Genetics

What is Loeys-Dietz syndrome?

-aortic root dilatation, aneurysm, dissection, rupture -75% have craniofacial manifestations (LDS I) -25% have minimal/absent craniofacial features (LDS II) -autosomal dominant (75% occur de novo) -TGFBR1, TGFBR2, TGFB2, SMAD3

What did the human genome project find?

- The haploid genome is approximately 3.2 billion bp - Genomes between individuals are 99.9% identical - A typical gene is mostly non-coding DNA - The genome had far fewer genes (~19,900 protein-coding genes) than expected and *half of the genome is made up of repetitive DNA sequences*

Describe hereditary hemochromatosis

- excess iron absorption in GI tract - heart failure, cirrhosis, diabetes, hormone deficiencies, bronze skin - usually adult onset Etiology: common mutation in the HFE gene (C282Y [ cyst -> tyr]) -8.5%-11% of population are heterozygotes -treatment: phlebotomy

What is Noonan syndrome?

-"the male Turner syndrome" - misnomer because affects females too -low-set, posteriorly-rotated ears, hypertelorism, short stature, webbed neck -pulmonary valve stenosis, ASD, hypertrophic cardiomyopathy -50% of patients have mutations in PTPN11 -7+ other genes involved -RAS/MAPK signaling pathway - RASopathy -testing: single gene sequencing or gene panel

What is Long QT syndrome (LQTS)

-1 in 1,000-3,000 carry a LQTS mutation -symptoms: episodes of dizziness, syncope, apneic seizuires, sudden caridac death. a. prolongation of cardiac repolarization can predispose to other abnormal rhythms -can be familial or sporadic, congenital or acquried a. Romano-Ward syndrome: autosomal dominant - 10+ genes implicated: KCNQ1 and KCNH2 (potassium channel genes) in more than 80% of cases b. Jervell and Lange-Nielsen syndrome: autosomal recessive with congenital deafness - pathogenic variants in KCNQ1 and KCNE1. Subunits for slow potassium channel in heart and cochlea

Describe the structure of mtDNA and how mutations impact the proteins it codes for

-16.5 kb circular dsDNA molecule encoding 37 genes -2 rRNAs and 22 tRNAs: point mutations impair mitochondrial protein synthesis -13 genes for polypeptides: missense mutations in coding regions alter activity of OXPHOS protein -other rearrangements generate deletions or duplications

Describe transposition of the great arteries

-30 per 100,000 live births -aorta arises from RV, ;pulmonary artery from LV -cyanosis in first days of lfie as ductus arteriosus closes -balloon atrial septostomy to allow atrial mixing; arterial switch operation -rarely associated with genetic syndromes -common heart malformation in infants of diabetic mothers

Describe Atrial Septal defect (ASD)

-50-100 per 100,000 live births -usually asymptomatic; present with murmur (not caused by blood flow across ASD, rather it's a flow murmur) -most often isolated -chromosomal abnormalities: trisomy 18, 21, 4p-, 5p- -some syndromes -autosomal dominant families identified: NKX2-5, GATA4

Describe variations in enhancer sequence activated by LEF1 transcription factor that controls KIT ligand (KITLG) gene (also called stem cell factor, SCF)

-8 genes linked to blond hair, mechanism for one linkage now identified as a variation in an enhancer sequence. Enhancer mutation leads to blond hair color -enhancer first identified as a SNP over 350 kb from target gene KITLG (involved in stem cell proliferation and differentitation). