) *Imprinting* *Microdeletion*

AD *15q11-13* --- *Loss of mat expression [Angel man misses his mom]* ------ ****UBE3A**** (ubiquitin-protein ligase E3A) ------ ****OCA2**** . *Normally expressed in mat inherited ch* . ****MAT 15q11-13 DEL**** (70%) . *Mat UBE3A mtn* (11%) . *upd(15)pat (3-5%)*: *usually involves entire ch15*=> *2 SNRPN copies* & *no UBE3A* (*think mom was killed by 2 SRPN bcs she did not take an UBEr*) . *Imprinting center (IC) defect* (3%) --- del in IC (0.5%) . Unknown cause (10-15%) Onset: 6-12 mo . *Hypertonia after infancy* . *HAPPY PUPPET: excited (paroxismal laughter) w hand flapping like a puppet* (*THINK HAPPY ANGEL*) . DD, *severe ID* w *no speech* (*less than 5 words!*) . *Fair skin, light-colored hair + eyes (if del includes OCA2)* . *Widely spaced teeth* . Ataxia, jerking movements . Acquired microcephaly . Seizures *Similar pheno to Rett!* Test: . *Methylation* to determine imprinting => . *FISH, array, WES, UPD, IC methl + del analysis, MLPA* . *UBE3A / multigene panel*

Juvenile Polyposis Syndrome (JPS) *Cancer* *Microdeletion*

AD *BMPR1A* (20%) (*think bumper smashed bcs so juvenile*) *SMAD4*=*SMADH4* (20%) *Microdel JPS+ hereditary hemorrhagic telangiectasia (HHT)* *Onset: 15+ y* >3 *juvenile* polyps (*hamartomatous or adenomatous* histology) (*JUVENILE TYPE of polyp NOT AGE at dx) anywhere in GI tract, usually w bleeding*: . Colon ca (common - 39%) . Gastric ca (21%) . Small bowel ca . Pancreatic ca Other criteria: . *Telangiectasia (nosebleeds) / vascular abn (9%; SMAD4) (HHT-like)* . Valvular heart disease (11%) . Macrocephaly (11%) Genetic test: *BMPR1A+SMAD4 seq* Management Colonoscopy 15 Every 3 y Upper Endoscopy 15 Every 3 y CBC 15 Every 3 y Refer if: Personal hx / FDR: ****3-5 juvenile GI polyps (anywhere in GI tract) - frequently presents w bleeding**** OR Juvenile polys & fhx of juvenile polyposis OR Juvenile polyps throughout GI tract Presence of multiple juvenile polyps; should be considered in anyone w >3 juvenile polyps

Central Core Disease (CCD)

AD *RYR1* (*think REALLY hot*) ****MALIGNANT HYPERTHERMIA**** (65-75%) Mild hypotonia during early infancy Delayed motor milestones Generalized muscle weakness; quite stable Hip dislocation, spinal deformities, arched feet, pectus excavatum Muslce bx: central cores

Saethre Chotzen Syndrome (SCS) *Craniosynostosis*

AD *TWIST1 (NOT FGFR!!! unlike other craniocynostosis)* ---Point mtn, dels, dups 1. Uni / bil *coronal synostosis* 2. *Facial asymmetry* 3. *Ptosis* 4. *2-3 syndactyly* 5. ****Small ears w small pinna, prominent crus, HL**** 6. Low frontal hairline 7. Strabismus 8. Cleft palate 9. Short *Nl IQ* *Similar pheno to Muenke except SCS less DD + SNHL Test: seq > deldup > structural abn @ 7p21 Tx: Cranioplasty in 1st y of life to prevent increased ICP (intracracial pressure)

Kabuki

AD . *KMT2D = MLL2* (8%) . KDM6A *Chromatin regulation* Criteria: . ****Fetal fingertip pads**** (*think japanese baby soft hands*) . *Postnatal GR* . *CHD (50%)* . *ID* (moderate) . Short 5th finger . Joint hypermobility . Face: --- Eyes: long palpebral fissures, eversion of lateral portion of lower eyelid, arched eyebrows w sparse lateral third --- Ears: prominent, abn, HL --- Nose: short

LEOPARD *Hearing loss*

AD . PTNP11 . RAF1 . BRAF PTPN11 causing LEOPARD is a LoF mtn (vs Noonan GoF) L LENTIGENES E EKG conduction abn (also HCM) O Ocular hypertelorism P Pulmonary stenosis (=pulmonary valve stenosis)-> HEART MURMUR A Abn of genitalia R Retardation of growth D Deafness (SNHL)

Lattice Corneal Dystrophy

AD Amyloid deposits cloud the cornea → → Corneal erosions, pain, light sensitivity => vision impairment

Hereditary Mixed Polyposis *Cancer*

AD BMPR1A GREM1 - AJ founder mtn Polyps of mixed histology: . Hyperplastic . Adenomatous . Juvenile polyps -> CC Refer if: Personal hx / FDR: 10+ colorectal polyps w mixed histology

Timothy = Long QT 8 (LQT8) *Cardiovascular* *Arrhythmia* *LQT variant*

AD CACNA1C Criteria: . LQT (470-480 ms) . CHD . Fingers/toes syndactyly . Long thin face . Neurodev prob

Spondyloepiphyseal Dysplasia

AD COL2A1 Disproportinate short-trunk dwarfism Face: flat, protruding/wide eyes Myopia, risk of retinal detachment Cleft palate/ club feet *nl size hands/feet Radiographic Findings: delayed ossification, flat/irregular vertebral bodies Tx: Surgical

Hereditary Coproporphyria (HCP)

AD CPOX Enzyme Deficiency: coproporphyrinogen oxidase *Similar to AIP but milder and w cutaneous lesions

Facioscapulohumeral Muscular Dystrophy (FSHD) *Muscular Dystrophy*

AD Del in D4Z4 (contraction in repeat number) on ch 4=> derepression and dysregulation of DUX4 Nl: 11-100 units Disease: 1-10 units Onset: adolescence: teens-20s Slowly progressive weakness around face (facio), shoulder blades (scapulo), and upper arms (humeral) and lower legs (may be asymmetric) . Typical first signs: trouble drinking from straw/whistling and/or winged shoulder blades . Need wheelchairs (20%) . HL and/or light sensitivity . Retinal changes Dx: Hi CK (but not >1500) EMG: myopathic Muscle bx: non-specific myopathic changes Dx made by genetic test following neuromuscular exam findings suggestive of FSHD

Hereditary Cataract

AD Eye lens progressively opaque => Early-onset blurred vision Difficulty seeing at night Light sensitivity

GTP cyclohydrolase 1-deficient dopa-responsive dystonia (GTPCH1-deficient DRD)

AD GCH1 Childhood onset Neuro dx: Dystonia (involuntary muscle contractions) Tx: . Responds to low dose levo-DOPA => Important to dx bcs treatable

Congenital Glaucoma

AD Incorrect development of eye's drainage system before birth (OR Galactosemia) => Enlarged eyes Cloudiness of cornea Light sensitivity

Familial Ectopia Lentis

AD Mtns near FBN1 3' end Ectopia lentis Variable Marfanoid body *No aortic dilation

Oculopharyngeal Muscular Dystrophy Muscular Dystrophy

AD PABPN1 Onset: 40-60 *Progressive myopathy of eyelids + throat* *No anticpation*

Variegate Porphyria (VP)

AD PPOX Enzyme Deficiency: protoporphyrinogen oxidase Neurovisceral and cutaneous photosensitivity (blistering in sun) Acute attacks that are identical to AIP (but less frequently) Tx: Sun protection

Carney Triad & Carney Complex *Cancer*

AD PRKAR1A Carney triad: 1. Gastric leiomyosarcoma 2. Pulmonary Chondroma 3. Adrenal Adenoma Carney complex: 1. ****Primary pigmented noduluar adrenocortical dysplasia/disease**** 2. *Spotty skin pigment changes* = dark brown/black lentigens (marks) on: . Lips . Eyes (conjunctiva, inner/outer canthi) . Genitals (vaginal/penile mucosa) 3. *Myxoma: . Heart . Skin = cutaneous . Mucosal . Breast myxomatosis . Osteochonromyxoma (bone) 4. Psammomatous melanotic schwannoma (nerve sheet tumor) 5. Br ductal adenoma 6. Growth hormone producing pituitary adenoma -> acromegaly 7. Sertoli cell tumor (large cell calcifying histology) 8. Non-medullary thyroid nodules / ca 9. Blue nevus, epithelioid blue nevus 10. Gastric, Pulmonary, Adrenal ca 11. Endocrine tumors or overactivity 12. Schwannomas

Costello *RASopathies*

AD RAS-MAPK pathway gene: HRAS (GoF mut) ****Papillomas**** *CHD: PULMONARY VALVE STENOSIS-> HEART MURMUR*

Townes Brocks

AD SALL1 Variable expressivity Hypoplastic / triphalangeal thumbs Imperforate anus HL CHD Renal abd VATER like

GLUT1 Deficiency *Metabolic*

AD SLC2A1 Enzyme Deficiency: GLUT1 (glucose transport) Seizures DD, ID Acquired microcephaly Complex movement disorder Symptoms increase with fasting/fever/infection Dx: Low CSF glucose w nl blood glucose SLC2A1 genetic test Tx: Ketogenic diet L-carnitine Avoid glucose intake

Schwannomatosis *Cancer*

AD SMARCB1 (INI-1) LXTR1 Multiple benign dermal and internal schwannomas (not vestibular, NO neurofibromas or acoustic neuromas) => Tumors may cause compression => biggest prob

Porphyria Cutanea Tarda (PCT)

AD UROD Enzyme Deficiency: uroporphyrinogen decarboxylase Skin: Blistering and scarring of sun exposed areas Fragile skin Thickened skin Hypotrichosis Hyperpigmentation Precipitating Factors: HepC Hemochromatosis HIV EtOH ERT Inc risk for HCC Tx: Serial phlebotomies or hydroxychloroquine to remove circulating porphyrins Protection from sun

Hypermobility Ehlers Danlos syndrome (EDS) (Type III) - ACMG -

AD (Rarely AR: TNXB ins or del) Unknown gene (rarely TNXB) Least severe! Major criteria: all must be met: 1. Joint hypermobility confirmed by a score of 5 or more on the 9-point Beighton scale:14 Passive dorsiflexion of each fifth finger >90 degrees (1 point each side) Passive apposition of each thumb to the flexor surface of the forearm (1 point each side) Hyperextension of each elbow >10 degrees (1 point each side) Hyperextension of each knee >10 degrees (1 point each side) Place palms flat on the floor when bending over with knees fully extended (1 point) 2. Soft or velvety skin with normal or slightly increased extensibility 3. No skin or soft tissue fragility (suggestive of other EDS subtypes) Minor criteria: 1. Autosomal dominant fhx of similar features without skin abnormalities 2. Recurrent joint dislocation or subluxation 3. Chronic joint or limb pain 4. Easy bruising, widened atrophic scarring 5. Functional bowel disorders (functional gastritis, irritable bowel syndrome) 6. Neurally mediated hypotension or postural orthostatic tachycardia 7. High, narrow palate 8. Dental crowding 9. Mild AEORTIC ROOT DILATION (->recommend echo) 10. Psych problems Dx test: Clinical 1. Physical exam 2. Fhx 3. Echo to eval for aortic root dilatation 4. Dilated eye exam (to exclude MFS)!! *No genetic test! Pregnancy: Can have early labor and delivery Tx Cardiovascular: cardiologist fwp A. Nl aortic root size: Repeat echo every 2-3 y until adult height reached B. Aortic root dilation: Echo every 6 mo if diameter >4.5 cm in adult or rate of increase in size is >0.5 cm/y. Annual echo for root diameter <4.5 cm in adult and rate of increase is <0.5 cm/year C. Bone Density: Calcium and vit D supplement Low-impact weight-bearing exercise DXA scan for height loss > 1 inch D. GI: Gastritis and reflux may require proton pump inhibitor, H-2 blocker, and sucralfate. Delayed gastric emptying may require promotility agent Irritable bowel treated w antispasmodics, antidiarrheals, and laxatives E. Musculoskeletal: Low-resistance exercise to improve joint stability by increasing muscle tone. Physical therapy for myofascial release is often necessary to facilitate participation in low-resistance exercise. Pain management specialist is crucial participant in care of patient w EDS hypermobile type w chronic pain

Familial Adenomatous Polyposis (FAP) & Attenuated FAP *Childhood Cancer* - ABGC -

AD ***20-30% DE NOVO**** >90% penetrant *APC* @ 5q21-22 suppressor LoF (gatekeeper): most families have unique mtns most mtns truncating Attenuated FAP: mtns on 3' & 5' end *AJ*: ****I1307K (c.T3920A)**** founder mtn in hypermutable region (****susceptibility allele****, 2-3x risk)(6% of AJ): pheno same as sporadic CRC => ****MILD****fMSH FAP -> not used clinically bcsof low PPV, NPV 1% of all CC Onset: Infantile / childhood *100-1000's* COLON ADENOMA polyps in recto-sigmoid region by 35y-> ~100% CC risk (aAFP: *10-100 (avg 35) polyps, older onset-> 70% CC risk*) -*DUODENAL ca* (small intestine)(4-12%) -*UPPER GI* ca (5-10%) -*Pancreatic* ca (2%) -*PAPILLARY THYROID ca* (*cribriform morular variant*)(2%) -****HEPATOBLASTOMA**** ca ****<5Y (INFANCY - CHILDHOOD)**** (1-2%) [BOARDZ] -brain (medulloblastoma) (<1%) Benign tumors: -****DESMOID**** tumors (*connective tissue growths*) in abdomen (painful, recur) -*Benign cutaneous lesions*: epidermal cysts, fibromas -*Osteomas* of jaw and skull Other criteria: -*CHRPE* (congenital hypertrophy of retinal pigment epithelium) ****NOT in attenuated FAP*** -*DENTAL* abn *HCCN "APC Testing Criteria"* (pt w any of): ->*100 adenoma polyps / 10-100 + FHx* -*CC <50* -*Desmoid tumor* -*Familial APC mtn* *attenuated FAP*: *Later onset w fewer colon polyps* *No CHRPE* *Upper GI lesions may be present* Genetic test: *APC seq (90% DR) > MLPA/deldup to look for del (10% DR)* Management (ca risk from *INFANCY/CHILDHOOD*): -*Colonoscopy* every 1-2 y starting @ *10-15*. If too much tumor burden-> colectomy. Post colectomy -> Image remaining rectum/colon if present -Upper GI screening: *UPPER *ENDOSCOPY* starting at *20* -Annual thyroid exam -Colectomy once polyps Refer if: . 10+ adenomatous polyps in person

Multiple Endocrine Neoplasia Type 2B (MEN2B) *Childhood Cancer*

AD --- ****DE NOVO (>50%)****, *APA* effect *RET* 10q11.2 ---*GoF proto-ONCOGENE* ---mtns in codons encoding cysteine ---*Low genetic heterogeneity* & geno-pheno correlation ------*Met918Thr on exon 16* (95%) ------A883F on exon 15 (rare) ---*Allelic heterogeneity:LoF -> Hirschprung* *More severe than MEN2A* (*think B Bad*) -*MEDULLARY THYROID ca* (~100%) in *childhood* (bil, multicentric). MEN2B accounts for <2% of MTC + 5% of hereditary MTC -*Benign PHEO (50%)* [BOARDZ] (= adrenal medulla = above adrenal gland) -****MUCOSAL NEUROMAS of lips/tongue**** -*Long face w big lips* -****MARFANOID BODY**** (*think B for Body*) -Diffuse *GI ganglioneuromas* -Modulated corneal nerve fibers *NO parathyroid hyperplasia/disease (vs. MEN2A)* Management: 1. Prophylactic thyroidetomy < 1y 2. Pheo screening annually> 3y Refer if personal hx / FDR: . MTC . Pheo . Oral (lips/tongue) / ocular (sclera/eyelids) neuromas . Diffuse ganglionerumatosis of GI tract

Li Fraumeni (LF) = Sarcoma, breast, leukemia and adrenal gland (SBLA) *Cancer* - ABGC -

AD --- *DE NOVO (7-20%)* TP53 = *p53* @ 17p13 (70%) - somatic mtns in 50% of tumors *p53 mtns are common in sporadic human tumors* *TUMOR SUPRESSOR* gatekeeper & caretaker LoF (DNA repair & cell cycle regulation) Ca: 50% by 35y - Usually after 20y for females, some males in childhood . *F: 90% ca risk* . M: 70-75% ca risk *THINK BBB (BONE+BR+BRAIN)* 1 . NON-EWING *SARCOMA* (*CHILDHOOD* Ca) . *SOFT TISSUE SARCOMA* (Most common in males (2nd most common ca in females) . *OSTEOSARCOMA* (3rd most common ca in M; 4th in F) . *RHABDOMYOSARCOMA* (skeletal muscle) 2 . *BR ca (ER+/PR+/Her2+)*@~32y: 54% risk ****most common ca in females**** 3 . *BRAIN tumor* (2nd most common ca in M; 3rd in F): *CHOROID PLEXUS CA*(common) Astrocytomas Glioblastomas Medulloblastoma 4 .*Bronchoalveolar lung ca* 5 . *Leukemia, lymphoma* 6 .*ADRENOCORTICAL tumor* (adrenal gland) Non-core ca: -*CC* (not common) -Stomach -Pancreatic -Esophageal -Renal cell ca, -Endometrial -Ovarian -Prostate -Neuroblastoma -Skin -Non-medullary thyroid c -Phyllodys tumor of the breast -ACC predictive of LFS Dx: Pt w sarcoma <45 + FDR w ca <45 + FDR / SDR ca <45 / sarcoma Test: TP53 seq > deldup Management: *Annually* -Physical w/ skin & neuro exam, Childhood, Annually -Breast MRI, 20-25, Every 6 months -Brain MRI exam at 20 (consider) -Whole body MRI, Childhood, Annually -*Colonoscopy, 25, ever 2-5y only IF FHX* -Clinical Breast Exam, 20, Every 6 months -PEx (Skin, Neuro) -Prophylactic Mastectomy (Consider) Refer if: Personal hx / FDR: . 2 relatives w LF tumor, one ≤45 . Br ca <30 . 2 LF tumors in same person . Adrenocortical tumor . Choroid plexus tumor . Childhood sarcoma

Myotonic Dystrophy (MD) type 1 *Triple repeat expansion*

AD --- *MAT ANTICIPATION* (esp if >1000 repeats) (*think Myotonic for Mat*) ****DMPK**** @ 19q13.2 --- ****CTG repeats**** (*Think "Myaooo" like "CAT THE GRANDMA") in 3' UTR -> affect RNA binding protein (sequester RNA processing factors) => ****toxic mRNA**** [BOARDZ] => GoF Criteria: . *Myotonia* --- Delayed relaxation of voluntary contraction --- Slowly progressive weakness: distal to proximal . Heart: --- *Arrhythmia* --- Cardiomyopathy . Eye: --- Early posterior subcapsular cataracts . Endocrine: --- Diabetes --- Hypothyroidism . Male infertility . CNS: --- LD --- ID Test: Targeted mtn by *PCR: for lower number of repeats* *Southern blot: for >1000 repeats* [BOARDZ] . *5-34: Nl* . *35-49*: *Premutation* (unaffected, risk of passing on expanded allele to offspring) . *50-80*: *Mild* (onset 20-70; death after 60) --- Asymptomatic --- Mildly affected: ------ Myotonia ------ Cataracts ------ Male pattern baldness . ****100-1000****: *Classic/Adult* (onset 10-30; death 48-55) --- ****CATARACT**** --- Cardiac conduction abn=>****arrhythmia**** --- ****Difficulty relaxing grip**** (*gripping doorknob*) --- Respiratory issues --- Sleep apnea --- Ptosis --- Male pattern baldness --- Myotonia --- Muscle weakness --- Diabetes --- Distal to proximal progression of muscle weakness & wasting --- Social + behavioral prob --- Male infertility ------ Hypogonadism ------ Sclerosis of seminiferous tubules => oligoazoospermia (males) . ****1000- >2000****: Congenital/Childhood (onset 0-10; death 45) --- Polyhydramnios --- Severe *NEONATAL HYPOTONIA* --- *RESPIRATORY PROB*=>may need mechanical ventilation --- ID --- Motor delays in childhood --- Clubfoot --- Joint contractures; arthrogryposis present @ birth (some) --- Poor suck/swallow --- Facial diplegia => Neonatal death (20%)

22q11.2 Duplication *Micrduplication*

AD --- 30% de novo --- 70% inherited . ID, autism . Short . Hypotonia

Blepharophimosis, Ptosis, and Epicanthus Inversus (BPES)

AD --- 50% de novo FOXL2 Test: Seq > deldup (looking for del)> deldup of regions upstream of FOXL2 > array . Blepharophimosis (bilateral ptosis w reduced eyelid size) . Ptosis . Epicantus inversus . Telecanthus BPES type I: Above + POF BPES type II: Above only Tx Surgical correction of eye abn

Weaver *Overgrowth*

AD --- Most denovo ECH2 --- Enz: histone methyltransferase. Criteria: . Pre / postnatal overgrowth . Dimpled chin

Langer Giedeon = Trichorhinophalangeal Type II *Microdeletion*

AD --- de novo *8q24-* (8q24.11-24.13-) --- TRPSA + EXT del ------ EXT1 del -> multiple exostoses . *MULTIPLE EXOSTOSES* = cartilage growths . ID . Trichorhinophalangeal syndrome = bone/facial defects . Cone shaped epiphyses . Short . Sparse hair . Microcephaly . Redundant skin . Dysmorphic face --- Bulbous nose --- Long/flat philtrum Test: Array / FISH *NOT* karyotype (25% DR)

Apert *FGFR related Craniosynostosis*

AD --- de novo (*APA* effect) ****FGFR2**** @ 10q26 GoF, 2 mtns: P253R (syndactyly more common) S252W (cleft palate more common) 1. ****CRANIOSYNOSTOSIS**** (brachycephaly, oxycephaly); midface hypoplasia 2. ****MITTEN hands**** = bony and soft tissue foot and hand syndactyly (*Think "I can't keep my fingers Apart!"*) 3. *ID* (50%) 4. Face: Eyes: prominent eyes, hypertelorism, strabismus Midface hypoplasia Nose: button Hypoplastic maxilla w relative prognathism

Shprintzen Goldberg *Craniosynostosis*

AD --- most de novo SKI --- protein regulates transforming growth factor beta (TGF-β) signaling pathway . Craniosynostosis . Dysmorphic face . Marfanoid body . CHD . Brain abn . Hypotonia in infancy . Umbilical hernia . Inguinal (lower abd) hernia *Pheno similar to Marfan + Loeys Dietz*

LMNA Related Dilated Cardiomyopathy

AD ---Some denovo LMNA Left ventricular enlargement Reduced systolic function Conduction system disease=>Arrhythmia

Hereditary Hyperekplexia

AD AR Many neuro-related genes . "Exaggerated surprise": pronounced startle responses to tactile / acoustic stimuli . NEONATAL HYPERTONIA

Transthyretin (TTR) Associated Amyloidosis

AD De novo rate: 2/3 (66%) TTR (Transthyretin): - Produced primarily in liver - transports vit A (retinol) and hormone thyroxine throughout body -To transport vit A (retinol) and thyroxine throughout body, 4 transthyretin proteins must be attached (bound) to each other to form a 4-protein unit (tetramer) >100 known mtns Most are single base pair substitutions that results in an AA substitution Cardiac Amyloidosis D18N, V20I, P24S, E42D, A45T, T49P, H56R, I68L, Q92L, R103S, L111M, and V122I Leptomeningeal Amyloidosis L12P, A18G, A25T, V30G, A36P, G53E, F64S, Y69H, Y114C Geno-pheno correl: Most mtns (incl V30M) cause TTR amyloid neuropathy form Two common mtns -V30M: Portuguese (1/538), Swedish, Japanese -V122I: African-American (3.0-3.9%) Onset: 3rd-7th decades of life Etiology: amyloid (protein exhibiting beta sheet structure) deposits in all tissues, including heart → may affected electrical signals => -Slowly progressive peripheral sensorimotor and autonomic neuropathy -Progressive restrictive CM -Nephropathy -Vitreous opacities (eye floaters) -CNS amyloidosis 3 pheno -TTR amyloid neuropathy -Cardiac Amyloidosis -Leptomeningeal/CNS amyloidosis Genetic test: TTR seq Tx: Salt / fluid restrictions Diuretics (water pills) to remove excess fluid Pacemaker Heart transplant Liver transplant (required in one type of secondary amyloidosis)

Dystonia Plus Dopa Responsive Dystonia

AD (45% penetrance for females; 15% for males) GTPCH1 Enzyme Deficiency: GTP cyclohydrolase Onset: Childhood (6 y) Site Onset: Limb Dystonia Progressive parkinson features Diurnal fluctuation Dx: Decreased neopterin and biopterin GTPCH1 enzyme analysis GTPCH1 genetic test Tx: L-dopa/carbidopa

DYT6 Dystonia

AD (60% penetrance; slight female excess) THAP1 Onset: 13 y Site Onset: arm, neck, face Distribution: 50% generalized, 10% focal Prominent neck and speech involvement Tx: DBS

Familial Meningiomatosis *Cancer*

AD (Variable penetrance) Meningiomas ONLY (no NF1/2 features)

Bethlem Myopathy

AD (can be de novo) COL6A1 COL6A2 COL6A3 Muscles: Congenital joint contractures and torticollis CK: nl to mildly elevated Initial joint hypermobility→ contractures (achilles tendons, elbows, deep finger flexors, pectoralis, quadriceps) Very slowly progressive; contractures may become a serious problem Lungs: Restrictive lung disease Nighttime hypoventilation

Hereditary Leiomyotosis & Renal Cell Cancer (HLRCC) *Cancer* - ACMG -

AD (homozygotes => fumaric aciduria) FH 1. *RCC* (15%) . ****PAPILLARY TYPE II w "fried egg-like" nuclei**** . Collecting duct . Tubulo papillary 2. *LEIOMYOMA* = *benign* soft tissue tumors arising from *smooth muscle* (rare) . Uterine (fibroids)-> early hysterectomy . Cutaneous: only of cosmetic concern Refer if personal hx of / FDR w: . Cutaneous leiomyoma OR . *RCC* w characteristic histology Management: Yearly renal MRI start at 30-35

Dyschromatosis Symmetrica Hereditaria = Reticulate Acropigmentation of Dohi = Symmetrical Dyschromatosis of the Extremities

AD (most) ---Hi penetrance DSRAD Enz def: double stranded RNA adenosine deaminase (same enzyme as ADAR) Heterozygous for loss of enzyme (lethal in mice but mild in humans) Onset: infancy or early childhood Hyper + hypopigmented macules on face and dorsal aspects of extremities *Homozygous loss of enzyme =>Aicardi-Goutieres syndrome (type 6)

Hereditary Spastic Paraplegia

AD (most) AR XL SPG4 SPG3A (most) Onset depends on genetic etiology (mainly childhood, some adulthood, rarely infancy) Progressive lower weakness and spasticity Vibration sensations of lower extremities Hypertonic urinary bladder (bladder contracts w higher frequency / bladder urgency) Pure/Uncomplicated: impairment is limited to the lower extremities Progressive lower extremity spastic weakness Hypertonic urinary bladder disturbance Mild decrease of lower extremity vibration sensation Complex/Complicated: other neurological involvement Progressive lower limb spasticity and weakness Impaired Vision Ataxia Epilepsy Cognitive impairment, dementia Peripheral neuropathy

Dystonia *Neurologic* *Movement*

AD (most), incomplete penetrance AR XL TOR1A (dystonia w 30% penetrance) Sustained or intermittent muscle contractions => abn repetitive movements and/or posture Twisting patterns Tremor Patterned postural adjustments Isolated (one motor issue), combined (w/ other motor issue), or complex (other neurological manifestations)

DYT1 Dystonia

AD (penetrance: 30-40%) TOR1A Onset: Childhood - adolescent Site Onset: arm or leg Distribution: spreads to other parts of body (not face) Involuntary, sustained muscle contractions Twisting/repetitive movements Tx: Anti-cholinergic meds Botox injections Deep brain stimulation

GNAL Dystonia

AD (reduced penetrance) GNAL Onset: 31 y Site Onset: neck Distribution: 50% spread to face Involuntary, sustained muscle contractions Twisting/repetitive movements Tx: DBS

Rapid Onset Dystonia Parkinsonism

AD (reduced penetrance) ATP1A3 Onset: abrupt following trigger (heat, exercise, emotional event) Site Onset: Face (spreads to arms and legs) Parkinsonian features Dysarthric speech Seizures Psychosis, cognitive impairment

Familial Pectus Excavatum

AD (some) No literature on whether pectus carinatum / combined anterior chest defects also occur (because ascertainment has been through surgeons consulted to repair excavatum defects) No systematic survey for other features of Marfan / FBN1 mtn

Prader Willi syndrome (PWS) *Microdeletion* *Imprinting*

AD (sort of) *15q11-13* --- Genes normally *expressed in pat* inherited ch 1. *PAT 15q11-13 (15q12) DEL* (35Mb)(70%): includes ****SNRPN**** [*"SNiff crying", "Poor Prader has no Father"*] [BOARDZ] 2. *upd(15)mat* (20-30%): usually involves *entire ch15* 3. *Impriting Center Defect (ICD)* (2-5%) --- mtn (often) --- del (0.5%) 4. Unknown (<1%) 5. Single-gene mtn . Severe neonatal *HYPOTONIA* . Poor suck, feeding prob => *FTT (infancy)* . Hyperphagia-> *obese (childhood)* . *RESPIRATORY INSUFFICIENCY* . Sexual: --- *HYPOGONADISM* --- *Cryptorchidism* (undescended testicle) --- Delayed puberty . Hypothalamic insufficiency . Short . Small hands + feet . DD/ID . Fair skin, light hair/eyes (some) . Dysmorphic face: --- Bitemporal narrowing --- Almond shaped eyes . Severe behavior prob --- Compulsive --- Skin picking --- Temper outbursts *Mimics mt dx* Genetic test: 1. *Methylation analysis w 5' SNRPN (99% DR)* -> If abn -> 2. *Array / FISH / karyotype / MLPA* (for del) > 3. *Polymorphism marker analysis* (for UPD) > 4. *IC analysis w seq / MLPA* Tx: . Obese: low calorie + exercise . Hypogonadism: human chorionic gonadotropin . Short: GH . Behavior: meds, therapy

Myoclonus Dystonia *Imprinting*

AD with imprinting (expression of mat allele) SCNE Onset: 10-30 y Site Onset: neck, proximal arms, trunk, face Myoclonus Psych features: OCD, GAD, depression *Symptoms responsive to alcohol--> may lead to alcohol abuse

Neurofibromatosis type 1 (NF1) *Cancer*

AD, *50% DE NOVO*, mild *APA* effect, 100% penetrance, variable expressivity! (Note: no homozygous cases have reported, it appears that at least one functional NF1 allele necessary for embryo dev) *GONADAL MOSAICISM* *NF1* @ 17q11.2 tumor suppressor *LoF* (gatekeeper) 80% of mtn -> *truncating* *Del (4-5%)-> severe NF1+ID* Dx: Note: Follow infants w 1 criteria as if they have NF-1 until more features develop (*50% of pts w no FHx meet criteria before 1y; almost all by 8y*), *dx clinical, genetic test rarely needed) (*>=2 *) - *6 CAL spots* (>5mm in prepuberty, >15mm postpuberty) - *Axillary / inguinal freckling* - *2 neurofibromas or 1 plexiform neurofibroma* (*BENIGN CUTANEOUS NEUROFIBROMAS AFTER PUBERTY*!) -> 50% *LD w/ NL INTELLIGENCE, IQ may be slightly lower* (ID if del)-> neuro complications of tumors are 2nd leading cause of death - *BENIGN OPTIC GLIOMA * (15% develop, 33-50% symptomatic) - ****2 eye LISCH NODULES**** (unique to NF1 and CMMRD only!!!) - Skeletal dysplasia (rare), visible by 1y: . *TIBIAL DYSPLASIA* (1-4%) . *SPHENOID DYSPLASIA*(cranial)(3-7%) . *ORBITAL* (skull) dysplasia . Thinning of long bones -*Affected FDR* Ca: lead cause of death -*Brain ca* -*Leukemia* (Br ca association unproven!) - *PHEO* - Malignant Peripheral Nerve Sheath Tumors (10-15%) -Familial Gastrointestinal Stromal Tumors (FGISTs) Other criteria: Skeletal: scoliosis, macrocephaly, short LD: ADHD Vascular Disease: HTN, renal artery stenosis Rarely: -CHD (0.4-6.4%) Onset: prenatal to childhood --plexiform neurofibromas --tibial dysplasia --development -school age --optic glioma --lisch nodules --short stature --hypertension --scoliosis -adolescence --dermal neurofibromas -adulthood --cosmetic --malignancy --osteopenia --fractures of long bones on US Life expectancy 15y less Test: *cDNA+NF1 seq > deldup* (>95% DR) (if neg & no FHx-> most likely *MOSAICISM*! better to test younger generation

Hereditary Paraganglioma Pheochromocytoma *Cancer*

AD, de novo SDHB (*B BAD*: *malignant*) Extra adrenal, head/neck, adrenal, RENAL CELL CA Less tumors, more ca *SDHD*: (****D DADDY****) Head/neck, adrenal, extra adrenal Many tumors, but unlikely ca Expressed (at ca risk) if inherited from father (maternally imprinted) SDHC/SDHAF2: (super rare) Paraganglioma in head/neck SDHAF2 (SDH5) MAX TMEM127 Missense, del 3 founder mtns in Dutch Test: epinephrine, norepinephrine, dopamine 1. Parasympathetic paraganglioma in *head base/neck* (most *non-secretory*) 2. Sympathetic paragangliomas in retroperitoneal/abd/thorax (hypersecrete catecholamines: dopamine, norepinephrine, epinephrine, adrenaline->paroxysmal HTN, headache, sweating, palpitations, pallor, anxiety) 3. Adrenal phenochromocytoma Refer if personal / fhx: Paraganglioma / pheo

Ashkenazi Jewish (AJ) Carrier Screening = Jewish Genetic Disorders (JGD) - ACMG 2008 -

AJ = Eastern European Jewish *ACOG + ACMG Panel recommended for all AJ precon/pregnant* *1/4-1/5 AJ carriers for AJ disease* All exhibit founder mtn phenomenon, whereby only 1-3 mtns account for majority of deleterious alterations found in this specific population *ACMG panel (2008)*: Should include *founder mtns* which will rslt in *95+% DR* for most dx: 1. Gaucher type I (LSD) 1 - 1/18, 4 mtns (89-95% DR) 2. CF - 1/29 (Numbers from GeneReviews)(tiny bit lower than Euro Caucasian), several mtn (97% DR) 3. TS (LSD)- 1/31, 3+ mtn (97% DR) 4. Fam dysautonomia - 1/31, 1 mtn (99%) 5. Canavan - 1/41 6. Fanconi Anemia C - 1/89, 1 mtn (99%) 7. Niemann Pick A (LSD)- 1/90, 3 mtn (97%) 8. Bloom - 1/107, 1 mtn (99%) 9. Mucolipidosis IV (LSD) - 1/127, 1 mtn (95%) ACOG core panel (2004): 1. *Tay Sachs* 2. *Canavan* 3. *Familial Dysautonomia* 4. *CF* ACOG expanded panel (2008) 5. *Mucolipidosis IV* 6. *Gaucher* 7. *Fanconi anemia group C* 8. *Niemann Pick type A* 9. *Bloom* NOT included in ACMG 2008 panel: 1. MSUD 2. Nemaline Myopathy 3. Familial hyperinsulinism 4. Glycogen Storage disease 1 A 5. Lipoamide dehydrogenase deficiency 6. Usher type 1 7. Usher type 3 Add disorder if: . Known morbidity or mortality in heterozygous or homozygous state . There should be: *> 90% DR* OR *Allele freq 1% or more in AJ* => *Usher not included bcs 70% DR* Offer if: . *One member of a couple is AJ: one Jewish grandparent* OR . *Unknown ethnicity* Ideal time to perform: preconception No specific panel of tests avail for non AJ Jews=> Fhx + ethnic origin should still be obtained & appropriate testing offered (e.g. hemoglobinopathy screening for those from Mediterranean basin) *Ultra-orthodox Dor*: *Yeshorim program has advocated for broad-based testing for decades* => Central Conference of American Rabbis, the rabbinic arm of the ReformMovement (North America's largest Jewish denomination) passed resolution urging all Reform Rabbis to counsel prospective couples on availability of testing Due to policies of arranged marriage but sentiment against prenatal care=> ****anonymous AJ carrier screening program**** was set up

Carpenter = Acrocephalopolysyndactyly type II *Craniosynostosis*

AR . RAB23 . MEGF8 Criteria: . CLOVERLEAF skull . Fingers / toes abn

Fatty Acid Oxidation Defects (FAOD) *Metabolic*

AR .FAO happens during times of fasting or stress when body needs to get energy (ATP) from triacylglycerides that have FA chains . Part of triacylglycerides not sent down the FA oxidation breakdown go to glycolysis ---You want to break them down into 2-carbon subuints and oxidize them to have access to energy ---------This will allow for creation of acetyl-CoA: 2 carbons, oxygen, and Co-A group ---From this point, acetyl-CoA can enter Krebs cycle in mt . You get a lot of energy from this process which is necessary since bitches be hungry . This process takes place in mt of liver ---FA need to cross mt matrix to be broken down ---Carnitine necessary to transport longer chains (>12) into matrix, but smaller ones can move freely Muscles (skeletal and cardiac) + liver use FAO at all times Mechanism: Insufficient energy Criteria: Nl @ birth Until time of prolonged FASTING/ ILLNESS (e.g. VIRAL INFECTION) / STRESS: when hi energy demands & body trying to use fats (ketones are byproducts of FA breakdown) When this happens... => . Hypoglycemia intolerance . Hepatic dysfunction: hepatomegaly, acute fatty liver disease, hi liver enz . ****ENCEPHALOPATHY****: Lethargy, recurrent vomiting, irritibality, coma => ****SIDS**** . Skeletal muscle myopathy (muscle weakness, muscle pain, excercise intolerance, exercise induced rhabdomyolysis w hi CK and myoglobinuria . Renal failure . Late-onset cardiomyopathy (VLCAD/LCHAD only), arrhythmia Hypoketotic hypoglycemia (low levels of kenotes because of hypoglycemia) which can result in encephalopathy, and sudden infant death syndrome. Biochem test: Urinanalysis: . ****HYPOKETOTIC HYPOGLYCEMIA****: low/no ketones w hypoglycemia (normally in older child/adult => nl ketone w hypoglycemia) in medium & long chain FA defects . Long chain defects have myopathy (cardiomyopathy->CK test=> hi CK) (unlike SCAD + carnitine transport defects) . Abn OA: dicarboxylic acid . Abn acylglycine +/- ammonia (bcs FA block UC) +/- hyperuricemia . Low carnitine . Hi Liver function tests . Blood: abn total and free acylcarnitine Conditions: . SCAD . MCAD (most common) . VLCAD (most severe) . LCHAD: in fetus causes HELLP and acute fatty liver in pregnant mother . TFP (like VLCAD) Carnitine Transport Defects (defects of plasma membrane carnitine transporter): Carnitine shuttles long chain FA across inner membrane of mt => Disorders of any of 4 proteins in carnitine cycle mimic long chain FAOD (skeletal myopathy, CM, fasting intolerance) -3 genes ---CPTI ---CPTII ---Translocase ---HMG-CoA Lyase Deficiency FA that need carnitine: C14-C18 FA that don't need carnitine C4-C12 Tx: Low fat diet Avoid fasting (hypoglycemia) periods (keep them short). if sick -> provide sugar via IV if cannot eat For longer chain defects, supplementation w carnitine may help although this not completely agreed on For long chain defects, supplementation w medium chain triglycerides (MCT) oil for CPT I, CACT and VLCAD Avoid intense exercies Avoid dehydration Carnitine supplement

Disorders of creatine synthesis = Creatine Deficiency Syndromes *Metabolic* *Lysosomal*

AR 2 creatine biosynthesis dx: ---Guanidinoacetate methyltransferase (GAMT) deficiency ---L-arginine:glycine amidinotransferase (AGAT) deficiency 1 XLR: Creatine transporter (CRTR) deficiency ID Autism Induced creatinine excretion Severe delayed language development Abn brain MR spectroscopy - low creatine Tx Creatine supplementation

Senior Loken Syndrome (SLS) *Ciliopathy*

AR 5+ cilia-related genes 1. Nephronophthisis (renal condition) 2. Leber congenital amaurosis (eye condition)

Aromatic L-Amino Acid Decarboxylase Deficiency

AR AADC Enzyme Deficiency: aromatic I-amino acid decarboxylase Infantile ID Hyper/hypotonia Dystonia, parkinsonian features, autonomic instability Oculogyric crises Dx: CSF: decreased HVA and H-HIAA; increased 3-O-methyldopa, 5-HT, and L-dopa AADC enz activity AADC genetic test Tx: MAOI, SSRI, B6, dopamine agonists

Harlequin Ichthyosis

AR ABCA12 Onset: birth Prenatal US: Ssnowflake sign Massive hyperkeratotic, diamond-shaped plates w deep fissures Severe ectropion, eclabium Missing/deformed ears, nose, fingers, toes Poor temperature regulation Generalized scaling and erythroderma if survive

Adenosine deaminase deficiency *Metabolic*

AR ADA Severe Combined Immunodeficiency (SCID) =>lack ~ all immune protection from bacteria, viruses, and fungi Tx: BMT

Generalized Lipodystrophy = Berardinelli Seip Congenital Lipodystrophy *Nuclear Membrane Disorders - Laminopathies*

AR AGPAT2 BSCL2 CAV1 CAVIN1 . No fatty (adipose) tissue in body . Muscular appearance

Dysbetalipoproteinemia

AR APOE2 Enzyme Deficiency: APOE2 Early-onset cardiovascular and peripheral vascular disease Palmar xanthomas Dx: APOE genetic test Tx: Dietary fat and cholesterol restriction Cholesterol and TG lowering meds

Ataxia with Oculomotor Apraxia Type 1/2

AR APTX (Type 1) SETX (Type 2) 1. Cerebellar ataxia 2. Oculomotor apraxis 3. Chorea 4. Muscle twitching (myoclonus) 5. Peripheral axonal sensorimotor neuropathy Other: high CK (type 2, high AFP in blood) Type 1: Earlier age of onset: 4-7 y More severe Chorea and myoclonus tend to disappear Wheelchair bound Cognitive impairment Type 2 Onset: 15 y Milder Chorea and myoclonus tend to persist Mobile for longer than type 1 Test: High CK (type 2, high AFP in blood) Single / multigene panel

Leber Congenital Amaurosis

AR Affects retina -> visual impairment => Onset: infancy Photophobia Nystagmus Extreme farsightedness Pupils don't react normally to light

Biopterin (BH4) Synthesis and Recycling Defects *Metabolic*

AR BH4 (tetrahdrobiopterin): cofactor for several enz: PAH (for PKU) TyrH TrpH NO synthase 1. Microcephaly 2. Dystonia 3. Seizures 4. DD NBS: 2% of pts w hi phe have BH4 def --- NOT ALWAYS PKU --- Dx: 1. Quantitative pAA: hi phe (corrected by BH4 suppl) 2. Abn urine biopterin 3. Abn blood dihydrobiopterin reductase Tx: --- LESS TREATABLE than PKU --- Control phe levels w 1. Diet 2. BH4 amine replacement for synthetic defects

Osteooetrosis with Renal Tubular Acidosis *Brittle Bone*

AR CAII mtns Onset: < 2 y Fractures Short DD, ID Renal tubular acidosis Cerebral calcifications Dental malocclusion

Carnitine Transporter Deficiency = Systemic Primary Carnitine Deficiency *Metabolic* *Fatty Acid Oxidation*

AR CLC22A5 => OCTN2 protein Enz def: carnitine transporter: carries carnitine into cells. Carnitine helps body make energy from fat in food and body

CPT1A Deficiency

AR CPT1A Enzyme Deficiency: carnitine palmitoyltransferase I Hypoketotic hypoglycemia Liver failure Dx: Acyl Carnitine: hi free carnitine and increased CP:C16+18 ratio CPT1A genetic test Tx Avoid fasting w frequent feeding and IV dextrose when will Supplement: cornstarch and MCT oil; high carb/low fat diet

Sly = Mucopolysaccharidosis type VII (MPS VII) *Metabolic* *Lysosomal Storage*

AR Enz def: *B-glucuronidase* Substance Stored (GAG): dermatan sulfate, heparan sulfate, chondriotin-4-sulfate, chondroitin-6-sulfate Onset: In utero w hydrops In utero: non-immune hydrops Dysostosis multiplex Organomegaly Neurodegeneration Later on resembles Hunter/Hurler (variable corneal clouding, coarse face) *No cardiac involvement* =>Death by 20s Dx: Urine GAG: elevated dermatan sulfate, heparan sulfate, chondroitin-6-sulfate, chondroitin-4-sulfate B-glucuronidase enz activity GUSB genetic test Tx: Supportive care BMT

Hereditary fructose intolerance *Metabolic* *Carbohydrate metabolism*

AR Enz deficiency: fructose-1-phosphate aldolase B =>inability to digest fructose (fruit sugar) or its precursors (sugar, sorbitol, brown sugar) => accumulation of fructose-1-phosphate in liver, kidney, small intestine *Nl w no dietary fructose . Nausea, vomiting, hypoglycemia, metabolic acidosis after fructose intake (sucrose, fruits, honey) . Acute liver disease-> renal enlargement and renal fanconi syndrome-> skeletal rickers => Life threatening in infants Mild to severe in older children + adults Dx Controlled fructose load molecular (A149P 70% of alleles) Urine test: neg for glucose and pos for Reducing Substances (RS): hi RS (glucose most common RS; worry if neg for glucose but pos for other RS=> could mean galactosemia or fructose intolerance) Tx Fructose and sucrose avoidance (fruits, juice, some baby formulas)

Fructokinase Deficiency *Fructose*

AR Enzyme Deficiency: fructokinase Benign condition

Fructose 1,6-diphosphatase deficiency *Metabolic* *Carbohydrate metabolism*

AR Enzyme Deficiency: fructose-1,6-bisphosphatase Episodes of: Hypoglycemia, lactic acidosis, hyperventilation Precipitated by: fasting, fever, fructose load Dx: uOA: elevated glycerol-3-phosphate Tx: Acute: correct hypoglycemia and acidosis, IV glucose Chronic: avoid fasting (Frequent glucose feeds); limit fructose

Fukuyama Congenital Muscular Dystrophy (CMD) *Muscular dystrophy*

AR FKTN Onset: at birth Muscle: congenital weakness progressive contractures and weakness high CK Brain: type 2 lissencephaly polymicrogyria cerebellar dysplasia abnormal white matter seizures severe ID Eye: myopia optic nerve hypoplasia Heart: CM Respiratory failure => Death by 10 y

Trimethylaminuria

AR FMO3 Enzyme Deficiency: flavin containing monooxygenase 3 Lifelong fishy odor in body fluids Dx: Urine TMA level FMO3 genetic test Tx: Dietary restriction of trimethylamine, choline, lecithin Decrease gut bacterial production: antibiotics, laxatives Also: riboflavin, acidic skin/oral products

Fraser

AR FRAS1 FREM2 GRIP1 *Cutaneous syndactyly* GU anomalies (esp. Renal agenesis) Face: Eyes: Cryptophthalmos (eyes covered by skin and malformed), missing eyebrows or eyelashes CLP

GALE Deficiency = Galactose Epimerase Deficiency

AR GALE Enzyme Deficiency: UDP-galactose-4-epimerase Vary from mild to severe: cataracts delayed growth/development ID liver disease kidney prob

Mucolipidosis type II alpha/beta = I Cell Disease *Metabolic* *Lysosomal storage*

AR GNPTAB Enzyme def: GlcNAc-1-phosphotransferase At birth: Hypotonia Weak cry Progressive DD Bone abn => Early childhood death

Glutathione Synthetase Deficiency

AR GSS Enzyme Deficiency: glutathione synthetase Mild: hemolytic anemia, metabolic acidosis Severe: neurodegeneration and infection Dx: Low glutathione, increase urine 5-oxoproline Glutathione synthetase enzyme activity GSS genetic test Tx: Correct acidosis Supplement w antioxidant vitamins

Alkaptonuria *Metabolic* *Amino Acid*

AR HGD=> cannot metabolize homogentisic acid Defect in phe/tyr pathway =>homogentisic acid builds up =>excreted in urine - oxidized - dark/BLACK URINE USUALLY ADULT ONSET: . Ochronosis (>30y) - build up and darkening of connective tissue, cartilage . Arthritis (>20y) Other criteria: renal stones prostate stones aortic or mitral valve calcification Dx test: urinalysis of HGA level w GC-MS

3 Hydroxy 3 Methylglutaryl (3-HMG) CoA Lyase Deficiency *Organic Acidemia*

AR HMGCL Enzyme Deficiency: 3-HMG-CoA Lyase May be asymptomatic until decompensation Liver dysfunction (Reye Syndrome) Hyperammonemia Hypoglycemia Dx: uOA: 3-HMG, hi 3-methylcrotonyl glutaconate, 3-OH-IVA, 3-methylglutarate Acyl Carnitine Profile: C5-OH Tx: Chronic: dietary restriction of Leu + Leu-free formula carnitine supplement

Isovaleric Acidemia (IVA) *Metabolic* *Organic Acidemia*

AR IVD @15q14 --- Defect in breakdown LEUCINE --- A282V (50%) Enz def: *isovaleryl-CoA Dehydrogenase* Nl @ birth Criteria ****SWEATY FEET ODOR* (urine + earwax) Poor feeding Lethargy Hypotonia Vomitting Encephalopathy=> seizures, coma, death Dx pAA: nonspecific hi glycine and glutamine uOA: hi isovaleric acid (IVA), isovaleryl glycine (IVG)=> *ACIDOSIS* (NO ketosis) Acylcarnitine profile: hi C5 acylcarnitine IVD genetic test NBS - tandom mass spec Tx: neutalization of toxic compounds (glycine-> isovalerylglycine) -Acute: ---hemodialysis ---protein restriction ---IV glucose/lipids ---IV carnitine ---IV ammonia scavengers ---antibiotics ---glycine supplement -Chronic: ---protein restriction + Leu-free metabolic formulas ---oral L-carnitine ---oral L-Glycine

Naxos *Cardiomyopathy*

AR JUP ARVC/D variant: + Wooly hair Palmo-plantar keratoderma (hand/feet blisters) Genetic test: 40-66% (DR) Tx: Antiarrhythmic meds B-blockers ICD Surgical ablation Heart transplant (rare) Avoid: -Vigorous athletic activity (competitive athletics) ---Engage in mild exercise and don't overexert -Stimulants ---Nicotine or caffeine Surveillance: 12-18y: echo, EKG (and MRI) and visit w a cardiologist annually > 18 y: screening every 5 y or more frequently if someone has symptoms

Merosin Deficient Congenital Muscular Dystrophy (CMD)

AR LAMA2 Muscles: Severe hypotonia and weakness at birth Independent walking not achieved if completely deficient (ambulation possible w partial deficiency) Mild neuropathy CNS: White matter changes and leukoencephalopathy on MRI Seizures, but nl IQ Dx: High CK (>> 1000)

Lecithin Cholesterol Acyltransferase Deficiency *Dyslipidemia*

AR LCAT Enzyme Deficiency: lecithin-cholesterol acyltransferase Renal failure Corneal opacities Anemia *Partial deficiency: fish eye disease Dx: Lecithin-cholesterol acyltransferase enz activity LCAT genetic test Tx: Renal or corneal transplantation

Restrictive Dermopathy *Nuclear Membrane Disorders - Laminopathies*

AR LMNA Other genes . Thin tight skin w erosion and scaling . Joint contractures => Neonatal death (<1wk)

Mandibuloacral Dysplasia *Nuclear Membrane - Laminopathies*

AR LMNA gene => MADA ZMPSTE24 gene => MADB . Bone: ---Mandible+clavicle (collarbone) hypoplasia ---Bone loss at ends of fingers+toes (acro-osteolysis) . Skin coloring+degeneration (cutaneous atrophy) . Partial lipodystrophy => abn fat distribution

MPI-Congenital Disorder of Glycosylation (MPI-CDG)

AR MPI Enzyme Deficiency: mannose-6-phosphate isomerase Infantile FTT Liver dysfunction: hepatomegaly, fibrosis, liver failure Coagulopathy, thrombosis Dx: Transferrin isoform analysis screening MPI genetic test Tx: Oral mannose supplement

Hypo/Abetalipoproteinemia *Dyslipidemia*

AR MTP APOB Enzyme Deficiency: apolipoprotein B Fat malabsorption GR Ataxia RP Acanthocytic RBCs Dx: MTP or APOB genetic test Tx: High dose vitamin E, MCT oi

Mevalonic Aciduria & Hyper IgD *Metabolic* *Cholesterol biosynthesis*

AR MVK Mevalonate kinase: early step in chol biosynth Recurrent fevers *Hyper IgD milder

Nijmegen breakage *Cancer*

AR NBN Chromosome breakage Ca: Non-Hodgkin Lymphoma (50% by age 15) Brain ca Other: Short Microcephaly, ID Dysmorphic face Primary amenorrhea Immunodef w rec infections

Bietti Crystalline Dystrophy

AR Numerous crystal-like fatty deposits accumulate in retina → progressive vision loss => Onset: teens Reduced visual acuity Night blindness Peripheral vision loss

Familial Arterial Tortuosity

AR Onset: infantile Tortuosity of aorta and its branches Dissection telangiectases of cheeks Lax skin Hi palate Joint laxity

Bruck *Brittle Bone*

AR PLOD2 mtn Osteoporosis Joint contractures Fractures Short

Congenital Disorder of Glycosylation type Ia = PMM2-Congenital Disorder of Glycosylation (PMM2-CDG)

AR PMM2 Enzyme Deficiency: phosphomannomutase 2 DD, ID Hypotonia Esotropia Cerebellar hypoplasia SQ fat maldistribution Liver and Kidney disease Dx: Transferrin isoform analysis screening PMM2 genetic test Tx: Supportive/symptomatic

GSD VI = Hers Disease *Metabolic* *Glycogen Storage*

AR PYGL Enzyme def: liver phophorylase GR Enlarged liver Hypoglycemia Hi ketones *Milder symptoms than most other glycogen storage diseases

Achromatopsia

AR Partial / total color blindness (black, white, grey) => Onset: infancy Photophobia Nystagmus Low visual acuity

Hypophosphatasia *Skeletal dysplasia*

AR Prenatal + childhood forms Prenatal US: Micromelia Undermineralized bones Bone fractures *Similar to OI

Juvenile Paget *Brittle Bone*

AR Progressive skeletal deformity Rapidly remodeling bone Osteopenia Fractures

Thrombocytopenia Absent Radii (TAR) *Blood*

AR RBM8A Prenatal dx: 1. US: *bil absent radii (lower arm bone) - thumbs present* 2. *PUBS -> to study fetal platelets* . *BLOOD* disorder . *ABSENT RADII*, *but NO missing thumbs*

Mitochondrial Depletion Syndromes

AR Reduced ratio of mtDNA to nuDNA content Genetically heterogeneous, incl def of: mt thymidine kinase mt deoxyguanosine kinase twinkle mtDNA helicase mt polymerase gamma adenine nucleotide translocator

Sialic Acid Storage *Lysosomal Storage* *Lysosomal Transport Disorder*

AR SLC17A5 => sialin: protein in lysosome membrane Nervous system abn Types: 1. Infantile free sialic acid storage dx 2. Salla dx 3. Intermediate severe Salla dx

OCTN2 Deficiency *Fatty Acid Oxidation*

AR SLC22A5 Enzyme Deficiency: OCTN2 Infancy: hypoglycemia, liver failure Child: myopathy and CM Late: mild myopathy or asymptomatic Dx: Acyl Carnitine: Low C0 acylcarnitine SLC22A5 genetic test Tx: High-dose carnitine Avoid fasting IV dextrose if ill

Sepiapterin Reductase Deficiency

AR SPR Enzyme Deficiency: sepiapterin reductase Hypotonia Dystonia, parkinsonian features, autonomic dysfunction, oculogyric crises Diurnal fluctuation Dx: CSF: decreased HVA and 5-HIAA; increased neopterin SPR genetic test Tx: L-dopa, carbidopa, 5-HT, SSRIs, MAOIs

Lamellar Ichthyosis

AR TGM1 ABCA12 ALOXE3 ALOX12B Onset: birth Newborn: Collodion baby Ectropion Eclabium Generalized erythroderma Sepsis Dehydration Membrane sheds in first few days/wks of life Child/Adult: Diffuse, large, dark plate-like scales Erythroderma Ectropion PPK Decreased sweat, heat intolerance Scarring alopecia Nail dystrophy

Congenital Erythropoietic Porphyria (CEP)

AR UROS Enzyme Deficiency: uroporphyrinogen III synthase Severe photosensitivity→ Bullae, blisters, scarring Erythrodontia Osteomyelitis w loss of digits Disfigurement of facial features Hemolysis, hypersplenism Tx: Protection from UV and fluorescent light (protective clothing, tinted windows) Chronic blood transfusions BMT in very severe pts; do before 2 y

CoQ10 Deficiency *Mitochondrial*

AR nuDNA Age Onset: Infancy, childhood Encephalomyopathy Infantile multisystemic disease Cerebellar ataxia

Stargardt

AR AD Macular degeneration (responsible for central vision) → progressive vision loss Central vision loss Problems w night vision Some impaired color vision

Nemaline Myopathy

AR AD (rare) Many genes: . NEB (common) . ACTA1 (common) . TPM3 . TNNT1 Onset: variable Criteria: . Muscle weakness: --- Distal limbs: should, arms, pelvis, legs (worst) --- Face --- Neck --- Bulbar --- Respiratory --- Diaphragm . Long, thin face . Higharched palate . Dysphagia (eating difficulty) Death can be <1 y from respiratory failure Test: . CK levels . Muscle bx --- myopathic changes --- Nemaline bodie --- Rod bodies . Multigene panel

Ullrich Congenital Muscular Dystrophy (CMD)

AR AD, de novo COL6A1 COL6A2 COL6A3 Muscles: Significant hypotonia and weakness (may have contractures) No or temporary ambulation Significant distal hyperlaxity and prominent contractures CK nl to high Skeletal: Kyphoscoliosis Torticollis Hip dislocation Talipes Skin: Palmar softness Proximal keratosis pilaris Abnormal scars Lungs: Early respiratory compromise

Cytochrome C Oxidase Deficiency *Mitochondrial* *Metabolic*

AR Matrilineal (mtDNA) 20 genes in nuDNA Some mtDNA Muscles used for movement (skeletal muscles) Heart Brain Liver Onset < 2y or later later if mild

Hypophosphatemic Osteomalacia = RICKETS *Metabolic* *Bone*

AR XLD Onset: < 2 Osteomalacia Poor growth Later hypophosphatemia Biochem: Low serum phosphorus Hi alkaline phosphatase Low urine calcium

Cerebral Creatine Deficiency Syndromes

AR XLR AGAT (AR) GAMT (AR) SLC6A8 (XLR) Enzyme Deficiency: depends on gene Global DD +/- autism (self-injury in GAMT) +/- seizures +/- muscular weakness/hypertrophy +/- ataxia, dystonia, chorea (not AGAT) Dysmorphic features (only in SLC6A8) Dx: AGAT and GAMT enzyme activity SLC6A8: creatine uptake in fibroblasts Genetic test Tx: AGAT: oral creatine monohydrate GAMT: oral creatine monohydrate; oral L-ornithine; restrict L-arginine SL6A8: oral creatine monohydrate, L-arginine, L-glycine

Metachromatic Leukodystrophy *Metabolic* *Leukodystrophy*

AR ARSA Enzyme Deficiency: arylsulfatase A Onset: at or after 1-2 y Early signs and symptoms may be vague and gradual, making disorder difficult to diagnose Unsteadiness when walking is often the first symptom observed Occasionally, the earliest symptom is DD or deteriorating school performance Over time, symptoms may include marked spasticity, seizures, and profound ID Weakness Falling Slurred speech Developmental stagnation Neurodegeneration Hypertonia Neuropathy Seizures Optic atrophy Blindness Rigidity Unaware Decerebrate posturing => Death 3-10 y Dx Arylsulfatase A enzyme activity ARSA genetic test Tx Preventative: HSCT/BMT if used b4 symptoms Symptomatic: maximizing/prolonging function while minimizing discomfort/suffering

Genetic Congenital Myasthenic Congenital Myasthenic Syndrome

AR CHRNE (+others) Onset: infancy or early childhood Fatigable weakness involving ocular, bulbar, and limb muscles CK nl or minimally elevated *No cardiac involvement; no cognitive involvement Tx: AChE inhibitors or potassium channel blocker

Tyrosinemia type 1 *Metabolic* *Amino acid* *Cancer*

AR FAH Enz def: Fumarylacetoacetate Hydrolase (deficiency -> cannot break down aa tyr => hi *tyr + succinylacetone*) Nl @ birth 1. Acute liver disease -> liver failure -> 2. *Renal tubular disease* = kidney trouble absorbing glucose, bicarbonate, other analytes (identified w urinanalysis)-> *liver cirrhosis* -> renal failure -> *renal Fanconi syndrome* -> 3. *Rickets* = "rachitic rosary": neck + trunk arching (vit D def -> imperfect calcification, softening, distortion of bones -> bowed bones) 4. Porphrin disturbances -> Neurologic crises (*porphyria-like crisis*, neuropathic pain, weakness, repsiratory failure), ID (****Type 1 NL IQ****) 5. *SELF-HARM BEHAVIOR* 6. ****LIVER CA**** (40% by 5y) 7. Tachycardia 8. ****HTN CRISIS****-> require meds 9. *ILEUS & abn distension* 10. *Cabbage or rancid butter odor in urine* 11. Poor growth Types: I - *Severe hepatorenal*! *HI PLASMA TYROSINE* => *lethal if untx* II - Oculocutaneous tyrosinemia (corneal findings, photophobia, keratoderma), *HI PLASMA TYROSINE* III - variable: ID + ataxia to nl NBS: Tyr (tyrosine) Dx test: . uOA: hi succinylacetone, generalized amnioaciduria (can identify renal tubular disease) . pAA: hi tyr, hi met . Hi serum AFP . Bld spot succinylacetone . Liver failure . Bleeding diathesis (hi plasma tyr) . FAH genetic test Tx: Diet: formula w AA (free of tyrosine and phenylalanine), vit, minerals Nitisinone (new approved med): Enz inhibition to reduce toxin production Liver +/- renal transplant

Muscle Eye Brain Disease

AR POMGNT1 Muscle: Neonatal hypotonia and variable weakness high CK delayed milestones but may walk By 5 y: deterioration w contractures, weakness and spasticity Eye: high myopia cataract glaucoma progressive abolished ERG retinal detachment Brain: type 2 lissencephaly polymicrogyria occipital agyria ponotocerebellar hypoplasia cerebellar cysts abn white matter mild to severe ID

McArdle *Metabolic* *Glycogen Storage*

AR PYGM Enzyme Deficiency: myophosphorylase Recurrent exercise-induced muscle cramps and pain (relieved by rest) Recurrent episodic myoglobinuria→ renal failure History of poor exercise capacity, fatigue, poor stamina Dx: Enzyme analysis on muscle bx PYGM genetic test Tx: Submaximal aerobic exercise Avoid meds that promote myopathy Carb-rich diet, creatine monohydrate supplement, pre-exercise simple sugars

Ataxia with Vitamin E Deficiency

AR TTPA (common in N. Africa) Onset: early teens Neuro: Progressive ataxia Dystharia Loss of proprioception Areflexia Other: Retinitis Pigmentosa Tx: Vit E supplements help w symptoms

3 MethylCrotonyl CoA (3 MCC) Carboxylase Deficiency *Organic Acidemia*

AR Incomplete penetrance MCCC1, MCCC2 Enzyme Deficiency: 3-MCC carboxylase Episodic liver dysfunction Hypotonia Hypoglycemia DD Seizures Dx: uOA: hi 3-methylcrotonylglycine, 3-OH-IVA Acyl Carnitine Profile: hi C5-OH Tx: Chronic: dietary restriction of Leu + Leu-free formula carnitine and biotin supplement

Neurodegeneration with Brain Iron Accumulation

AR (also AD, XLR) Many genes (10 disorders) CNS: movement disorders, neuropsych disease, optic atrophy, with/out cognitive decline of cerebellar atrophy Non-CNS: DM, anemia, increased liver iron Dx: Brain MRI: increased iron (with/out atrophy) Genetic testing Tx: PT, OT Botox/DBS Psych meds

BH4 Deficiency

AR (and AD) GTPCH PTPS PCD DHPR Enzyme Deficiency: multiple Asymptomatic at birth Infancy: abn muscle tone, poor sucking/coordination, seizures, delayed motor development Long term: neurologic deterioration: ID, seizures Dx: Urine pterins and BH4 load test GTPCH, PTPS, PCD, DHPR genetic test Tx: Oral BH4 supplementation Dietary restriction of phe + tyr metabolic formula Supplement: L-Dopa/carbidopa, 5-HT, SSRIs, MAO inhibitors, folic acid

Chondroectodemial Dysplasia = Ellis Van Creveld

AR (common in Old Order Amish population) EVC1 EVC2 Short-limb dwarfism Postaxial polydactyly Ectodermal dysplasia Small chest Dental abnormalities CHD: common atrium Radiographic: Scoliosis, Knock knee Tx: Surgical

Kyphoscoliotic Ehlers Danlos (Type VI)

AR (vs. other subtypes) PLOD1 PLOD1 enzyme deficiency→ hi ratio of Dpyr (Deoxy PYRidinoline) to Pyr (PYRinoline) cross-linking Pregnancy: SAB risk, membrane rupture Criteria: . *Progressive severe scoliosis, often present at birth* . Friable, hyperextensible skin, thin scars, easy bruising . Joint laxity and severe hypotonia at birth . *Arterial rupture or respiratory compromise* . Scleral fragility and globe rupture of medium-size arteries Test Urine analysis for cross-link OR Enz analysis in fibroblasts PLOD1 seq+deldup

Congenital Heart Defects (CHDs)

Abn in any part of heart present @ birth (1/125 births) RR (Practical Genetic Counseling, 6th Edition): RR for isolated CHD: *Sib: 2-4%* *SDR: 1-2%* *Offspring of father: 2-3%* *Offspring of mother: 5-6%* *2 Sibs: 10%* *3 FDRs: 50%* RR for sibs of specific isolated CHD: VSD: 3% ASD: 2.5% PDA: 3% TOF: 2-3% *AV Canal Defect: 2.5%-10%* *Pulmonary Stenosis: 2-8%* *HLHS: 3%-14%* *Bicuspid Aortic Valve: 11%* Aortic Stenosis: 2% Coarctation of the Aorta: 2% TGA: 1.5% Pulmonary Atresia: 1% Common Truncus: 1% Tricuspid Atresia: 1% Ebstein's Anomaly: 1% TGA: Minimal CHDs w highest *familial* predisposition: ---*Left-sided flow defects (often exist w bicuspid aortic valve)* ---*Conotruncal defects*

Porphyrias *Metabolic*

Accumulation of porphyrins (molecules that combine w iron to produce heme => which gives blood its red color & combines w globin to form hemoglobin) . AD . AR Multiple genes Acute: Episodes: abd pain, vomiting, constipation, diarrhea, fever, tachycardia, HTN Cutaneous: Blistering / non-blistering photosensitivity Dx: Genetic testing (depends on type) Tx: Preventative (avoid attack triggers / sun) Pain meds (panhemitin) Acute: Encourage pt to wear medical alert bracelets Avoid known triggers for attacks Monitor: HCC, kidney function, iron+ferritin levels, PBG levels Test family members and children whenever Cutaneous: Avoid precipitating factors in CEP *Sun protection*! (clothes, sunglasses, tinted windows, etc.) Plans for school/work (*tinted windows* etc.)

Precision Oncology

Advantages of Ca Genomic Analysis: Accurate molecular dx and classification of ca type Prediction of individual prognosis Prediction of tx response Monitoring tx efficacy Detection of recurrence => Some therapeutic targets for cancer tx have already been identified Tumor NGS: WGS: Broad coverage, lots of information High input DNA, higher costs, longer TAT Low sequencing depth WES: Targeted Panels Focus on genes w actionable significance Detection of low level mosaicism Lower input DNA, lower cost, shorter TAT Coverage limited Challenges: Low tumor content: ca cells may only be a fraction of total sample Multiple sub-clones: heterogeneity within tumor specimen Aneuploidy: may modify mtn abundance Need to r/o germline mtns (informed consent) Demonstration of clinical utility (including cost effectiveness)

Multiplex Ligation-dependent Probe Amplification (MLPA)

Amplifies many exons at once Amount of amplification is proportional to amount of DNA in original sample Allows analysis of most (if not all) of a gene in one reaction (cost, time) Two reactions: ligation and amplification MLPA uses just one primer pair for amplification Design probe pairs for different parts of gene of interest Each probe consists of two parts: A tail that will hybridize to one primer for PCR reaction A body that hybridizes to the gene The pairs hybridize adjacent to each other, and are then ligated together After ligation, all products will have X-Y Need one primer pair, complementary to X and Y for PCR Stuffer sequence makes PCR products vary in length After PCR amplification, each ligated primer pair will run on gel/column at a different size See peaks of product corresponding to different exons Compare to control DNA—peaks that are from deleted/duplicated regions will be different Missing copy in sample (deletion) will give smaller/absent peak Extra copy in sample (duplication) will give larger peak

Misoprostol *Teratogen*

Asymmetrical defect of cranium and overlying scalp, w exposed dura mater through which cerebrum can be seen Uterine contractions Uterine bleeding Expulsion of uterine contents Arthrogryposis Hydrocephalus Holoprosencephaly Transverse limb defects Ring-shaped constrictions of extremities Exstrophy of bladder

DRPLA (Dentatorubropallidoluysian atrophy) *Triple repeat expansion*

CAG repeats = poly-glutamine --- EXON 1 (coding region) Onset: 30y (can appear anytime from infancy to mid-adulthood) Progressive brain disorder => . involuntary movements . mental and emotional problems: decline in thinking ability

Hemoglobin Electrophoresis

CBC: to check for reduced MCV (alpha and beta), reduced MCH (alpha and beta), reduced Hgb (i.e. anemia) (alpha and beta) MCV MCH Hgb (amount of Hb) Hemelec: reflects percent of Hb types present → changes in pattern can identify specific Hb disorder * can detect sickle cell + thalassemia MCV (80-100): 89.1 (male), 87.6 (female) MCH 30 Hgb Hb: 15.9 (male) 14(female) HbA 96%-98% HbF 1-2% HbA2 2%-3.5% If nl hem elec - could be alpha thal If abn hem elec - which species determine what dx -- For beta thal carriers: ---- HbA2 increased >3.5% ---- HbA decreased Test: . Hem elec for potential carriers or at-risk children post-natally . DNA analysis for prenatal dx or PGD

Melanoma Astrocytoma Syndrome (MAS) *Cancer*

CDKN2 p14ARF p14AF alone ANRIL (antisense noncoding RNA) 1. Melanoma 2. Astrocytoma Refer if personal hx / FDR: . Melanoma + astrocytom

Amphetamines *Teratogen*

CHD + CL in some mice

Cystinosis *Lysosomal Storage* *Lysosomal Transport Disorder*

CTNS Protein def: cystinosin (transporter) Excessive cystine (AA) storage in body cells => Renal dysfunction Light sensitivity GR Types: Infantile (most common + most severe) Juvenile Adult Tx: Renal transplant

Prenatal Diagnosis

CVS: Time: 11-13 wk Sample: small amount of placental villi Procedure: US guided transabdominal/transvaginal needle/catheter Risks: Fetal loss: 1/300-1/500 (depends on experience) Infrequent Complications: limb hypogenesis, infection and leakage Mosaicism (CPM 1-2%) Test: chromosomes only Amniocentesis: Time: 16-22 weeks Sample: small amount of amniotic fluid Procedure: US guided transabdominal needle to retrieve sample The first few cc's of fluid have increased likelihood of MCC (4-fold increased risk compared to rest of sample) Risks: Fetal loss: 1/300-1/500 Infrequent Complications: spotting, leakage, fetal injury Premature rupture of membranes after amnio is usually okay if there is reaccumulation of amniotic fluid Tests: Ch MSAFP/AChE Viral Testing SLO Biochem Test PUBS: Retrieve blood from umbilical cord Risk of fetal loss 2%

Cancer Concepts

Ca Background: Ca is disease of genome - mtns in regulators of cellular process can cause uncontrolled division/differentiation - causing cancer Mtns can occur in many kinds of genes but primarily in: Oncogenes Tumor Suppressor Genes =>Knudson's Two Hit Hypothesis Assessment of Br Tumors for Somatic mtns: Oncotype Dx: analyzes expression of 21 genes from tumor specimen using RT-PCR; recurrence score is generated to determine benefit of chemo Her2-Neu Expression: somatic amplification of this gene is associated w poor prognosis, and also specific tx - Herceptin Ca Fhx Affected Relatives: type of ca/stage, location, tx, 2nd ca (primary or new metastasis), environmental exposures Unaffected Relatives: age, cause of death, health status/history of significant illness, presence of other physical findings in syndrome, ca screening hx, hx of preventative surgery TRY to confirm fhx information! Targeted vs. Pan-cancer Panels Must consider high-risk vs. moderate-risk, vs. low-risk genes and what to do if the result doesn't fit what's in fhx Benefits: Casting wider net increases chance to find pathogenic mtn May be more cost-effective May be more time effective As more people tested - data will be captured and uncertainty will be lessened Drawbacks: May increase anxiety depending on tolerance for uncertainty May be overdone (i.e. start w Multisite testing in AJ women w BrCA)

Ethnicity Based Carrier Screening

Carrier screening limited to particular groups of people determined to be at higher risk for specific disorders Purpose: to detect couples at risk for prenatally diagnosable genetic disorders Types of tests offered based on her/partner's ethnic background Offered to all individuals of that ethnic background Certain Ethnicities may be at increased risk because: Founder effect Centuries of having children within same population Heterozygote advantage

Male Infertility

Causes: . Anatomical: ---Hypospadias ---CF / CBAVD: isolated CBAVD => obstructive azoospermia & occurs in 1-2% of infertile men; 85% of men w CBAVD have at least 1 CFTR mtn ---Testicular maldevelopment ---Obstructive azoospermia ---Vericocele . Endocrine . Genetic: ch abn, androgen receptor abn *Ch abn*: [BOARDZ] *8-10x higher in infertile males; increase w decreasing sperm count* ---*5% w oligospermia have abn karyotype* ---*10-15% w azoospermia have abn karyotype* . 47,XXY: most common; nonobstructive oligo/azoospermia . 46,r(X)Y . 46,XY/45,X . 46,XY/47,XXY . *46,XX w SRY (bcz of transl of part of Y ch)* *except 47,XYY: FERTILE* . *Balanced transl: more common in oligospermia (vs azoospermia)* (3-5%) [BOARDZ] . *Unbalanced transl: more common in azoospermia* *If apparently nl karyotype 46,XY > array => . Y microdels (usually denovo): 4-10% of males w less than <5 million sperm/mL: more common in azoospermia (10%) >> oligospermia* --- *SRY gene del: on Yp* --- *DAZ genes dels (DAZ=deleted in azoospermia): DAZ1 on Yq* Tx: . Intrauterine Insemination (IUI) Wash sperm→ choose best swimmers→ insert into uterus . Therapeutic Donor Insemination (TDI) Choose donor sperm→ insert into uterus . Intracytoplasmic Sperm Injection (ICSI) Inject single sperm into single egg Indications: < 2 million motile spermatozoa per ejaculate Antisperm antibodies causing infertility Fertilization failure w standard IVF protocols Frozen sperm limited in quantity and quality Obstruction of male reproductive tract >95% abn morphology Genetic factors: chrom abn, Y microdels, Androgen receptor abn, CF

Cell-free DNA screening (cfDNA) - ACMG 2013 -

Cells in trophoblast break down → DNA released into mat blood → DNA in small fragments → Detectable > 7 wks GA cffDNA makes up 2-20% (10%) of total cfDNA in woman's circulation Methods: MPSS (Massive parallel signature sequencing) = next generation seq: Millions of amplified genetic fragments sequenced in parallel => counting method Fetal + mat DNA fragments in mat blood collected → cfDNA fragments sequenced → Compare individual sequential ch against reference for analysis → Fetus w/ trisomy contributes 50% more cfDNA from trisomic ch → Does not separate fetal from mat cfDNA DR; FPR: T21: 99%; 0.2% T18: 99%; 0.3% T13: 92%; 1% SNP Mat + fetal cfDNA collected (mat DNA collected from WBCs) → SNP sequencing → Array for mat + fetal DNA → Computer analyzes fetal DNA signal and determines personalized risk score SNP Advantages: Distinguishes btw mat + fetal DNA Detect triploidy DR; FPR: T21: >99%; ~0% T18: >99%; ~0% T13: >99%; ~0% 45, X: 92%; ~0% CANNOT use SNP: Multiples Pregnancies conceived w donor eggs Consanguinity BMT / other organ transplants Discordant Results (cfDNA doesn't match Dx) Confined Placental Mosaicism Placenta has different ch makeup than fetus =>CVS has CPM risk=>amnio may be best fwp =.Pregnancies w CPM => may have higher risk for GR and fetal demise Co-Twin Demise 3% of pregnancies are multiple gestations → 27% (ish) have spontaneous reduction < 7 wk → Demise twins' DNA can circulate in mom's blood → Can give discordant rslts for ongoing twin Mat Medical Conditions Maternal Obesity: lower fetal fraction and can be harder to get result Mom w transplanted organ Mom w genetic condition (i.e. Mosaic turner) Mom w malignancy Other Fetal CNVs (large del/dup) Random: lab error, specimen mix-up No rslt (3-5% of tests), bcs: ---Low fetal fraction or ---Placental issues 2+ 'no rslt' => inc risk of fetal prob *ACOG Opinion:* -Can be offered to pts at inc risk of aneuploidy ---*Sould not be part of routine prenatal labs* ---Should include pretest counseling ---*Should not be offered if multiples* Indications: Mat 35+ at delivery US finding associated w aneuploidy Hx of a prior preg w trisomy Positive test result for aneuploidy Parental balanced rob translocation at inc risk for T21 Limitations: 50% of cytogenetic abn identified w amnio will not be detected when T 21, 18, 13 are only aneuploidies being screened (but many miscarry early) If <35 or >35 are considered separately, 75% & 43% of cytogenetic abn will be missed

Acrocentric Chromosome

Centromere is near end of ch

Xeroderma Pigmentosum (XP) *Cancer* *Microdeletion*

Common in *Japanese* *AR* --- Variable expressivity *7+ genes*: (genetic heterogeneity) *XP*A (25%) XPC (25%) ERCC2 (15%) POLH (21%) *Many* others *Ch breakage*: ---*Nucleotide excision repair defect caused by UV-induced DNA lesions (thymine dimers)* ---*TRANSCRIPTION-COUPLED REPAIR* defect Criteria: . Ca: 1st usually <10y - 1000x *skin ca* risk --- BCC --- Squamous cell --- Melanoma 10-20x *internal ca* risk --- Lung --- Brain --- Uterus --- Renal --- Leukemia - *Eye ca* - Mucosal tissue ca - Tongue ca . *Sun sensitivity* (*think xpats are blonde*) --- *Sunburn* --- *Freckling*, hypopigmented macules --- Erythema --- Photophobia . Skin aging . *Neuro progressive acquired degeneration* (30%) --- *SNHL* --- *ID* --- *Ataxia* --- *Spastisity* --- Microcephaly --- Eye: ------ *Photophobia* ------ Cataracts ------ Keratitis ------ Eyelashes loss Dx test: . DNA repair functional test (cellular UV sensitivity assay): cell response to DNA damage w pyrimidine dimers within strand from UV radiation -> but limited availability => proceed to . Genetic test (50% DR) --- Sequential single gene / multigene panel Management: . Avoid sun (UV) *Microdel XP + Cockayne (dwarfism, microcephaly, neurologic abn, premature aging)* (*think Xpats like coke*)

Hereditary Diffuse Gastric Cancer (HDGC) *Cancer*

Common in Maori (New Zealand) *AD* *CDH1* (*E-cadherin*) (20-25%) ---Frameshift/premature truncation ---"Second hit" epigenetic allelic inactivation due to promoter hypermethylation 1. *DIFFUSE (aka SIGNET RING) (multiple foci) GASTRIC ca* (70%) --- higher risk in men 2. *LOBULAR BR ca* (39-52%) Refer/test if: Personal hx / FDR: . Diffuse gastric ca < 40 . Lobular br ca + diffuse gastric ca in person . Lobular br ca in one person + diffuse gastric ca in relative, 1 <50 . 2 w gastric ca (1 diffuse gastric <50) . 3 w gastric ca Management: Colonoscopy 40 every 3-5 y Total Gastrectomy after bx-proven DGC Recommended Upper Endoscopy 20 Every y Self br and clinical br exam 35 Every mo Mammogram 35 Every y Br MRI 35 Every y

Hermansy Pudlak

Common in Puerto Rico *AR* *HPS*1 HPS3 . ****Albinism**** (light pigments of skin/hair/eyes) . *Skin ca by sun* . *Vision prob*, nystagmus . Easy bruising/bleeding . *Pulmonary fibrosis* in 30s => fatal by 10 y after onset Test: 1. Electron microscopy: absent dense bodies 2. Sequential / multigene panel

Hurler & Scheie = Mucopolysaccharidosis type I (MPS I) *Metabolic* *Lysosomal Storage* *Mucopolysaccharidosis*

Common in Scandinavian + Russian *AR* [BOARDZ] *IDUA* --- *Allelic heterogeneity*=> Hurler / Hurler-Scheie / Scheie Enz def: *hydrolase alpha-L-iduronidase* => accumulation of carbohydrate called glycosaminoglycan (GAG) - *dermatan & heparan sulfate* in tissues & organ systems Types: *Hurler: severe*; onset: 6-18 mo Hurler-Scheie: intermediate; onset: 3-8y => childhood death (by 10y) *Scheie: mild*; onset: >5y (residual enx activity), nl lifespan & IQ Before 1 y: . Hernia . Frequent upper respiratory infections After 1y: . ****CORNEAL CLOUDING**** . *HEPATOSPLENOMEGALY* . Macrocephaly . Coarse (thick) face (thick, wide nose; full lower face), coarse hair . Large tongue . Short, poor growth, developmental regression . Skeletal: joint contractures, claw hands . Otitis media, nasal congestion . Hernia . HL Dx: +MPS spot Corneal clouding Iduronidase deficiency in WBC / fibrobalsts Urine GAG: berry spot - pos for glycosaminoglycan Hi dermatan sulfate & heparan sulfate on thin layer chromatography of urine Alpha-L-Iduronidase enz activity IDUA genetic test Tx: symptomatic . Early BMT (before 2y) . ERT can reduce non-neurologic complications: Laronidase = Aldurazyme - for Hurler & Hurler-Scheie & for pts w Scheie form who have moderate to severe symptoms *Before ERT, only possible way was BMT*

Ovarian Teratoma = Dermoid Cyst

Contain *mat ch only* *Benign ov tumor that contains hair, teeth, bone, thyroid*

Sudden Cardiac Death

Definition: Death from an abrupt loss of heart function: Within 1 h of the onset of cardiac symptoms Natural, rapid, unexpected (chest pain, palpitations, dizziness, lightheaded, syncope) 25-50% have no prior heart medical history Causes: Structural Disease: 95% of sudden cardiac death in one autopsy study E.g. coronary artery disease/heart attack, cardiomyopathy, myocarditis, valvular heart disease, CHD, ARVD, cardiomyopathy Apparently Structurally Nl Heart 5% of sudden cardiac death in autopsy study Primary heart rhythm abnormalities: LQTS, Brugada, Preexcitation syndrome, commotio cordis

FISH Analysis

Detects submicroscopic (<5 Mb) DNA probes = unique seq probes: ● Clones to interrogate specific locus on ch ---Bacterial Artificial Ch (BAC) ---Yeast Artificial Ch (YAC) ---Cosmid ● Repetitive sequence probes identify centromeric regions of individual ch ---Alpha-satellite sequences ● Whole Ch Painting (WCP) probes Use ch libraries of clones for hybridization along length of specific ch

Disorders of Sexual Development

Differentiation of External Genitalia Male: Genital Tubercle→ penis Urogenital Fold → ventral penis Labioscotal Swelling→ Scrotum Female: Genital Tubercle→ Clitoris Urogenital Fold→ Labia minora Labioscrotal Swelling→ Labia Majora Differentiation of Internal Ducts Males Testes produce MIS→ inhibits female development (degeneration Mullerian ducts) Testes produce androgens→ enhance male development (growth of Wolffian ducts) Females Ovaries do not produce MIS→ enhance female development (growth of Mullerian ducts) Ovaries do not produce androgens→ inhibit male development (degeneration of Wolffian ducts)

Benzodiazepines

Drug Use: anti anxiety Neonatal adaptation syndrome Valium (diazepam) CL+/-CP in mice, not humans Neonate withdrawl Hypotonia Dcreased sucking Cyanosis Impaired temperature maintenance

Reye

Dx of exclusion (like SIDS) Metabolic differential dx Test for metabolic disorders since that could be underlying cause Onset: children + teenagers recovering from viral infection (flu/chickenpox) Rapidly progressive encephalopathy: Confusion Swelling in brain Liver damage => can be fatal

Germ layes

Ectoderm : Skin + nervous system Endoderm : Visceral organs + gut lining Mesoderm : Connective tissue, muscles, bones, vasculature, lymphatic and hematopoietic systems

Asbestos *Carcinogen*

Familial lung ca + mesothelioma

DNA Replication

Features: Semi-conservation (1 template strand and 1 newly synthesized strand) Bidirectional (2 replication forks that move in opposite directions) Semidiscontinuous (leading strand copies continuously; lagging strand copies in Okazaki fragments) Process: DNA synthesized from 3' to 5' DNA polymerase cannot start strand de novo so primase creates short RNA primers that attach to 3' end DNA polymerase attaches to primer and proceed w replication→ at the end, RNA primer removed and DNA synthesized to replace the gap

DNA Repair

First line of defense: proofreading by DNA polymerase DNA polymerase has 3' to 5' exonuclease activity that proofreads growing strand→ if base pairing is not correct, 3' end removed→ polymerase incorporates the correct base For other errors: DNA repair enz Mismatch Repair: if proofreading does not catch a mtn, mismatch repair system used Mismatch repair recognizes mismatch→ mismatch region removed→ DNA polymerase fills in gap→ ligase seals the nick Excision Repair: Base excision repair and nucleotide excision repair act in 3 steps: Endonuclease removes damaged DNA DNA polymerase fills gap DNA ligase seals the nick Base excision repair: Occurs when purine or pyrimidine has been damaged DNA glycosylases recognize and cut bond btw base and sugar→ AP endonuclease cleave site of gap→ DNA polymerase fills gap→ DNA ligase seals remaining nick Nucleotide excision repair: Recognizes and corrects bigger, bulky lesions that distort double helix A large, multienzyme complex recognizes helical distortion rather than specific change Diseases that result from mtn in NER: DNA Repair of Double Strand Breaks Double-stranded breaks in DNA are serious problem Two mechanisms to fix double-stranded breaks: End Joining (Non-homologous recombinational repair) Process: Does not require a template Broken DNA ends are aligned and rejoined by DNA ligase Result of repair is usually loss of ntds at repair site→ tolerated well as long as damage is not within gene coding or regulatory sequences Problems: Could remove nucleotides from an essential gene Could join 2 different ends together if multiple breaks are present Homologous recombinational repair Process: Double stranded DNA break→ 5' ends of DNA are digested, leaving single-stranded 3' ends Free 3' ends search for homology using base pairing Strand displacement occurs between 2 strands from homologous chromosome pairs DNA synthesis and branch migration occurs→ this allows the cell to copy sequence in the gap Repair is finished when newly synthesized strand returns to pair with original→ DNA polymerase refills rest of gap→ ligase closes nick Many Proteins Involved: BRCA1 and BRCA2 play essential roles in homologous recombinational repair

Primidone (Mysoline) and Phenobarbital *Teratogen*

Folic acid antagonis Unclear effect similar to hydantoin?

Klippel Feil

GDF6 (AD) GDF3 (AD) MEOX1 (AR) Fusion of cervical vertebrae bones => Limited neck movement

Genetic Code & Stop Codons (Nonsense Mutations)

Genetic Code: . Degenerate (some AA are specified by more than one triplet) . Non-overlapping (adjacent triplets read continuously from start to stop) . Unambiguous (e.g. AUG is always met) . Nearly universal (similar in prokaryotes + eukaryotes) *Start codon: AUG* (*think A start*) Stop codons: *UGA - U Go Away* *UAA - U Are Away* *UAG - U Are Gone* => Truncated protein + Mutant mRNA degradation by nonsense mediated decay *Premature stop codons + framshift mtn => most deleterious*! [BOARDZ]

Genetic Screening

Genetic Screening Tests I • Early dx where early intervention is of benefit to affected individual / family: ---Common serious dx of adult life: Hypertension, CAD, ca, hemochromatosis ---Newborn screening • PKU - Fetal screening • Prenatal dx • MMS for NTDs,T21 Genetic Screening Tests II • Identification of individuals at-risk of transmitting genetic disease (i.e. carrier screening) ---Tay-Sachs ---Hemoglobinopathies ---CF

SADDAN *FGFR related craniosynostosis*

GoF Lys650Met

HB Kempsey

GoF mtn Locks HB in high oxygen affinity state => reduces oxygen delivery to tissues

Zika *Teratogen*

Gullain-Barre syndrome (immune system attacks nerves=>ascending paralysis) OR Microcephaly

Familial Prostate Cancer *Cancer*

HOXB13 Referral if: Personal hx of / FDR: . 3+ FDR w prostate ca OR . 2+ prostate ca <55 OR . Aggressive prostate ca (Gleason score ≥7) & 2+ br / ov / pancreatic ca

Adenylosuccinate (AS) Lyase Deficiency *Metabolic* *Urea Cycle*

HSM Neuro=> encephalopathy => psychomotor delay autism seizures Dx: in body fluids: ---succinylaminoimidazole carboxamide riboside (SAICAr) ---succinyladenosine (S-Ado)

Congenital Diaphragmatic Hernia

Hernia in diaphragm (thin sheet of muscle separating abd from chest) => lung hypoplasia => neonatal death (hi risk) Prenatal US: . *Large NT* in --- 40% of affected pt --- 80% of cases ending in neonatal death

Mycophenolate Mofetil *Teratogen*

Hypertelorism Arching eyebrows Thick everted lower lip Micrognathia Chorioretinal colobomas Micropthalmia Microtia Meatal atresia CLP Congenital diaphragmatic hernia CHD Renal CNS Hypoplastic nails Clinodactyly Polydactyly

Disorders of carbohydrate metabolism = Carbohydrate disorders *Metabolic*

Inability to metabolize specific sugars, aberrant glycogen synthesis, or disorders of gluconeogenesis Energy deficient pheno (not intoxication pheno) Lethargy Hypoglycemia Hepatosplenomegaly Lactic acidosis Ketosis Dysfxn due to low energy - brain, liver, muscle (myopathy), heart (CM) Dx Galactosemia GSD

Expanded Carrier Screening (ECS) - ACMG 2013 -

Inclusion criteria: 1. Disorders should be of a nature that most at-risk patients would consider having a prenatal dx to facilitate making decisions surrounding reproduction: Cognitive disability Need for surgical/medical intervention Effect quality of life Exclude adult onset and low penetrance 2. When adult-onset disorders (disorders that could affect offspring of individual undergoing carrier screening once offspring reaches adult life) are included in screening panels, pts must provide consent to screening for these conditions (follow autonomy and nonmaleficience) 3. Frequency in pop should be known to provide accurate residual risk 4. There must be validated clinical association between mtn(s) detected and severity of dx 5. Compliance with the American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, including quality control and proficiency testing Reporting criteria: Variants w clear and well-associated pheno (don't report VUS) Residual risk estimates should be reported *A recent categorization of risk denotes carrier screening as moderate risk*

Genetic Profile

Individual's unique set of genetic markers, detected most often today by PCR or, previously, by electrophoresis and nucleic acid probes

General Inferility & Neonatal Death & Childhood Death

Infertility definition: 1 y of unprotected intercourse w/out conception Affects 10-15% of couples in reproductive age Causes: *Female factors*: 50% (35% Tubal, 15% Ovulation) Male factors: 35% Other factors: 5% Unknown: 10% Resources: [BOARDZ] 1. ****RESOLVE****: resolve.org - support group for *infertility* 2. *The Compassionate Friends*: thecompassionatefriendsfw.com - support group for families grieving *death of child* of any age, from any cause

Non-Compaction Cardiomyopathy (NCCM) = Left Ventricular Noncompaction (LVNC) *Caridomyopathy*

Isolated (common) Familial (44-70%) AD ---50-100% penetrance Genetic causes overlap w DCM/HCM: -TAZ ----unknown function Associated w multiple clinical diseases including dilated cardiomyopathy, XL infantile cardiomyopathy, and Barth -LDB3 ---in muscles -LMNA ---support to cells, other unkown functions -MHY7 ---in muscles -MYBPC3 ---in muscles TNNT2 ---in muscles, regulates muscle contractions -ACTC ---in muscles, regulates muscle contractions Dx: ACG, echo, and sometimes MRI: -Standard criteria not established Agreement: -Absence of any other coexisting cardiac structural abn -Numerous, excessively prominent trabeculations and deep intertrabecular recesses Variation: -Size of trabeculations in relation to thickness of compacted wall in different echo views and at different levels of left ventricle in end-diastole vs detection of two myocardial layers, compact and non-compact, in short-axis views of left ventricle in end-systole vs. number of prominent trabeculations visible in apical views of left ventricle in diastole Occurs through an error in heart formation: -Embryonic development of heart is very complex -Myocardium is muscle of heart and starts off as a spongy layer ---Starts off as trabecular fibers and recesses (spaces) -Between wk 5 and 8, this spongy material compacts ---The recesses disappear or become capillaries ---If myocardium does not compact as tightly as it should (failure of normal cardiac muscle development), NCCM/LVNC is result: myocardium w spongy appearance NCCM usually seen as LVNC Wide range of age of onset Adult form = av age of onset 40y Congenital form: av age of onset 6 y Thromboembolic events Atrial fibrillation Ventricular tachycardia Heart failure Management: No guidelines for NCCM Management Includes treatment of arrhythmias, thromboembolic events, and heart failure Options include ICD Oral anticoagulants Heart transplantation Beta blockers, calcium channel blockers, other agents

Mendel's Laws

Law of Segregation: Gametes contain one homologous chromosomes (=> one gene copy for each trait) Law of Independent Assortment: ch (& genes) inherited independently from other ch

Restrictive Cardiomyopathy (RCM) *Cardiomyopathy*

Least common CM (<5%) Fhx may be present in some pts w idiopathic form *AD* --- 40% penetrance *Genes: overlap w HCM/DCM* *MYH7* TNNI3 ACTC1 TNNT2 DES *Walls (heart muscle) of ventricles become stiff*, w no apparent dilation, thickness or hypertrophy => resist nl filling w blood Non-idiopathic RC: Endomyocardial fibrosis Previous radiation therapy Infiltrative disorders Amyloidosis Sarcoidosis Hemechromatosis Metabolic disorders Gaucher Mucopolysaccharidoses Fabry Carcinoid syndrome Shortness of breath (at first with exercise; but over time it occurs at rest) Fatigue Inability to exercise Edema Weight gain Nausea, bloating, and poor appetite Palpitations Highest SCD risk (28% of children suffered from SCD w/I 1 year) Dx: Not well defined Genetic test: evidence for utility is limited (unknown DR) ---Small study reported that TNNI3 mtns accounted for 7/10 families w RCM Screening guidelines: Not well defined Unaffected known mtn carrier: EKG and echocardiography -Annual screening beginning in childhood -Eval every 1-3 y in adults FDR w RCM: -EKG and echo -Eval every 3-5 y beginning in adulthood

Lysosomal Storage Disorders (LSDs) *Metabolic* *Cardiomyopathy*

Lysosomes: organelles that contain enzymes => to digest things Progressive neurodegeneration: --- enz def => substrate accumulates in lysosomes => tissue/organ mass (HSM) Criteria: . Coarse face . Develop regression . DD, ID . HSM . Cardiomyopathy . Movement prob . Seizures . HL . Blindness . Lung prob 50 types: Tay Sachs Sandhoff Fabry Gaucher MPS I, II Pompe Lysosomal storage diseases that do not involve CNS: A. Hunter B. Type I Gaucher C. Niemann-Pick A D. Tay-Sachs E. Krabbe Tx: ERT

Maternal Cell Contamination (MCC)

MCC: can occur when fetal specimen comes into contact w mat blood or tissue MCC risk is associated w amnio, CVS If MCC present, mat DNA may mask results of any genetic test performed on fetal DNA→ results of prenatal test may be compromised To R/O MCC, mat blood specimen necessary for comparison of mat and fetal ch markers MCC test: Detects presence of and estimates percentage of contamination 5 polymorphic loci examined Test result, in conjunction with prenatal test result, sensitivity of the prenatal test to MCC, and known mat genotype, provides basis for accurate prenatal dx Presence of both mat and nonmat l alleles for each fetal marker indicates fetal specimen not contaminated MCC confirmed when both alleles in fetus are mat Indication: Required in conjunction w molecular and biochem testing only MCC testing limitations: Not possible in monodi twins Not possible if consanguineous May incidentally identify / be suggestive of presence of a ch aneuploidy

Nonprocessed Pseudogenes

May be byproducts of evolution: "dead" genes that were functional but now vestigial, bcs inactivated by mtns in coding / regulatory sequences

Sephardic Jewish Carrier Screening

Mediterranean Jew . Beta thal: 1/5 in Kurdish + Iranian jews . Alpha thal: Yemenite + iraqi Jews . FMF: 1/3-1/7 in N. African + Iraqi Jews . G6PD deficiency . Glycogen storage disease type III . Tay-Sachs: 1/45 in Moroccan Jews (other Sephardic Jews: low/same as non-Jew) Recommendations: Currently there is no consensus for testing, but should test: . Hemoglobinopathies . TS if Morrocan Jew . G6PD prior to giving sulpha / related drugs . Familial mediterranean fever . Glycogen storage disease type III . Hereditary inclusion body myopathy and others

Allele Specific Oligos

Method for identifying specific mutations Results: Positive result is conclusive Negative result means that mtn looked for not present Low FP rate, minimal handling, easily automated; but being replaces Used for: ∆F508 mutation in CFTR

Advantage of microsatellite repeats vs. restriction fragment length polymoprhisms

Microsatellites: multi-allelic => often informative for linkage

Neonatal adrenoleukodystrophy *Peroxisomal* *Metabolic*

Milder than adrenoleukodystrophy No dysmorphic features

upd(14)mat

Mosaic Rob transl Isoch Short Hypotonia Hyperextensible joints Scoliosis Minor dysmorphic face DD Precocious puberty *Less severe than upd(14)pat

Myasthenia Gravis Congenital Myasthenic Syndrome

Most common autoimmune disorder of neuromuscular junction Not genetic: acquired autoimmune disease Fatigable muscle weakness involving: ocular, bulbar, skeletal, and respiratory muscles

Congenital Minamata Disease = Methylmercury

Most unaffected people have levels of 2 ppm Threshold: must have mercury levels of 5-110 ppm Methylmercury complications: Cerebral-palsy-like symptoms Microcephaly Recommendations: Preg women should avoid fish high in mercury (shark, swordfish, Mackerel)

Hepatitis C *Teratogen*

Mother to child transmission <10%

Trafficking Disorders = Diseases of Lysosomal Protein Trafficking *Lysosomal Storage*

Mucolipidoses II and III

Coronary Heart Disease

Multifactorial Disease Risk Factors: fm hx sedentary lifestyle smoking obesity hi fat diet Genetic testing not a part of routine care currently

Buprenophrine *Teratogen*

Neonatal withdrawal

LSD *Teratogen*

No evidence of malformations

Marijuana *Teratogen*

No evidence of malformations Possible decreased growth May affect executive functioning

Isolated hemihyperplasia = Isolated hemihypertrophy *Overgrowth disorder* - ACMG -

No known genes Embryonal tumors: . Wilms tumor (most common) . Hepatoblastoma Recommendations 1. Refer to clinical geneticist for eval 2. Abd US every 3 mo until 7y for ca screen 3. Serum AFP every 3 mos until 4 y for hepatoblastoma screen 4. Consider teaching parents the "daily caretaker abd examination"

Antithrombin II *Thrombophilia*

Not associated w SAB!!!

PeriMortem Considerations (for critically ill metabolic patient)

Notify pathology in anticipation of autopsy FREEZE serum, plasma, and urine; CSF if possible (to preserve enz stability) Perform skin bx for fibroblast culture Obtain permission for autopsy If a complete study refused, limited study If also refused, multiple biopsies Key organs - liver, muscle, heart, kidney, brain Flash-freeze all specimens (-70C) as soon as possible after death to preserve enzyme stability for future studies YOU photograph the patient if dysmorphic features are present

DNA structure

Nucleotides (ntds): - Building blocks of DNA/RNA - Consist of: --- Nitrogenous base --- Pentose sugar --- Phosphate group - Adjacent ntds linked by phosphodiester bond btw phosphate at C-5' & OH on C-3'=> giving DNA polarity - Complementary ntds linked by Hydrogen (H) bonds --- 2 H-bonds btw A - T --- 3 H-bonds between C - G (more energy to break this pairing) Nitrogenous bases: -Purines --- A (Adenine) --- G (Guanine) -Pyrimidines --- C (Cytosine) --- T (Thymine) --- U (Uracil) DNA - Has sugar Deoxyribose (hence "D" in DNA) - Right-handed double helix - Antiparallel - hydrogen bonds join base pairs - Contains A,G,T,C DNA Packing: - Nucleosomes (beads on a string): DNA wrapped around 8 histone proteins - Histone: can be covalently modified to affect gene expression --- HAT (histone acetylation transferases) can add acetyl groups ------ Hi histone acetylation→ inc gene expression --- HDACs (histone deacetylase complexes) remove acetyl groups RNA - Has sugar Ribose (hence "R" in RNA) RNA contains the sugar ribose (RNA) - Contains A,G,U,C Histones can be: - Acetylated - Phosphorylated - Methylated: Hi methylation→ dec gene expression - ADP can be --- Ribosylated --- Ubiquinylated --- Biotinylated → all modifications reversible but can be long-lasting

GSD III = Forbes/Cori disease *Metabolic* *Glycogen Storage*

Onset: 1y Enzyme def: Amylo-1,6 glucosidase (debrancher enz)

Maternal PKU (MPKU) = Mat PAH def

PHE transported across placenta 65% of PAH-deficient moms have poorly controlled PHE before 8 wk GA *Mat phe >1,200* -> *>90% of infants affected* Prenatal US: . *MICROCEPHALY* (5-18% if untx by 10 wk->67% if untx by 30 wk) . *IUGR*: if untx btw 0-10 wk . *CHD* (8-12% if untx btw 0-10wks, since heart develops btw 8-10 wk). CHD risk may also be increased due to poor protein intake + vit B12 def Postnatal: . *LOW BIRTH WEIGHT* . *DD, ID* (>90%): linear relationship btw mat PHE levels >360 µmol/l throughout gestation + lower IQ of fetus . Short, small . Dysmorphic face . Behavior prob . Strabismus . Hip dislocation *If well-managed mat PKU-> Nl IQ but slightly lower than unaffected sibs* Tx: Bcs high PHE toxic to fetal brain => . *For several mos BEFORE conception => <360 µM = <6 mg% (120-360) per ACMG* BUT international recommendations: <240. If less than 100 persistently in 2nd + 3rd tri-> IUGR . *Breastfeeding: safe (if maintain phe-restricted diet): infants unaffected by PAH def can metabolize slightly higher PHE levels in mother's breast milk w/out difficulty* Reference concentration range: Nl: 30-90 µmol/L (i.e. µM) Benign hyper: 120-600: Hyper: 600-1,000 *Abn >1,000-1,200 (>20 mg%)*

POSSUM *Database*

POSSUMweb (Pictures of Standard Syndromes and Undiagnosed Malformations): possumcore.com/nuxeo/login.jsp *Database for dysmorphology*: For *PROVIDERS* --- Tool to assist in dx, but using *trait searching* does not guarantee retrieval of a specific dx / info, but rather offers *selection of possible dx for consideration by clinician* --- It is advised to check w original referenced source material to further assist in making dx

Define Genetic Counseling

PROCESS of helping people to understand and adapt to medical, psychological and familial implications of genetic contributions to disease 1) Interpretation of family and medical histories to assess the chance of disease occurence/recurrence 2) Education about inheritance, testing, management, prevention, resources and research. 3) Counseling to promote informed choices and adaptions to the risk or condition Who provides genetic counseling? Everyone! Genetic counselors, clinical geneticists, genetic nurse clinicians, other genetic subspecialies (i.e. cytogenetics) and Non-geneticists What are the 7 guiding principles of genetic counselors/services? 1) NONdirective counseling 2) Voluntary 3) Equal access (this is an ideal, often easier in urban areas) 4) Patient education (this is central to practice) 5) Complete disclosure of information (not being selective yet assessing what is relevant to the patient's decision making) 6) Attention to psychosocial and affective dimensions of patient and family (helping people cope with what impact it has on them or the families) 7) Confidentiality When does genetic counseling taking place (at what age)? ANY age. Preconception, prenatal, pediatric, adult What happens during a genetic counseling interaction (overview of the things discussed during the process): Contracting, Intake and family history, clinical features, differential diagnosis, etiology, diagnosis/testing options, treatment/management, psychosocial issues, support resourse, references

Cobalamin C deficiency = Methylmalonic Aciduria and Homocystinuria, cblC type

Pathway: Cobalamin needed in both ethylmalonic acid and homocysteine metabolism Acidosis and ketosis UOA: methylmalonic acid PAA: hi homocysteine Acylcarnitine: hi C3 Vomiting, poor feeding Neurologic symptoms Pigmentary retinopathy Tx: Parenteral hydroxocobalamin (OHCbl) injections

Aspartylglucosaminuria

Patients appear nl for several mos after birth Then present w recurrent infections, diarrhea, and hernias Later, there may be a gradual coarsening of facial features, enlarged tongue (macroglossia) and enlargement of liver (hepatomegaly).

Amniotic Bands

Placenta denuded of amnion Fetal entanglement to firbous amnion remnants => *Oligohydramnios* *Malformations: body wall defects + facial clefts* *Disruptions: constriction bands + amputations*

Pierre Robin Sequence

Primary anomaly: Mandibular growth restriction *micrognathia* , hypotonia, generalized growth retardation or an obstetric issue (oligohydramnios) that causes a deformation -> superior/posterior displacement of tongue => glossoptosis (downward tongue displacement) ->failure of palatal shelves to close bcs of obstruction ->U shaped cleft and glossoptosis => can cause airway obstruction -50% due to genetic syndrome ---****50% Stickler**** - most have eye involvement (penetrant as newborn). When you hear Pierre-Robin: think Stickler! => Eye exam can help in dx ---****25% 22q11.2**** -Associated w SOX9 disregulation

MASS (Mitral Valve, Myopia, Aorta, Skin and Skeletal) Phenotype

Probably many causes FBN1 mtn (rare) . MVP . Myopia . Aortic root diameter may be at upper limits of nl but NO progression to aneurysm/dissection! (unlike Marfan) . Striae atrophicae Dx: Cannot be made w certainty w/out multigenerational fhx documenting NO progression of aortic root dilation

Meiosis

Process: Prophase I: condensation of chromatin; members of each homologous ch pair undergo synapsis; crossing over occurs between homologous ch; prophase I is extended to allow for recombination Metaphase, Anaphase, Telophase I are similar to mitosis Centromeres split at anaphase II of meiosis II Outcome: Meiosis reduces the ch number from diploid to haploid (proceeds through 2 cell divisions without DNA synthesis) Regarding meiosis I: --- chromosomal compositions of the parent (diploid) and daughter (haploid) cells

Mitosis

Process: Prophase: ch condense; centrioles divide and move apart Metaphase: centromeres align on metaphase plate Anaphase: centromeres split and daughter ch migrate to opposite poles Telophase: daughter ch arrive at poles and cytokinesis starts Outcome: Diploid daughter cell that is identical to progenitor cell (any mtns present will pe present in future clones)

X Inactivation

Random process in cells w 2 X ch, creating 2 populations of cells in females (genetic mosaicism) Lyonization One of X ch in every somatic cell randomly/genetically inactivated→ dosage compensation X Inactivation Center (XIC) - *XIST*z: cis-acting gene transcribed from inactive X (@ Xq13) - Functions as RNA molecule, which coats X chromatin and prevents DNA from being transcribed (methylation of CpG, acetylation of histone tails) - Inactive state is 'locked-in' by methylation of CpG islands - Some genes escape X-inactivation: --- *PAR1 (Xp22.3)* (*think "il par" in French*) --- *PAR2 (Xq)* --- Several other genes

Colon Cancer

Risk Factors . Age . Phx / fhx of CC / adenoma . High fat, low fiber diet . Inflammatory bowel disease *Hereditary CC* . Prior Probability Models: *chance of carrying mtn* --- *Bayes Mendel* (based on Bayes) - not just for CC --- *PREMM* - for Lynch

Maternal Diabetes *Teratogen*

Risks *6-10% if poorly controlled* *Up to 20% if very poorly controlled* *OB Complications*: Maternal HTN Preeclampsia SAB Stillbirth Preterm Prenatal US: ****NTD**** *HOLOPROSENCEPHALY* *CAUDAL REGRESSION* *CHD* (ASD, VSD, transposition of great arteries, Tetralogy of fallot) Polyhydramnios Situs inversus CNS abn Urinary, reproductive, GI abn *VATER-like* At/After birth: *Hyper/hypoglycemia* Hypocalcemia Jaundice Macrosomia Hyperketonemia Hypoxia Hyperbilirubinemia Recommendations: *Well-controlled diabetes BEFORE pregnancy* Pregnancy testing: Level II anatomy scan 18-20 wk MSAFP, AFAFP at 16-20 wk Fetal echo at 20-22 wk

Cardiovascular tests

Routine Tests Electrocardiogram (ECG/EKG): records the electrical activity of the heart including the timing and duration of each electrical phase of the heartbeat Holter Monitor: ambulatory electrocardiogram monitoring (records heart activity for 24-48 hours) Cardiac Event Recorder: portable devices that the patient controls to tape record the heart's electrical activity with symptoms (need to be activated to record) Chest X-Ray: Visualize- heart size and silhouette, enlargement of specific cardiac chambers, pulmonary blood flow/pulmonary vascular markings Echocardiogram: use u/s to provide anatomic and functional information Cardiac Computed Tomography (CT): produces image of the cardiac anatomy, but also adjacent structures; short test but exposure to radiation Cardiac MRI: provides information about flow dynamics and ventricular function; should not be used in patients with pacemakers, defibrillators, metallic objects Invasive Testing: Cardiac Catheterization: definitive invasive dx testing for most cardiac patients; measures hemodynamics; selective angiography Angiograms (intravascular ultrasound) Specialized Testing: . Six Minute Walk: assess distance walked over 6 minutes as a sub-maximal test of aerobic capacity and endurance . Exercise Stress Testing: ECG, O2 saturation and BP monitoring throughout exercise (bicycle, treadmill) Stress Echocardiogram . Nuclear Stress Test: diagnostic test used to evaluate blood flow to the heart Cardiac Devices . Pacemaker: an electronic device implanted to provide electrical impulses to regulate the heartbeat (used for slow heart rate or cardiac conduction problems) . ICD: an electrical device is implanted to monitor for and correct cardiac arrhythmia (used for people at risk for sudden cardiac death)

Lymphocytic Choriomeningitis Virus (LCMV) *Teratogen*

SAB Microcephaly Hydrocephalus Chorioretinitis Cataract Micropthalmia Optic atrophy Intracranial infections ID Spastic quadriplegia Blindness => 35% mortality

Cocaine *Teratogen*

SAB Premature labor/birth, abruption, uterine rupture Cerebral infarction (stroke), intracranial hemorrhage Brain disruptions Nonduodenal intestinal atresia Limb reduction defects Behavior prob

Aspirin *Teratogen*

SAB risk when exposed around conception Avoid in late pregnancy due to concerns for premature constriction of ductus arteriosus & bleeding abn

Hyperornithinemia Hyperammonemia Homocitrullinuria (HHH) *Metabolic*

SLC25A15 => encodes ORNT1 (mt ornithine transporter 1) involved in: ---urea cycle ---ornithine degradation pathway Triad: 1. Persistent hyperornithinemia 2. Episodic / postprandial hyperammonemia 3. Urinary excretion of homocitrulline Test: Hi ornithine Hi ammonia Tx Restrict protein Supplement citrulline

Rhadoid Tumor Predisposition *Cancer* *Childhood cancer*

SMARCB1 (type I: hi denovo + gonadal mosaicism) SMARCA4 (type II) Aggressive rhabdoid tumors in child: . Hypercalcemic ov small cell ca in child & young women (type II) Refer if personal hx / FDR: . Rhabdoid tumor

Klippel Trenaunay Weber

SPORADIC Mosacisim PIK3CA . Hemihypertrophy . Port wine stain . Vein malformations

Proteus *PTEN hamartoma* *Cancer* *Overgrowth*

SPORADIC (de novo) AKT1 ---post-fertilization mtns=>mosaicims Asymmetrical OVERGROWTH [BOARDZ] Connective tissue nevus

Sequencing

Sanger: Looks at small regions Sequence errors in genes Slower than NGS and doesn't read as many times, but still the gold standard Confirmation for NGS NGS: can assess entire exome or genome (massively parallel seq) Use: general population screening after pos genotype array Strengths: Identified more carriers of deleterious mtns Valuable in a diverse ethnic population Weaknesses: Difficult to calculate post-test risk Identifies VUS OR only looks at certain exons to decrease VUS

Genetic Marker

Specific gene that produces recognizable trait and used in family or population studies

Hallermann Streiff

Sporadic Alopecia Brachycephaly Short and broad skull Congenital cataract! Convex nasal ridge = Beaked nose Dermal atrophy

Wolf Parkinson White (WPW) *Cardiovascular* *Cardiomyopathy*

Sporadic (most) AD (rare) PRKAG2 Glycogen deposits in heart => . HCM + . Conduction abn

Epidermolytic Ichthyosis

Sporadic (most) AD (rare) KRT1 KRT10 Onset: neonate Denuded skin +/- blistering and secondary infection

Chromosome Structure

Telomeres: Sequences at end of each ch; provide stability to ch ends Telomere Synthesis: Lagging strand synthesis at end of ch is a problem because there is no 3' hydroxyl group from which to elongate→ after each round of DNA replication, the DNA molecule becomes slightly shorter Telomere Replication: Telomerase is a ribonucleoprotein that adds ntds to end of template DNA (uses RNA as template) This maintains length at the end by extending one strand to allow other strand to be copied by replication machinery Most somatic cells in humans do not make telomerase Centromere: Maintains sister chromatid adhesion prior to anaphase; site where kinetochores form and mostly composed of heterochromatin Origins of Replication: Multiple origins of replication on each ch (having multiple helps replicate genome faster; generally these are AT rich regions)

Epidermolysis Bullosa

Types: 1. Epidermolysis Bullosa Simplex (EBS) AD KRT5, KRT14 Onset: Birth Skin blistering 2. Junctional Epidermolysis Bullosa (JEB) AR LAMA3, LAMB3, LAMC2, COL17A1 Onset: Birth Skin blistering Hoarse cry Bad teeth 3. Recessive Dystrophic Epidermolysis Bullosa (RDEB) AR COL7A1 Onset: Birth Skin blistering (fragile as a butterfly "butterfly boy") Mitten deformity

Cyclophosphamide (Cytoxan) *Teratogen*

Use: Chemo Supress immune system HL if genetic predisposition 1st Tri: Skeletal Palatal abn Limb Eye abn 2nd & 3rd Tri Fetal pancytopenia IUGR (Infertility in tx pt)

Warfarin & Coumadin *Teratogen*

Use: *anticoagulant* *1st tri*: 8-11 (6-9) wk post LMP => ***HYPOPLASTIC NOSE*** CALCIFIC ****STIPPLED EPIPHYSES*** of 2ndary epiphysis ****SKELETAL ABN: LIMB HYPOPLASIA**** (1/3) IUGR, GR CNS damage => DD, ID Eye abn: optic atrophy HL CHD (less common) Low birth weight Stippled epiphyses, and skeletal abn 2nd-3rd tri => SAB, stillbirths, prematurity *Heparin is not teratogenic!* BUT if subcutaneously / IV, may inc SAB, stillbirth, prematurity

Phenytoin *Teratogen*

Use: *anticonvulsant* (also used for Fabry tx) *1st tri* 6-15% BD risk *PHENYTOIN ("dilantin" is the brand name) - contains HYDANTOIN* 1. *Dysmoprhic*: . Wide anterior frontanelle . Oular hypertelorism . Metopic ridge . Broad depressed nasal bridge . Short antevereted nose . Bowed upper lip, *CLP* . Short webbed neck . No hairline 2. Hypoplastic (small) distal phalanges + ****HYPOPLASTIC NAILS****; low arch fingertip pattern 3. *ID* 4. IUGR (10%), short 5. CHD 6. Bleeding disorder from deficient vit K dependant clotting factors (50%) Trimethadione (Tridone)/Paramethadione: 70% risk 1. DD, ID, speech problems 2. IUGR 3. Microcephaly 4. CHD 5. Dysmorphic face: V-Shaped Eyebrows hypertelorism cup-shaped microtia CL+/-CP irregular teeth

Fluconazole *Teratogen*

Use: anti-fungal for mycotic infections HI DOSE => . Craniofacial abn . Limb abn . CHD ****Antley Bixler phenocopy****

Selective serotonin reuptake inhibitors (SSRIs) *Teratogen*

Use: antidepressant CHD (2-fold) Possible associations: Neonatal adaptation syndrome Persistent pulmonary hypertension of newborn Critical Period: Throughout pregnancy→ neonatal adaptation syndrome After 20 wk→ persistent pulmonary hypertension of newborn

Cytotoxic Drugs *Teratogen*

Use: ca tx 1st 3 mos SAB and malformations

mtDNA Depletion *Mitochondrial*

Very low mtDNA copy number per cell *AR* mtns in *nuDNA* necessary for ---mtDNA replication (POLG = *GAMMA POLYMERASE*, C10orf2 = Twinkle) ---maintenance of deoxynucleotide pools (TK2 and dGK) ---other genes: ECGF1, SUCLA2, MPV17 => mtDNA instability + secondary mtDNA mtns Disorder of inter-genomic communication Genetically heterogeneous ---Thymidine kinase (TK2) mtns=>late-onset myopathic form ---Deoxyguanosine kinase (dGK) mtns=> early-onset hepatocerebral form Onset: Neonatal 1. Neonatal ***LIVER FAILURE*** 2. Infantile ***MYOPATHY*** 3. Encephalopathy (brain dysfunction) => *INFANT DEATH* Note: *Anti-retroviral drugs used in AIDS can cause reversible mtDNA depletion*

Danon *Cardiovascular* *Cardiomyopathy*

XL LAMP2 Glycogen accumulates in vacuoles => . HCM w preexcitation . Skeletal myopathy . Retinal dystrophy

Lowe = Oculo cerebral renal

XL OCLR @ Xq26 Dx: Enzyme activity <10% (on fibroblasts) PCLR seq (95% DR) Defect in inositol metabolism => -DD, hypotonia, DTRs absent -Delayed motor milestones -Cataracts!!! (all affected boys), infantile glaucoma (50%) -Generalized aminoaciduria -Renal tubular dysfunction (fanconi type)

Glycogen Storage Disease IX *Metabolic* *Glycogen Storage*

XL PHKA1, PHKA2, PHKB, or PHKG2 genes Enz def: Phosphorylase kinase (PK) enzyme Hypoglycemia Liver enlargement

Wiskott Aldrich

XL WAS WASP . *Thrombocytopenia* usually at birth . Intracranial *bleeding* . Intermittent mucosal bleeding and bloody diarrhea . *RECURRENT BACTERIAL/VIRAL INFECTIONS* including recurrent ear infection and risk of developing autoimmune condition, at risk to develop lymphoma Tx: BMT Survival w/out BMT childhood, adolescence

X-linked Adrenal Hypoplasia Congenita *Microdeletion*

XL, 50% de novo NR0B1 . Adrenal insufficiency beginning in infancy → including saltwasting episodes . Underdeveloped reproductive tissue → cyptorchidism, delayed puberty, infertility Test Low Na, high K, acidosis, elevated ACTH NR0B1 seq+deldup *Microdel kinase deficiency + DMD

Oto Palato Digital

XLD FLNA 1. HL 2. Face: Frontal and occipital prominence Eyes: Hypertelorism Nose: small Midface: hypoplasia Mouth: small, cleft soft palate; absent or impacted teeth 3. Skeletal: Small trunk Pectus Small iliac crest Limited elbow extension Bowing of tibia Short, broad distal phalanges (esp. Thumbs and great toes) Widely spaced toes Mild ID

Focal Dermal Hypoplasia = Goltz *Ectodermal Dysplasia*

XLD --- *LETHAL in MALES* PORCN Criteria: . Skin . Skeletal . Eyes . Face

Conradi Hunermann

XLD --- de novo (most) EBP . Face/body asymmetry . Skin abn . Cataracts . Short

CHILD *Metabolic* *Cholesterol biosynthesis*

XLD NSDHL Enzyme Deficiency: NSDHL Ichthyosiform skin (on one side of body only) Ipsilateral limb defect With/out: heart, lung, kidney, CNS abn Dx Methyl Sterol test: elevated methyl sterols in cultured cells NSDHL genetic test

Kennedy = Spinal Bulbar Muscular Atrophy (SBMA) *Triple repeat expansion*

XLR *AR gene* @ Xq11-12 *CAG* = *polyglutamine* - in *EXON 1* Nl <34 (no premutation) Reduced penetrance 36-37 Full penetrance 38+ *Slight PAT anticipating, but not as common as HD* (*think president is male w boobs*) Onset: 22-66 (typically 40's) Slowly progressive 1. *Progressive neuromuscluar*: . proximal muscle weakness and atrophy . Fasciculations . Dysphagia (trouble swallowing) . Bulbar (facial) weakness=> . Dysarthia (slurred words/ articulation) . Involuntary facial twitching in portions of the face . Tremors when earlier onse 2. Gonad: Gynecomastia, testicular atrophy, *INFERTILITY* (mild androgen insensitivity) *nl lifespan*

Choroideremia

XLR Atrophy of cells in retina and nearby network of blood vessels (choroid) => Night blindness Tunnel vision Reduced visual acuity

Monoamine Oxidase Deficiency

XLR MAOA MAOB Enzyme Deficiency: monoamine oxidase A and B ID Psychosis Impulsive Aggressiveness Antisocial behavior Dx: Decreased 5-HIAA, HVA and VMA; increased 5-HT MAOA, MAOB genetic test Tx: None

CK Syndrome

XLR NSDHL Enzyme Deficiency: NSDHL CNS: severe cognitive and behavioral problems, microcephaly CNS cortical malformation Dysmorphic Features: marfan-like body habitus almond eyes hi palate micrognathia Infantile seizures Dx: Methyl Sterol test: hi methyl sterols in cultured cells NSDHL genetic test Tx: Symptomatic only

Barth *Metabolic* *Mitochondrial* *Lipid metabolism* *Cardiovascular* *Cardiomyopathy*

XLR TAZ Enz def: tafazzin in mitochondria => 3-methylglutaconic aciduria . *HCM/DCM* . Skeletal myopathy => movement prob . Neutropenia => recur infection . Short Biochem: uOA: abn

Simpson Golabi Behmel

XLR . GPC3 . GPC4 (some) Criteria: . Macrosomia (big newborn): in males . Neonatal hypoglycemia => serious . Overgrowth . Abd/chest: --- Supernumerary nipples --- Diastasis recti --- Umbilical hernia --- Diaphragmatic hernia . Coarse face: --- Hypertelorism --- Macrostomia --- Macroglossia, glossoptosis (tongue further back/down), micrognathia => obstruct airway --- Broad nose w upturned tip Other criteria: . CHD . Renal abn . HSM . Skeletal abn . Ca: --- Wilm's Tumor --- Neuroblastoma Dx: Clinical + GPC3/GPC4 test Tx: . Prompt tx of neonatal hypoglycemia + airway obstruction . Tx other prob as usual

Carnitine Palmitoyl Transferase II (CPTII) Deficiency *Fatty Acid Oxidation* *Metabolic* *Mitochondrial*

mt beta oxidation defect CPTII @ 1p32 --- Ser113Leu mtn (60%) . Dysmorphic . BD

Mitochondrial Cariomyopathy

tRNA-ile (transfer RNA isoleucine) gene mtns Cardiomyopathy

Newborn Screening (NBS) - ACMG -

• Mandated by law Invented by Robert Guthrie Criteria for NBS I: 1. Dx important health problem 2. Dx w latent / pre-symptomatic stage 3. Well-known natural history 4. Accepted tx avail 5. Facilities for fwp avail 6. Screening w low false pos and false neg 7. Screening acceptable to public 8. Cost of case-finding, including dx and tx, economically balanced to expenditures of medical care as a whole 9. Case-finding is an ongoing process (looking for missed cases, false neg...) Rslts: Truly abn: single / multiple analytes >> cut off -lab notifies MD ASAP: gives contact for metabolic specialists -ACT sheet specific to dx -FACT sheet for families Dx on MS/MS: By blood acylcarnitines -9 OA (IVA, GA-1, HMG, MCD, MUT, Cbl A,B, 3MCC, PROP, BKT) -5 FAO (MCAD, VLCAD, LCHAD, TFP, CUD) By AA - 6 AA disorders (PKU (Guthrie blood test 1962 high sensitivity, low specificity), MSUD, HCY, TYR I , ASA, CIT) Hematology -Hb SS -Hb S/beta thal -Hb S/C Others -CH -Biotinidase -CAH -GALT -HEAR -CF Hemoglobin dx: by HPLC FS (Hb SS) -> CBC and/or DNA -> refer to specialist FSC (Hb SC) -> refer to specialist FSA (Hb Sbeta thal) -> refer to specialist FAS (Hb AS) -> no further test AA dx and their metabolities -PKU - high phe -HCY - high met -MSUD - high leucine -Argininemia - high arginine -Arginosuccinic aciduria (ASA) -Citrullinemia I (CIT) & II - citrulline -TYR I, II & III - tyrosine FAOD: -Carnitine uptake deficiency - C0 -CPT 1 deficiency - C0, C0/C16+C18 -CPT2/CACT - C16 &/or C18:1 -Glutaric acid 2/ethylmalonic encephalopathy - C4, C5 -LCHAD TFP - C16-OH +/- C18:1-OH -MCAD - C8, C6, C10 -SCAD/ethyl malonic enceph/isobutyryl CoA Dehydro D - C4 -VLCAD - C14:1 +/- OAD: -Biotinidase, HMC - C5-OH -Glutaric acidemia 1 - C5-DC -IVA, short/branched chain acylCoA dehy d - C5 -MMA, PA - C3 Endocrine dx: TSH >24hr of age confirm w T4, TSH, TRH -Expanded NBS in MA (1999): AA, OA, FA, CT -20 primary targets: HRSA/ACMG Uniform Panel (MS/MS) 22 Secondary targets -New additions: . Pompe (pilot) . Gaucher (pilot) . Fabry (pilot) . Krabbe . Niemann Pick A, B

NARP (Neuropathy, Ataxia and Retinitis Pigmentosa) & Leigh *Metabolic* *Mitochondrial*

****MT**** (*think N for MNM for mt*) *MT-ATP6 = ATPase subunit 6* --- point mtns: ------ ****T8993G**** (most common) [BOARDZ] ------ *T8993C* ------ *T9185C* --- *HETEROPLASMY* --- <60% nl --- ****70-90% mtn heteroplasmy -> NARP => less severe****[BOARDZ] (*think N for NOT severe*) --- ****>90% mtn heteroplasmy -> Leigh****[BOARDZ] Onset: childhood NARP: . N *Neuropathy* - peripheral: proximal neurogenic muscle weakness w sensory neuropathy . A *Ataxia* - cerebral . RP *RP* Other criteria: . Lactic acidosis . DD, ID *NARP + Leigh: part of continuum of progressive neurodegenerative dx*

Trisomy 16

****Most common trisomy in human conceptions**** ****Most common autosomal trisomy in human conceptions**** Most common cause of chromosomally abn SABs SAB < 10-13 wk If 100% T16 on CVS -> ~ 100% CPM => Preeclampsia & IUGR risk => ~ 0% fetal mosaic T16 risk

Neural tube defects (NTDs)

***1-2 / 1,000 (0.1%) CAUCASIAN LIVEBORNS*** F >> M (especially anecephaly) Usually sporadic / multifactorial 95% no fhx Neural tube closes in ****1st TRI**** by 3-4 wks after conception ---- top closes by 26-28d ---- bottom by 28-30d Prenatal test: . Anencephaly: --- ****Hi AFP + low uE3 [BOARDZ] (other analytes nl)**** --- 50% polyhydramnios risk→ premature labor => always lethal . Spina Bifida: --- US (skull): ------ lemon sign (parietal scalloping) ------ banana sign (cerebellar distortion due to Chiari malformation) ------ *not spinal lesion --- Risk for other BD: 2-16% --- Recommend fetal MRI => Postnatal: --- Paralysis --- Vertebrae abn --- Bowel/bladder dysfunction --- Cerebral cervical nerve dysfunction Tx: surgery + shunt . Omphalocele = herniation of intra-abd contents into cord (covered by membrane) --- Risk of other BD: 50% --- Risk for: ------ BWS ------ Cloacal exstrophy (OEIS) ------ T13 --- Recommend fetal echo + karyotype . Gastroschisis = herniation of intra-abd contents (no membrane) --- Usually sporadic; but associated w *young mat age* --- Risk for: ------ Bowel dilation ------ Ischemic bowel ------ SGA US 80% DR US + MS-AFP > 96% DR US + AF-AFP >98% DR: acetylcholinesterase (AChE) present w open NTD only (not closed NTD, not AWD) MS-AFP higher in: AA (BUT caucasian + hispanic inc NTD risk) Non-diabetic (BUT diabetic / obese higher NTD risk) Multiple gestation RR: *Sib 2-3%* Parent 3-4% ****2 sibs 5-10%**** SDR 1% TDR 0.5% Spina bifida occulta RR FDR 0.1% (= background risk) Folic acid & pregnancy: start *before conception* . ****Gen pop: 400 mcg (0.4 mg) / day**** . ****If previous preg w NTD → 4 mg 4000 mcg (4 mg) / day**** => decreases incidence by > 70%

Loeys Dietz Syndrome (LDS) - ACMG -

*AD* *TGFβ* receptors: TGFβR1 TGFβR2 SMAD3 TGFβ2 TGFβ3 . Vascular -- *Arterial tortuosity* --- *Aneurysm (like Marfan)* ------ Aortic ------ Arterial: cerebral, thoracic, abd . Face --- Craniosynostosis --- Eyes: hypertelorism --- Mouth: *bifid (split) uvula* / cleft palate . Skeletal --- Marfanoid body --- Hypermobile --- Lumbosarcal dural ectasia . Other --- CHD --- Brain abn-> ID --- Easy brusing, scars *NL EYES!!! (unlike Marfan)* Dx test: 1. Physical 2. Fhx 3. Echo 4. Dilated eye exam (to exclude Marfan)!!! 5. Magnetic resonance angiography of head, neck, thorax, abdomen, pelvis 6. TGFβR1 + TGFβR2 seq Dx criteria: . *Facial features w bifid uvula + tortuosity* => confirm dx w TGFβR genetic test *Arterial tortuosity can be isolated (e.g. only in head + neck), requiring magnetic resonance angiography of head, neck, thorax, abd, pelvis for complete eval*

Alagille *Microdeletion*

*AD* --- de novo (50-70%) . *JAGGED1 = JAG1 del/dup* (>95%) @ ch20 [BOARDZ] (*think gile like a jagget*) . *NOTCH2* del/dup (2%) ---*exon 34 mtns cause HadjuCheney (serpentine fibula polycystic kidney) . *20p12-* Criteria: *think BCC wearing jacket BCs Cold* . *BUTTERFLY VERTEBRAE* . *CRANIOFACIAL DEFECT* --- Broad forehead --- Pointed chin . ****CHD**** (90%) [BOARDZ]: --- Peripheral pulmonary arteries stenosis --- TOF . Xanthomas = fatty growths under skin . Posterior embryotoxon (corena abn) . Eye abn: posterior embryotoxin . Histology: *think BC for Bile duct Cholestasis* --- *BILE DUCT PAUCITY/abn-> CHOLESTASIS* (reduced bile flow from liver) => *LIVER FAILURE*

Turcot *Mismatch Repair Deficiency* *Childhood Cancer* *FAP variant*

*AR* ****APC @ 5q21-22 (2/3)**** ****MMR (Lynch) genes (1/3)**** => MSI hi tumors *FAP* + . *GLIOMA* (CNS: brain / spine) (*think T for Tasseh 3a rassa*): ---*if APC => MEDULLOBLASTOMA (often)* [BORADZ] ---*if MMR => GLIOBLASTOMA* [BOARDZ] . T-cell leukemia (common) . Colon adenoma -> CC (less common) . CAL spots Dx: *Genetic test*

Homocystinuria *Metabolic* *Amino Acid*

*AR* *CBS* Enz def: *cystathionine beta synthase (CBS)* (*think C for Cystinuria) Homocysteine => 1) cystathionine -> (via CBS enz) -> cysteine + 2) methionine CBS def => hi homocysteine+methionine & low cystine Nl @ birth Onset: child (3y) - adult -Eyes: . ****ECTOPIA LENTIS**** (lens *dislocated down vs up in Marfan*) . Severe myopia -Skeletal: . *MARFANOID* ---****tall****, thin ---****arachnodactyly**** ---****pectus**** ---long bones . *STIFF JOINTS* (*unlike Marfan*) . Osteoporosis . Scoliosis . Pes cavus (high arched feet) -Neuropsych: . *ID / LD (ADD)*! (*unlike Marfan*) . Seizures . Psychosis -*THROMBOPHILIA*: venous/arterial (*unlike aortic dissection in Marfan*) ****Nl aorta**** (*unlike Marfan*) ****NBS: hi methionine**** Dx: . pAA: --- *hi homocysteine, methionine* --- *low/no cysteine* . CBS genetic testing Tx: . Diet ---Restrict methionine ---Formula w AA except methionine . Vit B6 -> stimulate enz activity . Betaine -> stimulate alternative pathway => clear toxic compounds . Pyridoxine *CANNOT DO LIVER TRANSPLANT*

Cystinuria *Metabolic* *Amino Acid*

*AR* *Hi cysteine AA in urine* => cystine *stones/crystals* in kidneys, ureter, and bladder

Carpenter syndrome

*AR* (*think you need your parents and head and bass to make a carpet) RAB23 (vesicle transport protein, neg. hedgehog signalling) Craynosynostosis: acrocephaly (POINTED HEAD) Digit abn: polydactyly, syndactyly and brachydactyly ID

Beare Stevenson *FGFR Craniosynostosis*

*FGFR2* . *Craniosynostosis* . Widespread *cutis gyrate* . *ID* (100%) . Ear abn . GU abn * Nl hands + feet

Holoprosencephaly

*Field defect* . *CHROMOSOMAL* (50%) . Syndromic (mtn in important developmental genes) --- Rubinstein Taybi (*think akal rasso la2anno taybin*) --- Kallman (think *akal rasso*) --- SLOS (*think O bi rasso*) . Nonsyndromic monogenic (rare): - AD familial - Variable expressivity - Reduced penetrance (70%) --- ****SHH**** (30-40% of familial AD, 5% overall) (*think H for HH) --- TGIF --- PTCH --- TMEM1 --- HPE6 . Teratogen (*mat diabetes*) Onset: prenatal *F >> M* (2 : 1) (unlike most BD) Ventral forebrain abn=> . Dysmorphic face: --- *Midline cleft* --- *Extreme hypotelorism* --- *Microcephaly* --- Cyclopia --- Cypotelorism --- Microphthalmia --- Absent frenulum --- Single incisor --- Poor temperature regulation . *Seizures, DD* *No anomalies below neck* Test: . Early detailed US (16-18 wk) . MRI/CT . *Karyotype* > *multigene seq*

Robertsonian Translocation

*If mom is a balanced Rob carrier, she is more likely to pass down unbalanced gametes than balanced gametes* Human cells contain 200 copies of t 45S rDNA in clusters on the *5 acrocentric ch: 13, 14, 15, 21, 22* A translocation btw 2 acrocentric chs by fusion of long arms at centromeres, w loss of short arm + satellite (no problem bcs short arms code rRNA for which there are many copies) When robs form, NORs (Nucleolar Organizer Regions in stalks of short arms of acrocentric ch) of 2 fusion ch are lost --- carriers have 8 (vs 10) NORs: not all NORs functioning, but we need 4-7 active for nl cell function Segregation: - Heterologous: 2 different acrocentric ch Meiotic Behavior: At meiosis, transl ch + 2 nl homologs synapse as trivalent Modes of Segregation: . 2:1 → 6 types of gametes . Alternate → nl/balanced gametes . Adjacent: 2 types of disomic + nullisomic gametes . 3:0 → rare! - Homologous: 2 of same acrocentric ch Mode of Segregation: 1:0 (no gametes balanced) Gamete is disomic Gamete is nullisomic ****RR of liveborn child w unbl ch****: . Parent balanced rob transl carrier (q10;q10): *REMEMBER IF 13;13 OR 21;21 => 100% RISK (HIGHEST)* *Mom has 14;21 (2nd most common rob transl; most common parental rob transl associated w transl T21) / 13;21 / 15;21 / 21;22 => 10-15% risk of baby w Down syndrome* *Mom has 13;14 (most common rob transl)/ 13;15 / 13;21 / 13;22 => 1% chance of having a baby w T13* *Mom has 14;15 / 14;22 / 15;22 => ~ 0% risk of having a baby w a trisomy, but possible risk of SAB or UPD* *Dad w any Robertsonian transl => low risk, below 1%, of any child being affected --- *t(13;13): 100%* --- *t(21;21) = isoch 21/21: 100%* --- *t(13;21): transl T21 risk* (and 1% risk for T13) ------ *15% T21 (if mat)* ------ *1% T21 (if pat)* --- ****t(14;21): T21 risk (& UPD 14 risk)**** ------ ****15% @ amnio & 10% @ birth (if mat)**** ------ *1-5% (if pat)* --- *t(21;22): T21 risk* ------ *10-13% @ birth (if mat)* ------ *1% (if pat)* --- t(15q;21q): UPD 15 risk ------ 0-11% (mat) ------ <0.5% (pat) --- Others: 1% --- t(13;14): 1% --- t(13;15): 1% --- t(13;21): 1% --- t(13;22): 1% . *Fetus w balanced rob transl carrier*: --- *de novo: 3% risk of abn* --- *inherited (from nl parent): no inc risk* *UPD risk in balanced carriers*: *Non-homologous rob: 0.4-0.6%* (*13;14: 0.6%*) *Homologous rob: 66-73%* (homologous acrocentric transl - usually isochrom) Presence of UPD in unbal ch pts: Non-homologous rob: 4.7% Homologous rob: 100% UPD test if: . 14 / 15 balanced rob transl in: --- Carrier fetus --- Patient w abn pheno

G6PD (Glucose-6-Phosphate Dehydrogenase) deficiency *Metabolic* *Glycogen Storage* *Carbohydrate Metabolism* *Blood*

*Most common RBC enz def* *XLR* --- Manifesting female carriers w mild disease --- Heterozygote advantage (*balanced polymorphism*) for *malaria*: 5-25% in *Mediteranean, Middle Eastern (Kurdish Jews), African, Asian* where malaria is common ------ African carrier freq: 1/10 males (variants milder than Medit variants) *G6PD @ Xq28* --- Allelic heterogeneity Enz def: *glucose-6-phosphate dehydrogenase* - involved in converting glucose to ribose-5-phosphate (DNA building block) Rslts in *hemolytic anemia* secondary to a decreased stability of G6PD protein & inability to synthesize mature RBCs (under conditions of oxidative stress) . Neonatal jaundice . Acute hemolytic anemia *Similar to sickle cell* Triggers: . Oxidative stress: --- *Fava beans* --- *Infections* --- *Oxidative drugs: some antibiotics & malaria meds* --- Toxins => hemolytic anemia (destruction of RBCs) Test: . Enz activity in erythrocytes . G6PD gene

22q11.2 deletion = DiGeorge = Velocardiofacial (VCF) *Microdeletion*

*Most common microdel* 1/4,000-6,000 (genereviews) *Familial occurrence by chance alone common, bcs condition NOT rare!* Co-occurring dx common: T21 Marfan CHARGE NF1 Achondroplasia FGFR3 mtn EDS T8 mosaic Co-occurring AR: Bernard-Soulier CEDNIK ****AD, 93% de novo vs 7% inheirted****: Low copy number repeats flanking recombination region → Non-allelic homologous recombination → aberrant interch exchanges => del / dup *Some somatic/germline mosaicism *~50 genes*: *TBX1→ conotruncal defects* (*think get me the tbox to drink tea for my heart*) *COMT* Test: ****FISH*****95%* *DR*, most w *SAME DEL* [BOARDZ] > *Array (better DR!)* Bcs analysis of metaphase ch requires stimulation of T-cells by mitogen (phytohemagglutinin) to enter mitosis -> pts may not have enough nl T-cells to yield adequate metaphases => *skin fibroblast cultures, which do not depend on phytohemaglutinin stimulation, used to evaluate ch* Intra + inter familial variable expressivity Prenatal US: *Polyhydramnios*, CHD, Cleftp palate *C A T C H 22* C ****Conotruncal CHD**** (74-85%): [BOARDZ] --- ****INTERRUPTED AORTIC ARCH**** --- ****TRUNCUS ARTERIOSUS**** --- ****ToF**** --- *ASD* --- *VSD* *22q-2nd most common cause of CHD (after T21)* A *Abn face*: ---hooded eyelids ---prominent nose w square nasal root ---bulbous nasal tip ---hypoplastic alae nasi ---asymmetric crying face ---malar hypoplasia ---ear abn T *Thymus hypoplasia + immune def*: --- chronic infection --- poor response to vaccine => *AVOID live viral vaccines until immune system matured* --- autoimmune disease (rheumatoid arthritis, Graves disease) C *Cleft palate / CLP*: --- ****PIERRE ROBIN**** --- *Submucous cleft palate* --- *Bifid uvula* --- Overt cleft palate --- Velopharyngeal insufficiency (nasal regurgitation, *feeding prob in CHILDHOOD*, hypernasal speech, ear infections-> HL => *ENT referral*) H Hypoparathyroid / hypocalcemia→ seizures *Endocrine prob, esp in times of stress* . Short . Growth hormone def . IUGR Other criteria: . *Psych illness (usually in ADULT)* -Children: --- ADHD --- Anxiety -Adults: --- ****SCHIZOPHRENIA**** (20-30%) --- Bipolar --- Depression --- OCD . Renal abn --- agenesis --- cystic --- dysplastic . GI: --- Esophageal dysmotility --- Intestinal malrotation --- Constipation --- Hernia . Sex organ abn: --- cryptorchidism --- hypospadias --- absent uterus . Vertebrae abn→ cervical scoliosis . Developmental disability: --- Mild LD in math + spatial learning --- ADHD --- ASD --- Anxiety --- OCD --- Oppositional defiance disorder --- Autism --- ID . Inguinal hernia Dx: Often missed *Pregnancy => biological stressor in affected women => new onset* --- Hypocalcemia --- Heart disease --- Psych illness Differential: CHARGE Goldenhar Kabuki SLO Alagille Jacobsen Tx: Multidisciplinary team => monitor + manage symptoms . Calcium supplement . Feeding strategies (different bottle/spoon) . Treat infections, prophylactic antibiotics, IVIG therapy

Large Nuchal Translucency (NT) & Large Nuchal Fold

*NT ≥3mm* i.e. ≥ 95th percentile Twins: DR: 75% FPR: 7% Large NT (measured @ 11-14 wk) . Ch - *T21, 18, 13* - *Turner (esp. cystic hygroma)* - *Triploidy* BD: - *CHD* - *Diaphragmatic hernia* . Single gene dx - *Noonan* - *Skeletal dysplasia* - *Arthrogryposis* (joint contractures) - *Multiple pterygium* (growths on eyes) Test: if karyotype nl -> det US + fetal echo *Large Nuchal Fold* (measured @ 18-24 wk) - *T21* - *CHD* - *Skeletal dysplasia* - *Noonan* - *Multiple pterygium*

Turner syndrome = Monosomy X = 45,X

*One of most common causes of chrom abn SABs* Sporadic ---usually *PAT nondisjunction* (missing Y) (*NO AMA factor*) ---Mat nondisjunction (missing X)-rare *RR: 1%* (higher than background risk) *MOST => SAB* Prenatal US: . Cystic hygroma, *congenital lymphedema* . CHD . Horseshoe kidneys . Hydrops . CHD (50%): [BOARDZ] -*Aortic coarctation* (20% risk) [BOARDZ] -Other L-sided CHD (15-20%) ----Aortic valve abn ----HLHS . *Aortic aneurysm (but not as high risk as Marfan and LDS)* [BOARDZ] . Renal: *horseshoe kidney* . LD: visual-spatial orientation + math ---ID if X-autosome transl . Low birth weight . Short . Thyroid prob . Lymphedema of hands/feet→ webbed neck . Shield chest . Sexual: -*GONADOBLASTOMA* ca if 45,X/46,XY -Gonadal dysgenesis (no ovaries) -Infertility -No menstruation -No breasts Dx: Karyotype Tx: -ERT during adolescence -Exploratory laparotomy if mosaic→ inc gonadoblastoma risk Fertility tx: Some women have given birth w IVF and donor egg *As common as XXX*

Protein C *Thromophilia*

AD PROC Protein C, S and antithrombin III: 5-15% of venous thrombosis . DVTs . PE . IUGR . Preeclampsia (highest risk in protein C/S) * NO inc SAB risk!!!*

Toxoplasmosis Gondii (toxo) *Teratogen* *Virus*

*Virus* in: . *undercooked meat* . *cat feces* . *soil* Prenatal: *Echogenic bowel* [BOARDZ] Nl @ birth Onset: several mos-1y . ****CHORIORETINITIS**** (eye inflammation) => blind . *Hydrocephalus* . *Intracranial diffuse calcifications* . HL . LD, ID (apparent after several mos-1y) . Epilepsy . Microcephaly . Encepalitis . Anemia, thrombocytopenia . HSM . Jaundice . Lympadenopathy . Pneumonia . Maculopapular rash . Petechiae . Nephritis . Spasticity Tx: *Prevention is key* Tx w antiobiotics decreases severity but doesn't decrease transmission

Protein S Thrombophilia

AD PROS1 . DVTs . PE . IUGR . Preeclampsia (highest risk in protein C/S) *NO inc SAB risk!!!*

ACOG 2007 Hemoglobinopathies guidelines

-Offer all women: -MCV, if low > hem elec -Offer MCV+hem elec to: --- African (sickle cell on hem elec) --- Asians (except Japan and Korea) --- Mediterannean --- Arabian --- Oceania Low risk: [BOARDZ] Korean Japanese Inuit Northern European Native americans (first nations) Dx test: -CBC + hem elec *Solubility test inadequate -Prenatal dx: DNA analysis

Bicuspid Aortic Valve Sequence

. Unknown cause . Heterozygotes for NOTCH1 mtns: ---4% of sporadic cases ---Some familial cases Variable expressivity May be caused by neural crest defects . Bicuspid aortic valve . Dilatation of ascending aorta (not usually sinuses of Valsalva) . Aortic coarctation . MVP . Thoracic cage abn

Cardiofaciocutaneous Syndrome

AD --- denovo (most) BRAF (75-80%) MAP2K1, MAP2K2 (10-15%) KRAS (5%) CHD: PULMONIC STENOSIS Dysmorphic face Skin abn ID

Brugada

1-5 in 10,000 *Causes of Brugada sign: . Nl variant . Structural defects ---- Blockage ---- Contusion/compression . Drugs and meds ---- Certain antidepressants ---- Drugs that interfere with sodium uptake . Electrolyte imbalances --- Sodium --- Potassium --- Calcium *Common in SEA* *AD*: --- 30% penetrance --- M >> F 16 *ion channel genes*: (25-40%) w similar pheno . ****SCN5A**** (10-30%) [BOARDZ] (*think SCH for channel*) . GPD1L . SCN1B . CACNA1C . CACNB2 . SCN3B . KCNE3 . *Abn EKG: coved-type ST segment* (type 1) . Syncope / nocturnal agonal respiration . Ventricular arrhythmia + sudden cardiac death (mean age 40, usually 1st symptom is sudden cardiac arrest/death in young male) *Can present as SIDS or sudden unexplained nocturnal death* - Brugada accounts for: --- 4-12% of all sudden deaths --- Up to 50% of sudden deaths w nl echo Clinical dx: . Brugada pattern on EKG: --- *Procainamide challenge (increases penetrance to 80%): administration of a sodium channel blocker to induce Brugada pattern * --- *(Fever may also incude pattern)* + . Ventricular fibrillation or . Polymorphic ventricular tachycardia or . Electrophysiologic inducibility of VF/VT or . Syncope / nocturnal agonal respiration or . Fhx of sudden cardiac death (<45) or . Fhx of coved-type EKG Test: Multigene panel: seq + deldup (25-30% DR) Surveillance: EKG yearly for at-risk pts (even if no known mtn) Tx: -Only effective tx: ---Implantable cardioverter defibrillator (ICD) ------ NOT recommended if asymptomatic -Other tx: ---Some *antiarrhythmic meds* may help prevent ventricular fibrillation (*most NOT useful*) ****Beta blockers COUNTER-indicated**** -*AVOID*: ----High *fever* ----Certain meds: [BOARDZ] ------- *Anesthetics* ------- *Some antidepressants* ------- *Some antiarrhythmics* ------- *Beta-blockers*

HFE Associated Hereditary Hemochromatosis (HFEHHC) *Metabolic* *Cancer*

1-5/1,000 ****AR**** --- Low penetrance --- Variable expressivity ------ Modifiers ----------Sex-depedent ----------Diet ----------Alcohol ----------His63Asp - lower penetrance => *Mendelian disease that behaves like a common complex disease* *HFE* @ 6p21.3 ---*Cys282Tyr/Cys282Tyr (90-95%) - high penetrance* ---H63D low penetrance, common ---Cys282Tyr/His63Asp (5-10%) Enz def: *HFE* protein *Carrier freq in Caucasians 1/9 (38%)* Common mtn: *Cys282Tyr* His63Asp" *Only about 2% of homoz for Cys282Tyr allele will have classical HFEHH, about 0.5% that are compound hetero* GI mucosa absorbs too much iron->Iron storage overload-> . *Fatigue (most frequent complaint)* . ****Progressive bronzing (pigments) of skin**** . Hepatomegaly, liver cirrhosis-> *HEPATOCELLULAR CA*-> liver transplant . Pancreas . Joint . Abd pain, weakness, lethargy, weight loss around 40s to 60s (secondary to cirrhosis) . Cardiomyopathy, heart failure, arrhythmia . Arthritis . Gland dysfunction: endocrynopathy, diabetes, hypogonadism *M >> F (menstruation protective for women)* Dx: -biochem: . *Hi serum ferritin (iron) (want <300ng/ml)* . *Hi transferrin iron saturation (TIBC)* . *Hi liver iron and dysfunction* > - HFE genetic test Tx: Asymptomatic: annual serum ferritin Symptomatic: -*Phlebotomy*: . Clinical HFEHH: weekly phlebotomy to maintain serum ferritin <50 ng/mL .Biochem HFEHH: consider phlebotomy for serum ferritin >500 ng/mL . Nonexpressing Cys282Tyr homozygotes: no phlebotomy needed -*Chelation* -*Liver transplant*

Autism Spectrum Disorders (ASD) & Intellectual Disability & Developmental Delay - ACMG 2013 -

1-6/1,000 Mild APA effect ASD: Complex behavioral disorder that presents in early development period: . Impairment in social communication + interaction . Repetitive patterns of behavior/interests/activities + sensory processing abn . Neurodevelopmental regression . Hyper and hyposensitivity to sound + touch . Odd behaviors around food . Impaired motor development (toe walking) . Abn sleep patterns . Tantrums + self-injurious behaviors . Disregard for danger . Epilepsy . ID (70%); high functioning = IQ>70 (30%) Dx btw 18-36 mos (<3y), bcs before that, even typically developing toddlers have relatively limited communication repertoire *Confirm dx of autism. Rule out HL since behavior could be due to HL Some children w autistic disorder have dx removed if primary communication delay resolves ("grow out of autism") Asperger = looser criteria than autistic disorder: . no onset < 3 y . no communication domain requirement New DSM criteria expected to remove some autism dxs DD: used for preschool children to determine services eligibility Primary (70%) = ASD w no underlying syndrome --Uncomplicated Autism (70%) ----No physical abn ----M >> F (4-5:1) ----More likely if there is pos fhx of ASD / behavioral prob --Complex Autism (20-30%) ----Autism + anomalies/dysmorphic; poorer prognosis ----M = F ----Lower RR (bcs more likely de novo mtn) -Genes in Primary Autism: --CNTNAPS, NLGN3, NLGN4, SHANK3 --Most mtns de novo & associated w APA -Genetic Causes (5-20%): ---Ch: CNVs ---Single gene: ------ FraX ------ Rett ------ Tuberous sclerosis ------ Mt dx ------ PTEN ------ NF1 ------ CHARGE ------ Cornelia de Lange ------ SLO ------ Sotos -Env: In Utero ------ Infections (rubella) ------ Meds --------- Misoprostol --------- Thalidomide --------- Antidepressants --------- Valproic acid Test for children w global DD/ID/ASD of unknown cause: 1st Tier Test: -FraX (1-5% DR; 2.5% DR for ID) - ACMG 2004 -Array (vs karyotype: 3% DR): . ID: 15-20% DR . Autism: 10-15% DR . Epilepsy: 9% DR . Schizophrenia: 5% DR Second Tier Test : -MECP2 (Rett) for girls (4% DR for females) -PTEN (5% DR if head circumf >2.5 SD) -Other single-gene causes, metabolic disorders if clinical symptoms (10%) -EEG, MRI RR: -Uncomplicated autism: --- Sib 5-10% ------ if affected F: 7% ------ if affected M: 4% --- 2 sibs: 25-50% - Only 2-3% families have 2+ affected children -Complex autism: --- Sib: 1%; 2% for milder symptoms

Romberg

1. FACIAL ASYMMETRY 2. Body asymmetry (rare)

HLA-linked Diseases

1. Narcolepsy 2. Ankylosing spondylitis 3. Reiter's

Trisomt 13 = Patau

1/5,000 - 12,000 80% nondisjunction 20% rob transl 1st tri: Large NT Low PAPP-A + HCG (same as T18) Not screened in 2nd tri US: . Holoprosencephaly . Polydactyly . IUGR . Oligohydramnios . Omphalocele . Cleft . CHD . Micropthalmia . Brain + spine abn > 95% => SAB 90-95% die < 1y Preeclampsia risk in mom RR < 1% for any ch aneuploidy

Trisomy 18 = Edward

1/5,000-8,000 *98% nondisjunction* 2% transl *RR: < 1% for any ch aneuploidy* Sex ratio: *4F >> 1M* 1st tri: *Large NT* *Low PAPP-A , hCG* 2nd tri: *Low HCG, uE3, AFP (NL INHIBIN)* US: ****CHD**** (90%) - *VSD* ****CHOROID PLEXUS CYSTS (CPCs)**** (50%): LR=7 (1% of all preg) *CLENCHED HANDS*/fist w overlapping fingers (2nd+5th) *ROCKER BOTTOM FEET* *IUGR* w polyhydramnios *Omphalocele* *Diaphragmatic hernia* *Strawberry sign* Microcephaly Cystic hygroma Single umbilical artery Meningomyelocele Ventriculomegaly ACC Renal & urinary tract abn Postnatal pheno ---Postnatal growth retardation ---Hypertonia ---Eye prob ---Severe ID => 90-95% die < 1y Dx Karyotype Tx Symptomatic + supportive

Trisomy 21 = Down Syndrome (DS)

1/800: --- Most common trisomy in newborns --- Most common autosomal ch dx --- Most common genetic cause of ID --- 61% conceived by moms <35 (av 31.5) (*80% of chromosomally abn babies are born to women < 35*) . *95% nondisjunction* (*90% mat*, 10% pat) . 3-4% transl (rob transl btw 21q & acrocentric ch: 1/3 inherited from bal parent) . 1-2% mosaic (post-fertilization bcs of trisomy rescue or early somatic nondisjuntion => may have milder, pheno but cannot predict pheno) . Rarely *isochromosome (e.g. 46,XX,i(21)(q10)): RR 1% if nl parental karyotypes* - Following the diagnosis of translocation 21 or isochromosome 21 DS, if both parents have normal blood chromosomes, the translocation or isochromosome is usually presumed to have arisen as a result of a new mutation (de novo), and the observed recurrence risk in a series of translocation cases was less than 1% (232). Gonadal mosaicism for isochromosome 21 has been reported and recurrences of DS are recorded (233), so a rounded-up 1% risk of recurrence is appropriate, and prenatal cytogenetic diagnosis should be offered to cytogenetically normal parents who had a fetus or child with DS due to a de novo structural abnormality. *75% SAB* . Short . *Hypotonia* (80%) . Feeding + digestive prob . CHD (40%): *AV (atrioventricular) canal, endocardial (atrioventricular) cushions, ASD, VSD, ToF* [BOARDZ] . GI: duodenal stenosis→ *DOUBLE BUBBLE* (⅓ of cases associated w T21) . Diabetes . Premature aging . ID: mild-mod (IQ 35-70), rarely severe (IQ <35). --- Most finish high school; most require some supervision as adults, particularly w finances + emergency --- Highest functioning: live outside of primary household, obtain driver's licenses, get married, maintain job . DD (motor + speech) . Attention + behavior prob . Autism (not common) . 50% have 1+ BD: ---40-60% CHD ---12% GI defect that requires surgery . Dysmorphic: --- Round, flat face --- Hypertelorism --- Upward slanting palpebral fissures --- Small mouth with protruding tongue --- Clinodactyly --- Transverse single palmar crease . HL . Vision prob . Hypothyroidism . Childhood ca: *ACUTE LEUKEMIA* . Early onset *Alz* . *Male infertility* (females usually fertile) *Life expectancy: 50-60y* (30y increase from 25y life expectancy in 1983) *ACMG 2007: offer prenatal screening AND diagnostic testing for DS to ALL preg* Serum screening: 1st tri : Low PAPP-A Hi HCG 2nd tri: *think getting hi* Hi HCG Hi Inhibin Low AFP Low uE3 Prenatal US: If pos screen + nl US => do Bayes 50% DR w US . BD: --- CHD --- Duodenal atresia --- Cystic hygroma --- Brachycephaly --- Hydrocephalus . Soft markers: --- Large NT ------ Inc T21 risk (LR=17) --- Ventriculomegaly --- ****Intracardiac Echogenic Focus (EIF)****: ------ Slightly inc T21 risk (LR=2) ------ Common in Asian ------ Does not effect heart function --- Echogenic bowel --- Short femur / humerus --- Absent/Hypoplastic nasal bone ------ Significant risk of T21 (LR=51) ------ Ethnicity dependent --- Renal pyelectasis (dilation in pelvis) ------ Slight inc T21 risk (LR=2) (or sign of GU structural anomaly) ------ More common in males --- Sandal gap toes = sandal foot --- 5th finger clinodactyly --- Choroid plexys cyst (CPC) - more common w T18 Dx: Karyotype Pregnancy continuation: Fetal loss rates until term: *After CVS: 32%* *After amnio: 25%* RR for ANY ch aneuploidy: . *Parent w T21 (or mosacic T21)-> up to 50% risk for T21* . *Both parents w T21 (or mosaic T21)-> as high as 66% risk for T21* . *FDR (previous preg/child) w T21* (nondisjunction / de novo transl / mosaic)-> inc risk of T21 & other ch abn: --- For T21: ------ *<35 at previous T21-> age risk x 3.5* ------ *≥35 at previous T21-> age risk x 1.7* --- For any trisomy: ------ <35 at previous T21-> age risk x 1.3 ------ ≥35 at previous T21-> age risk x 1.5 (~1% or higher if AMA) . SDR or more distant-> no inc risk *Risks may be overestimated if fhx of mosaic T21* Tx: Symptomatic . Best outlook if nl family life in own home . Community groups help families deal w emotions & future plans . Special ed required to be offered by school . Monitor for thyroid/leukemia Resources: 1. *lettercase.org* *For expectant parents who received prenatal dx of DS, but UNDECIDED regarding pregnancy* Book prepared by: --- ACMG --- ACOG --- NSGC --- National Down Syndrome Society --- National Down Syndrome Congress 2. *Brighter Tomorrows* - brightertomorrows.org *For medical professionals + expectant parents* - provides accurate info about DS --- Provides simulation training for health-care professionals who deliver prenatal dx to expectant couples --- info, in English + Spanish, about DS to new & expectant parents who received prenatal dx of DS 3. *Health supervision for children w Down syndrome: pediatrics.aappublications.org/content/128/2/393* --- Clinical report written by Committee on Genetics of the American Academy of Pediatrics --- *Provides guidance to health-care professional* involved in prenatal consultations --- *Resources for parents also listed*

Mitochondrial Deafness = Mitochondrial Hearing Loss

10% of HL MT + multifactorial mtDNA: --- HOMOPLASMY --- 12S rRNA (ribosomal RNA) [BOARDZ] ------ ***A1555G (most common)*** [BOARDZ] ------ A7445G Progressive SNHL in a multifactorial manner: --- Other genetic factors: ------ tRNA processing genes ------ mtDNA haplogroup --- Env factors: ------ Aminoglycoside antibiotics: used in Asia for sepsis in newborns, TB, etc => most common cause of HL in China!

Teratogens Birth Defects

20% of all recognized preg->SAB 3-5% of newborns have BD (1% CDH), DD, ID ---5-10% of BD due to teratogens Teratogen = meds / chemical / infection / environment agent that might interfere w development of fetus and result in preg loss, BD, adverse preg outcomes 50-90% of women are exposed to meds during preg (risk ~25%, but not all cause BD) 50% of preg in U.S. unplanned 1) 1-15 d (*1st two wks*) after conception: ALL OR NONE (if any damage-> SAB) . E.g. if woman drinks EtOH/CT scan for 1st 2 weeks of pregnancy and then realizes she is pregnant and stops→ no inc risk to fetus (NOT APPLICABLE TO INFECTION!* 2) 18-60d (3 or 4 - 8 wk) after conception: EMBRYONIC PHASE = organogenesis = embryo's organs developing=> sensitive for teratogens -> BD ---23-30d: neural tube closes 3) > 8 wk: FETAL PHASE: fetus growing - Growth + functional maturation of organs + systems (brain still developing) - BD less likely (may cause heart or brain defects) - Teratogen affect growth (IUGR), organ size + function => "FETAL TOXICITY" - Psychoactive agents (antidepressants, antiepileptics, alcohol) can affect CNS => "BEHAVIORAL TERATOLOGY" Factors: . Timing . Dose: There may be threshold dose below which no effect . Genetic Susceptibility: some pts more susceptible / tolerant . Pattern of Malformation . Tissue Access: teratogen must be present in mat circulation in hi enough amounts to cross placenta FDA Categories: . A: Humans studies show no risk ------ e.g. thyroxine . B, C, D - mat benefits may outweigh risks --- B: No evidence of risk in humans (e.g. prednisone): ------ No human studies OR ------ Humans studies show NO risk, but animals studies show risk --- C: Risk cannot be ruled out: ------ Human studies lacking + animal studies lacking/positive (eg. lorazepam) --- D: Positive evidence of human fetal risk ------ eg. warfarin, valproic acid, lithium . X: Contraindicated in pregnancy --- Fetal risk clearly outweighs benefits (eg. thalidomide, isoretinoin (retinoic acid/accutane) ****"Pregnancy and Lactation Labeling (drugs) Final Rule" (PLLR or Finale Rule)**** - New requirements since 12/3/14: --- The PLLR requires changes to the content and format for information presented in prescription drug labeling in the Physician Labeling Rule (PLR) format to assist health care providers in assessing benefit versus risk and in subsequent counseling of pregnant women and nursing mothers who need to take medication, thus allowing them to make informed and educated decisions for themselves and their children. The PLLR removes pregnancy letter categories - A, B, C, D and X. The PLLR also requires the label to be updated when information becomes outdated. Structures and their Origin: Hindbrain: . Metencephalon→ pons + cerebellum . Myelencephalon→ medulla Midbrain: . Mesencephalon→ midbrain Forebrain: . Diencephalon→ thalami . Telencephalon→ cerebral hemispheres Placenta: 3 functions: . metabolism . substance transfer . endocrine synthesis/secretion Amniotic Fluid: . Protects fetus by: --- barrier to infection --- cushions against injuries to mom --- prevents adhesion to amnion, maintains homeostasis (temp, fluid, electrolyte balance) . Movement of fetus in amniotic fluid: allows muscle + lung development ---Most common cause of oligohydramnios: premature rupture of membranes (PROM) (also caused by renal insufficiency) ---Most common cause of polyhydramnios: unknown (also severe CNS/ esophageal/swallowing problem) Sensitive time for each organ (in wks): NTDs: 3-4 Heart: 3-6 Brain (->ID): 3-16 Upper limb: 4-5 Lower limb: 4-5 Eyes: 4-8 Ears: 4-9 Upper lip: 5-6 Palate: 7-8 Teeth: 7-8 External genitalia: 7-9

Congenital cytomegalovirus (CMV) *Teratogen*

20,000-40,000 infants born w congenital CMV infection per yr CMV is leading cause of non-genetic HL If pos mat infection -> 30-50% fetal infection risk ----> of those, 10-15% asymptomatic * => overall for mat infection => MOST fetuses asymptomatic . nl @ birth! . > 10-15% develop SNHL, unil/bil, progressive starting in early childhood (AFTER passing newborn screen) . Chorioretinitis, retinal lesions, OPTIC ATROPHY-> BLIND . Seizures . GR . Cerebral periventricular calcifications . HSM . Ventriculomegaly . Blueberry muffin rash . ID . Microcephaly . Fetal hydrops . SAB Prenatal test: US (abn only in 15% of affected) --- *ECHOGENIC BOWEL* [BOARDZ] --- Intracranial calcification --- Ventriculomegaly --- IUGR --- Hydrops --- Microcephaly Mat serum antibody screen: IgG for past exposure + IgM for current/recent infection Amnio: viral DNA in amniotic fluid PUBS: screening tool

Birth Defects (BD)

3-5% of newborns have BD (requiring medical attention by age 5) or ID/DD --- 1% CHD Some isolated Some syndromic RR: FDR: 3-5% 2 sibs: 8-12% Both parents: 30-40% >3 FDR: 45-50%

Acute Intermittent Porphyria (AIP) *Metabolic* *Porphyria* *Hepatic* *Cancer*

AD 1% de novo *INCOMPLETE PENETRANCE* (unlike other metabolic dx) Enz def: Hydroxymethylbilane synthase (HMBS) - 50% of nl -> involved in heme biosynthesis in mt . *Life threatening acute attacks w severe neuropathic PAIN* ---Triggers: ------Sulfa drugs ------EtOH ------Hormones ------Infections ------Surgery ------Stress ------Diet ------Smoking . Nausea, vomiting, constipation . Pain in extremities, back, thorax . Dark urine . Hyponatremia (low blood sodium), seizures . HTN, tachycardia, palpitations . Muscle weakness . Psych illness . Chronic renal failure . Hepatocellular ca (HCC) Dx: . Spot urine test during attack: ---Hi porphobilinogen (PBG): 5-10x ---Hi 5 delta-aminolevulinic acid (ALA) . Genetic test (> 98% DR) Tx: . Hemin / Panhematin . Opiate -> for pain . Liver transplant => cure (last resort)

Andersen Tawil = LQT 7 *Arrhythmia* *LQT variant*

AD KCNJ2 . LQT . Periodic paralysis . Dysmorphic face: --- Low-set ears --- Ocular hypertelorism --- Small mandible . Skeletal: --- Short --- Scoliosis . Digits: --- 5th finger clinodactyly --- Syndactyly

Hereditary Papillary Renal Carcinoma *Cancer*

AD MET (ONCOGENE) Late onset *PAPILLARY TYPE I RENAL CLEAR CELL CA* (95%) Other ca: Gastric Rectal Lung Pancreas Bile Duct Screening: -Start @ 40, yearly --- Renal MRI --- Urinalysis + cytology

MTHFR - ACMG 2013 -

AD ---- Incomplete penetrance: ------ Homozygote => higher risk Enz def: 5,10-methylenetetrahydrofolate reductase (MTHFR): ---Converts 5,10-methylenetetrahydrofolate -> 5-methyltetrahydrofolate ------ Primary circulatory form of folate ------ Cosubstrate for homocysteine remethylation to methionine Common variants: missense -> decreased enz activity: 1. "Thermolabile": c.C665T, historically called ****C677T**** (p.Ala222Val) --- Homozygous: ------ >25% of Hispanics ------ 10-15% of Caucasians 2. ****A1298C**** (p.Glu429Ala) Test: Hi homocysteinemia ACMG recommendations: . MTHFR test has minimal clinical utility -> not recommended for thrombophilia or recurrent SAB eval (ACOG) . Not recommended for at-risk relatives . *If pt HOMOZYGOUS [BOARDZ] for "thermolabile" variant*-> geneticist may order fasting total plasma homocysteine (if not previously ordered) to provide more accurate counseling: --- if nl homocysteine-> no inc risk --- *if hi homocysteine-> mild inc risk*: ------ *VT odds ratio 1.27* ------ *Recurr preg loss pooled risk 2.7* . ****MTHFR status does NOT change recommendation standard dose of folic acid supplementation to reduce NTD risk**** Previously hypothesized that reduced MTHFR enz activity -> . Mild hyperhomocysteinemia => --- VT (DVT): BUT recent meta-analyses disprove association --- Coronary heart disease: BUT recent meta-analyses disprove association --- Recurrent preg loss, preeclampsia --- NTD: Women homozygous for "thermolabile" => inc risk (odds ratio 1.6) for offspring w NTD Tx: BUT no evidence that specific tx reduce risks associated w hyperhomocysteinemia / MTHFR genotype Pt may elect to take: -Daily vit B: multivit / prenatal vit -Folic acid *Low risk w vit/folic acid daily supplements -Pyridoxine: RISK for ataxia + sensory neuropathy

Von Willebrand Disease (VWD) *Bleeding disorder*

AD (7 types) AR (less common) VWF Most common hereditary bleeding disorder (1% of general pop) . Type 1: --AD: most common, mild-moderate quantitative reduction in VWF . Type 2: --2A: AD, loss of platelet-dependent function --2M: AD, VWF binding to platelet GP defective --2B: AD --2N: AR, absent VWF-F8 binding . Type 3: --AR, severe, resembles mild hemophilia, extremely low VWF . Easy bruising . Muco-cutaneous congenital bleeding (esp. epistaxis) . Prolonged bleeding after tooth extraction or surgery-may only become apparent on hemostatic challenge . Menorrhagia *No joint bleeding Test: Clotting activity Dx: . Personal/fhx of excessive bleeding . Lab eval consistent w qualitative/quantitative defect in VWD . Immunological test for the amount of protein (VWF: Ag) . Test of VWF's ability to aggregate proteins in presence of ristocetin (VWF: RCo) . Test ability to bind F8 (VWF: F8) Tx: . DDAVP (vasopressin analog) . Amicar (amino-caproic acid)- an antifibrinolytic agent . Physical measures: pressure, ice . VWF containing F8 concentrates derived from plasma . Recombinant VWF concentrates (in trials)

GM1 gangliosidosis *Lysosomal storage*

AR GLB1 => β-galactosidase Cherry red spot Tx: Pharmacologic chaperones

Sandhoff = Sandhoff Jatzkewitz = GM2 Gangliosidosis Type II *Metabolic* *Lipid storage* *Lysosomal storage* *AJ*

AR HEXB Onset: 3-6 mos . Neurodegenerative . CHERRY RED SPOT *Pheno same as Tay Sachs*

Niemann Pick A & B *Metabolic* *Lysosomal storage* *AJ*

AR SMPD1 Enz def: sphingomyelin phosphodiesterase 1 (sphingomyelinase enz) - involves lipid breakdown/transport out of endosome/lysosomes to cell membrane AJ carrier freq (type A): 1/90 (95% DR) ---R496L (43%) ---L302P (29%) ---fsP330 (25%) *Recommended in AJ panel* (ACMG) -Type A (neuropathic) Onset <1y Neurodegeneration *CHERRY RED SPOT MACULA (eye)* (50%) *HEPATOSPLENOMEGALY* HSM Cytopenia Irritabile FTT, poor feeding Lung infections-> respiratory prob <6mos Hydrops fetalis, death <3-4y -Type B (non-neuropathic): Later onset, slowly progressive Hepatosplenomegaly Diffuse pulmonary involvement-> decreased lung function HSM Abn lipids Dx: ---Foam cells in marrow ---Enz activity ---Genetic test: SMPD1 Tx: -Supportive, symptomatic . Platelet transfusion . Avoid splenectomy . Cholesterol-lowering meds . Respiratory support -Preventative (type B): . BMT . ERT

Patterns of Inheritance

AR Transmission: horizontal Sex ratio: equal Segregation: either parent passes trait to daughter/son RR 25% XLR Transmission: vertical (w skipped generations) Sex ratio: males favored Segregation: Mom Carrier: 50% of sons affected/unaffected, 50% of daughters carrier/not Affected Dad: 100% of sons unaffected, 50% of daughters carrier RR depends XLD Transmission: vertical Sex ratio: females favored Segregation: Mom Carrier: 50% sons affected, 50% daughters affected Affected Dad: 0% sons affected, 100% daughters affected RR depends YL Only in males; Y ch contains few genes Transmission: vertical Sex ratio: males only Segregation: father to son (100%) Mt (mtDNA) = matrilineal (non-medelian) Segregation: mat inheritance - all children affected if penetrance complete Heteroplasmy Imprinting = phenodepends on which parent passed on gene Multifactorial = genetic + env Polygenic = caused by combination of multiple genes No characteristic pattern of inheritance Empiric Risk: may not apply to all families RR is higher if: Closer relationship More than one relative More severe pheno in proband Pheno common in one sex and opposite sex affected Things that Complicate Inheritance Pattern Rules: -Reduced Penetrance -Age-Dependent Penetrance: delay of onset of symptoms (carriers may die before onset of symptoms); may reproduce before they know they are affected -Variable expressivity -Depends on: env exposures, modifier genes -Anticipation: more severe expression/earlier onset in successive generations; sometimes due to trinucleotide repeat expansions; expansion may be more likely if passed through mom/dad -New Mtn: affected proband has no fm hx of dx (esp AD); if germline not affected - risk to sibs is gen pop -Germline Mosaicism: 2+ offspring affected w no fm hx because more than one genetically distinct germ cell line; inc risk to sibs in affected proband (e.g. DMD, Hemo A, Achondroplasia, NF1, OI) -Sex-Limited: pheno may only occur/be favored by one sex -Male Lethality: condition lethal in males before birth -Skewed X-Inactivation: females may be mildly affected if nl X is inactivated -Phenocopies: individual w similar pheno does have disease-causing gene and pheno is caused by another NON-GENETIC factor -Consanguinity: relatives share genes from common ancestor→ offspring more likely to have recessive disorder -Small families: pattern of inheritance may not be evident

Aminopterin & Methotrexate (folic acid antagonists) *Teratogen*

Current use: Aminopterin for abortions Many severe BD => fetal demise 1-Aminopterin . Dysmorphic: --- Ear abn --- Ocular hypertelorism --- Microignathia --- Craniosynostosis . IUGR (50%) . Short . Delayed calvarial ossification . Hydrocephalus . Cleft Palate . Limb abn . Digital abn . NTD 2-Methotrexate . Dysmorphic: --- Cloverleaf skull --- Macrocephaly --- Swept back hair --- Low-set ears --- Prominent eyes --- Wide nasal bridge . Limb defects . Absent ossification centers . NTD . Hhydrocephalus

Positional Cloning

Family-based study that utilizes DNA markers w known locations that will help to identify gene of interest nearby

Glycogen Storage Diseases *Metabolic* *Carbohydrate metabolism*

Glycogen not metabolized into glucose to supply energy body=> . Glycogen accumulation in tissues (esp liver/muscle) . Low blood glucose (sugar) *Muscle + liver prob . Hepato +/- splenomegaly . Small intestine prob . Renal failure . +/- Gout (some) Biochem test: . *Hyperketotic hypoglycemia* . Lactic acidemia . *Hi CK* . Hi liver function tests (LFT's) . Myoglobinuria . Dyslipidemia

Amino Acid Disorders *Metabolic*

Gradual build up of substrate -> toxic => CHRONIC irreversible cognitive impairment (vs acute after illness / fasting in OA + FAO) *MILDER than OAD . DD . Unexplained acute illness . FTT Dx: Hi aa (3-10x nl) Specimen: . Blood (plasma) / urine (quantitative) . Fasting (bcs slight AA elevations common for everyone after eating) Biochem: . metabolic *ACIDOSIS* . mild *KETOTIC HYPOGLYCEMIA* (vs. FAO: hypoketotic hypoglycemia) AA measured in NBS Conditions: . Alkaptonuria . Homocystinuria . Nonketotic hyperglycinemia . Glycine encephalopathy . PKU . Tyrosinemia

Short Stature - ACMG 2009 -

IUGR/SGA & short Classic definition: Length or weight < 10th % for sex + GA => i.e. 10% of nl infants are SGA Alternative definition: Length or weight 2 SD below mean (< 3rd %) for sex + GA Short: Height < 2 SD below mean Causes: 50% non-pathologic: ---constitutional growth delay ---familial short stature 19% ch abn ---Turner ---SHOX del/mtn 3% known MCA dx 2% endocrine cause No established data to support dx eval of isolated short stature by medical geneticist => ACMG guideline assumes that nonpathologic familial short stature, constitutional delay of growth, hypothyroidism, and occult disease were R/O ACMG guideline also applies to pts w short stature as main concern, but minor + major anomalies may be identified SHOX (1-13% of idiopathic short stature): mtn or del in/near gene => . Isolated short stature + rarely subtle skeletal abn (madelung deformity + mesomelia) . Langer mesomelic dysplasia ---Usually del in both copies (AR) ---Severe short stature + skeletal abn . Léri-Weill dyschondrosteosis ---Del in one copy (AD) . Milder short stature + skeletal abn --- Onset childhood/puberty Test: If isolated + subtle changes consistent w Madelung deformity / mesomelia-> SHOX If non-isolated + no recognized syndrome -> array If recognized dx-> specific test

Physiologic Omphalocele

If omphalocele seen on US <15wk -> may be completely nl = physiologic If resolves by 15 weeks -> no further test

Lysosomal Storage Diseases (LSDs) *Metabolic*

Individually rare, but collectively common (1/5000) Lysosomes = units in cells that digest complexes using enz Most enz def inside lysosome, except: --- I-cell + pseudo-Hurler polydystrophy: def of enz trafficking into lysosome --- Niemann Pick: def of transport out of endosome / lysosomes to cell membrane Common dx: -Gaucher -Tay Sachs -Hurler -Infantile Pompe . AR (most) . XL ---Fabry ---Hunter ---Danon Onset: in utero - several y Progressive accumulation of toxins -> degenerative => irreversible . 54% CNS involvement (hallmark), but NO FDA tx crosses BBB . *Movement disorders* . *HL* . Eye: --- *Blind* --- Corneal clouding --- Cherry red spots in retina --- Pigmentary retinopathy . Hepato +/- splenomegaly . DD . Seizures . Otitis media . Respiratory infections . Hernia . Coarse face . Dysostosis multiplex w contractures . Claw-hand deformity . Skeletal dysplasia: kyphosis scoliosis . Heart disease Dx: . Enz test (GOLD STANDARD) but --- Can have pseudodef --- Not accurate for carrier . Blood smear . Radiologic exam . Eye exam: fundoscopic + slit lamp . Uring glycosaminoglycans (mucopolysaccharides) --- oligosaccharides --- glycoproteins . Nl urine ammonia . Serum lysosomal enz . Consider bone marrow . Biochem studies of fibroblast +/- leukocytes . Genetic test->misses mtns, chance of VUS NBS (for several, *BUT MOST NOT ON NBS BCS REQUIRE ENZ ASSAY); limitations: --- Confirmatory test needed --- Pseudodef in MPSI --- Unable to distinguish btw infant vs. late onset Pompe --- Krabbe - mostly late onset Tx: no cure - Tx for many => improves QOL + prognosis

Trisomy 13

Mosaicism possible *80% sporadic* (*AMA* effect) --- nondisjunction (usually *mat*) *20% transl*: - 46,XX,*+13,der(13;14)*(q10;q10) --- *55% inherited from carrier parent*: 45,XY,*der(13;14)*(q10;q10) - *most common transl in humans* (1/1,100) ------ *Carrier parent has 1% empiric risk of liveborn child w T13* *RR: <1% for any chrom aneuploidy* (higher if transl) Prenatal US: (*think 3 is crumpled like fetus w no hair on head and no lip*) . Dysmorphic face: --- ****CLP*** ("8 becomes a 3 w cleft") --- Midface hypoplasia --- Myclopia, hypotelorism --- Microophthalmia --- Low set ears --- Broad, flat nose . *HOLOPROSENCEPHALY* . *MICROCEPHALY* . ****CLENCHED HAND+POSTAXIAL POLYDACTYLY**** / syndactyly . *MICROPHTHALMIA* . *SCALP CUTIS APLASIA* . *Spina bifida, omphalocele (in T13+18)* . IUGR . ACC . Single umbilical artery . CHD: ASD, PDA, VSD . Renal abn . Cartilage islands in eye . Ambiguous genitalia . Echogenic bowel . Echogenic kidneys . Radial aplasia . Severe ID => 80% neonatal death <1 mos Prenatal screen: *Large NT + Low PAPP-A + Low hCG* (like T18) *Hi AFP* Dx: Karyotype Tx: Symptomatic + supportive

DFNB1 related Hearing Loss *Hearing loss*

Most common AR nonsynd prelingual SNHL DEFNB1= DEaFNess, B (for recessive vs. A for dominant) 2-3/1,000 . AR . AD: GJB2 mtn (rare) -> syndromic HL + skin finding . GJB2 (connexin 26): > 150 mtns - 2 mtns (98%) --- 5delG (Caucasian) --- 235delC (Asian) --- Del35G (AJ) --- 167delT . GJB6 (connexin 30): 2 common dels (2%) Some pts w GJB2 mtn + GJB6 del HL: . Congenital . Bil . Nonprogressive . Mild - profound * If truncating mtn (rare) -> progressive / late onset If infant fails NB hearing -> 1 . Auditory Brainstem Response (ABR) / evoked otoacoustic emissions (OAE) response (dysmorph eval + CT scan to eval temporal bone abn) -> If HL confirmed + isolated > 2. GJB2 seq (incl common splice site mtn) + 2 GJB6 dels

Factor V Leiden *Thrombophilia* - ACMG -

Most common inherited thrombophilia --- 12-14% of venous thrombosis --- 2-15% (4-10%) of Caucasians are carriers AD --- Incomplete dominant --- Incomplete penetrance => Moderate VTE risk AR => hi VTE risk F5 --- Substitution: Arg506Gln (R506Q): GoF bcs resistant to deactivation by protein C Hi factor V -> hi thrombin -> blood clots => ------ DVT ------ PE (10%) ------ slightly inc SAB risk Test: . Arg506Gln: the only FVL mtn indicated in routine thromobophilia eval . Population screening for FVL NOT recommended Test recommended if: . Personal/fhx of venous thrombosis <50 . Venous thrombosis in unusual sites (hepatic, mesenteric, cerebral veins) . Recurrent venous thrombosis . Venous thrombosis + fhx of thrombotic dx . Venous thrombosis in pregnant women / women taking oral contraceptives . Myocardial infarction in female smokers <50 Test considered if: . Venous thrombosis >50, except when active malignancy present . Fhx of FVL . Recurrent SAB / unexplained severe preeclampsia, placental abruption, IUGR, stillbirth Tx: . Avoid oral contraceptives, surgery, long periods of inactivity . Heparin in women w DVT

Pregnancy Termination (TAB)

Most spontaneous losses occur < 10 wk *Common symptoms within first 3 days after TAB*: *Nausea* *Vomiting* *Tiredness* => similar to morning sickness 1st tri symtpms of pregnancy! First tri: 1. < 7 wk: Mifepristone → softens uterus → wait 24 h → misopristol → contractions → lose preg 2. Dilation and Curettage (D&C): Dilation of cervix (laminaria) → suction→ curettage --- Complications: ------ *Pain* ------ *Bleeding* ------ Perforation (rarely need hysterectomy bcs complication) 2nd tri 1. Dilation & Evacuation (D&E): Dilate cervix (laminaria) → fetal demise w med → fetus removed in pieces --- Complications: ------ Bleeding ------ Infection ------ Perforation ------ Placenta accrete ---Considerations: ------ Outpatient ------ General anesthesia ------ Predictable / planned delivery ------ No option to see / hold baby ------ No burial / autopsy 2. Induction: Fetal demise < 16 wk → induce labor --- Complications: ------ Hemorrhage --- Considerations: ------ Inpatient ------ Can be less than 24 h ------ Less predictable course (don't know how long will take) ------ Concern for pain / discomfort ------ Option to see / hold baby ------ Private burial, autopsy Multifetal Pregnancy Reduction (MPR) & Selective Termination (ST) . MPR: reduce all fetuses . ST: reduce specific fetus for specific reason --- Considerations: ------ Fetuses have to be large enough to be seen / accessed by transabd US --- Usually @ 10-13 wk ------ US to create map of sacs + placenta -> --------- If di-di: -> inject KCl into fetal heart --------- If not di-di -> cord occlusion --- Complications: ------ 5% loss rate (for entire pregnancy)

Chronic Myeloid Leukemia (CML) *Cancer*

Mtns in myeloid progenitor stem cells -> Proliferation of granulocytes 95% have *Philadelphia ch*: *der(22)t(9;22)*(q34;q11.2)

Fatty Acid Oxidation (FAO) defects *Metabolic*

Normally: Liver oxidizes FA -> ketone bodies => energy for: -Gluconeogenesis, ureagenesis -CNS *Crisis @ FASTING OR VIRAL INFECTION*: -Recurrent vomiting -Lethargy -Coma => affects: - Muscle - Liver (hepatomegaly) - Kidneys - Small intestine - Gout (some) Biochem: . *HYPOKETOTIC HYPOGLYCEMIA* = low urine ketone + low blood sugar (usually hypoglycemia associated w hi urine ketones) . Abn blood acylcarnitine profile . Low carnitine . Hi CK . Hyperammonemia (some) . Hi LFTs . Abn UOA *Long chain defects: LCHAD and VLCAD: - Myopathy - Cardiomyopathy bcs long chain fats preferred substrate for cardiac + skeletal muscle

Gene Resource

Online Mendelian Inheritance in Man (*OMIM*): ****ncbi.nlm.nih.gov/Omim**** --- *catalogue of genes + genetics disorders + traits* --- focuses on relationship btw pheno & geno --- Updated daily --- Entries contain copious links to other genetics resources - Intended for use primarily by: --- physicians and other professionals concerned with genetic disorders --- genetics researchers --- advanced students in science and medicine - *Not intended for pts*: While the OMIM database is open to the public, users seeking information about a personal medical or genetic condition are urged to consult w a qualified physician for diagnosis and for answers to personal questions => Does not provide you w support info for a family w a new diagnosis

Cleft lip and palate (CLP)

Primary defect occurring by *8-10 wk* . 75-90% isolated (multifactorial) => good prognosis -> craniofacial referral --- *non-syndromic CL: P63* . 10-25% syndromic: *CP alone 2x as likely to be syndromic: 25-40% - Associated w conductive HL --- CL: 7-13% associated w other BD ---- CLP: 11-14% associated w other BD - Syndromes: . Pierre robin sequence (CP) . 22q del (CP) . Stickler (CP) . Treacher Collins (CP) . Van der woude (CL +/- CP, or CP) . T13/18 (CL +/- CP) . Apert, Crouzon (CP) . Waardenburg (CP / CL) Sex ratio: --- CL/P - M >> F (2 : 1) --- CP - F >> M (2 : 1) Ethnicity: Native Am >> Asian >> Caucasian >> Hispanic >> African RR: . Sib: --- Unil CL w/out CP (80%): 2-4% --- Unil CLP: 5% --- Bil CLP: 8% . Parent: 3-4% . 2 sibs / parent + sib: 10%

Population Carrier Screening

Purpose: Detect couples at risk for prenatally diagnosable genetic dx Criteria for cost-effective program • Clinically significant dx • 'Common' in pan-ethnic community • High-risk population that's receptive • Cost effective; high sensitivity/specificity • Definitive test for specific dx avail • Reproductive options avail • Counseling & education • Offered to all individuals ACOG (2017): -CF mtn panel (not seq) -SMA -FraX if risk factors -Tay-Sachs: AJ, French-Canadian, Cajun -4 dx core AJ panel if Jewish (consider 9 dx expanded panel) -CBC (+ hem elec if hi risk ethnicity) *If requested by pt, can offer any of these w counseling ACMG (2008, 2013): -CF 23 mtn panel (2013) -SMA (2008) -FraX if risk factors (2013) -9 dx AJ panel if Jewish NSGC (2012, 2014): -CF (2014) -FraX if risk factors (2014) New technology: Genotyping Array: Use: population carrier screening: Strengths: Can test for many disorders simultaneously Offered at lower cost than individual mtn analysis Weaknesses: Have to choose disorder on array - which to pick Treats all pts as though they have same a priori risk DR low/unknown (falsely reassure or cause anxiety)

Chromosome Inversion

RR of abn child if carrier parent (actual risk depends on inversion): If incidental on amnio + de novo: 9% risk of abn pheno . Paracentric (breaks in short arm or long arm; no centromere involved => difficult to detect w karyotype) 0.1-0.5% risk --- Autosomes Do not involve centromere→ can't produce unbalanced offspring => not viable: if recombination formed→ gametes would be ascentric or dicentric which are both nonviable --- Sex ch Familial paracentric inv(X): no abnl pheno Paracentric inv(Y): few cases reported . Pericentric (break in short + long arm of ch = involves centromere) 1% (if liveborn affected child) 5-15% (if no fhx) --- Autosomes: Carrier produces unbalanced gametes if recombination in inverted segment at meiosis: Inversion homolog + nl homolog do not match up→ loop formed to match and align segments of both homologs Crossover in loop btw chromatid from inv homolog and chromatid from nl homolog leads to production of 4 possible gametes: 1. Nl homolog 2. Inverted homolog 3. Dup of part of short arm; del of part of long arm 4. Dup of part of long arm; del of part of short arm => offspring w partial trisomy + partial monosomy *Bigger inverted segment => bigger risk for liveborn (bcs if bigger inversion -> del/dup of part that's not involved is smaller) *Inv (1)(2)(9)(16): nl variants in gen pop --- X Ch: - X inv transmitted by males + females - X inversion forms in same way as autosomes w different implications - Breakpoints in X critical region influence female pheno - Imbalance in 46, X,rec(X) female mitigated by selective inactivation of abn X - Different rslts in fetus depending if fertilization of rec(X) is by X or Y bearing sperm: ------ 46, Y, rec(X) fetus: partial X nullisomy + functional X disomy ------ Female inv X carrier: appears nl, but breakpoints in X critical region (q13-q22, q22-q26) -> gonadal dysfunction ------ 46, X, rec(X) fetus: each daughter has variant Turner (Xp has stature genes and Xq has ovarian genes; loss/gain affects pheno) ------ 46, Y, rec (X) fetus: Nullisomy for deleted X segment not viable; functional X disomy also results in deleterious effect→ lethal in utero ------ Male inv X hemizygote inv(X) has no effect on reproductive pheno (no recombination will occur during meiosis) => All daughters: heterozygotes All sons: receive dad's nl Y and mom's nl X --- Y Ch: inv(Y)(p11q13): nl variant in gen pop

Reciprocal Translocation

Reciprocal = exchange of ch material btw non-homologous ch e.g. transfer of fragment of ch 6p to ch 8q, and transfer fragment of ch 8q to ch 6p *70% of balanced reciprocal transl are inherited* Possible outcomes: --- Nl gametes --- Balanced transl gametes --- Unbalanced gametes (partial trisomy + partial monosomy) -> most non-viable Meiotic Behavior: . At meiosis, 4 ch w segments in common come together as quadrivalent . To match homologous segments, 4 ch form cross-shape . As meiosis proceeds, distribution of homologs to poles is termed segregation Modes of Segregation: . 2:2 segregation: 2 ch go to 1 cell and 2 go to other cell ---*Alternate segregation* (most common): each centromere goes alternately to one or the other pole => *2 daughter cells are nl / balanced (no abn)* ---Adjacent segregation: centromeres travel together to daughter cell ------ ****Adjacent 1 segregation: (most common)**** => Unbalanced: centromeres segregate as expected (i.e. homologous centromeres separate; unlike centromeres travel together) e.g. if parent had transl=>*child w derivative ch (unbalanced transl)* ------ Adjacent 2 segregation: like centromeres travel together (rare) => Unbalanced: most abnormality of 2:2 segregation patterns (homologous centromeres segregate to same pole/daughter cell -> fertilized egg w 3 copies of 1 ch (2 nl and 1 derivative) and monosomic for other ch . 3:1 segregation: 3 ch go to one cell and one goes to other Gametes w 22 & 24 chs are formed . Tertiary segregation: 2 nl ch & 1 translo (most abn offspring have tertiary trisomy) . Interchange segregation: 2 transl and 1 nl . 4:0 segregation: all 4 homologs go to 1 cell (not viable) Predicting segregation: If transl segments small: adj-1 most likely If centric segments small: adj-2 most likely If quadrivalent top sided: 3:1 most likely If transl & centric segments large: no unbalanced segregants viable *RR of liveborn w unbl ch (depends on transl): 0-30%* (carrier parent: ~11%) --- carrier parent *46,XX,t(11;22)(q23.3;q11.2): 6%* --- *If fhx of pt w unbalanced ch: 20-25%* --- *If no liveborns w unbalanced ch & couple w rec SABs: 2-4%* . *If incidental balanced (eg. amnio for AMA): 2-5% risk of abn pheno* . *If inherited balanced: low risk* *Liveborn aneuploidy demonstrates viability for abn combination to occur; however, SAB w abn combination harder to predict *ch effect - if unbalanced ch tolerable (13, 18, 21, 8, 9, 4p, 5p 18p) -> higher risk of liveborn w unbal ch*

Triploidy

Sporadic - 1-3% of recognized preg - 6% of SAB - 15-20% of ch abn SAB - <1/20,000 liveborns Diandric (85%): extra ch pat - 2 sperm most common cause . *well grown fetus . 3/4 syndactyly . large placenta w partial hydatidiform mole ****usually don't survive to term**** Dyginic: extra ch mat . IUGR . macrocephaly . 3/4 syndactyly . small + fibrotic placenta ****can survive to term = result in liveborn (usually miscarry / die within h after birth)**** Pat Set: (same pattern as T21) Large NT Hi hCG, low PAPP-A Hi AFP Mat Set: -Low hCG, PAPP-A -Low-nl AFP -US: Large NT IUGR *Placental abn: large placenta / small+calcified *3-4 syndactyly* *Early onset IUGR affected skeleton > head* Omphalocele Ambiguous genitalia CHD CNS - holoposencephaly, ACC, meningomyelocele, Dandy Walker malf Hypertelorism Micrognathia Respiratory difficulty Mom at-risk for: HTN Edema Preeclampsia

Valproic Acid = Valproate = Depacon *Teratogen*

Use: *ANTICONVULSANT + mood disorder* ****NTD**** (1-2%) [BOARDZ] CHD CL Hypospadias Limb defects (radial aplasia) IUGR Craniosynostosis Long fingers+ toes, maxillary + fingernail hypoplasia (hyperconvex) Dysmorphic face: . Hypertelorism . Narrow bifrontal diamtere . High forehead . Epicanthal folds . Infra-orbital creases . Telecanthus . Broad / low nasal bridge . Short nose w anteverted nares . Midfacial hypoplasia . Long philtrum . Thin vermilion border . Small mouth . Cupid bow lip

Thalidomide *Teratogen*

Use: *sedative in 1950's* *1st tri - 34-50 d after LMP* (20% risk) . ****PHOCOMELIA**** (missing limbs): 20-50% (*think thal for tail fish* [BOARDZ] . *Ear abn -> HL* . Facial hemangioma . CHD . Renal abn . GU abn, gut musculature abn . Mesodermal tissue abn . Esophageal abn, duodenal atresia

Retinoid = 13 cis Retinoic Acid = Isotretinoin = Accutane = Vitamin A *Teratogen*

Use: cystic acne . Retinoid: oral . Accutane: topical retinoid (not recommended, but risk likely low) 30-35% of pts born to women exposed at *15th day after conception* ****SAB (40% risk) & premie**** ****BD (20-30% risk): NEURAL CREST DERIVED****: ****ID (30-60%) even w/out BD**** ****CNS abn**** ****Craniofacial**** - microtia or anotia, accessory parietal *CHD -Aortic Arch Anomalies, conotruncal, VSD* sutures, narrow sloping forehead, micrognathia, flat nasal bridge, CLP, ocular Limb abn Ear abn: Microtia, Anotia, HL! Hydrocephalus Hypertelorism Thymus abn Facial nerve paralysis

Ondansetron *Teratogen*

Use: nausea in pregnancy (use *Diclegis* instead) 6 - 12 wk *CHD* (2x)

Diethylstilbestrol (DES) *Teratogen*

Use: synthetic *estrogen for recur SAB* (in 1950's-1960's) *1st tri* - SAB - preterm labor *Females exposed prenatally*: - *BD in cervix, vagina, uterus, tubes* - *Vaginal clear cell adenocarcinoma* (90% >14y) - Benign vaginal adenosis *Males exposed prenatally* - *Abn sperm* (32%) - *Epididymal cysts* (25%) - Hypotrophic testes - Genital lesions

Ring Chromosome Syndromes

Usually only ONE (same) ring ch in each cell Unusually has deleted material=> GR BD ID

Thrombophilias

Venous thrombosis: --- Antithrombin III, Protein C and S: 5-15% of venous thrombosis Pregnancy: . Preeclampsia: --- Highest risk w: ------ Protein C ------ Protein S --- Inc risk w: ------ Antithrombin II ------ FVL ------ MTHFR homozygote . Stillbrith: --- Highest risk w: ------ Protein S ------ Factor V Leiden . VTE: --- Highest risk w: ------ FVL ------ Prothrombin: G20210A Tx: Warfarin, heparin, aspirin [BOARDZ]

Blood Type Incompatibility

[BOARDZ] Rh incompatibility (Rh factor is a protein on red blood cells): ---mom Rh-neg ---baby Rh-pos Does not usually occur in 1st newborn, unless mom had previous SAB/TAB (mom's serum contains antibodies => breakdown of baby's RBCs = bilirubin (orange pigment formed in liver by hemoglobin breakdown)) => Hemolitic disease (more severe than ABO incomp) Hydrops fetalis Jaundice after birth: occurs when there's a buildup of an orangish substance in blood called bilirubin that's produced when RBCs break down naturally Brain damage Hypotonia Serizures Prevention: *rhoGHAM* (immune globulin): - *During EVERY pregnancy* (if 1st preg, given at 28 wk + after delivery) - If previous SAB/TAB - After cvs/amnio - After injury to abdomen during P ABO incompatibility: 20-25% of pregnancies Especially if *mom is O and baby is A, B or AB, and if baby is premature* *Can occur in 1st-born babies (unlike Rh incompatibility) + NOT more severe in future preg* Mild hemolitic disease in newborn (mom's serum contains anti-A or anti-B antibodies against baby's blood => breakdown baby's RBCs = bilirubin)-> Jaundice Mild-moderate anemia Rarely death, in severe cases *Prenatal testing for anti-A or anti-B antibodies or analysis of amniotic fluid for bilirubin is not typically done bcs condition usually mild*

Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE) *Metabolic* *Mitochondrial*

nDNA: . *AR* (*think min giranna 2rayebna tjawwazo*) . AD - rare ECGF1, ANT1, POLG => secondary mtDNA mtns (multiple dels) Enz def: Thymidine phoshorylase (common) @ nDNA --- point mtn -> imbalance in nucleotide pools (too much T): tDNA instability => secondary mtDNA mtns (including depletions + multiple dels) Onset: late teen-adult Disorder of inter-genomic communication NeuroGI encephalomyopathy: GI: diarrhea, pseudoobstruction Ptosis, opthalmoplegia Peripheral neuropathy Leukoencephalopathy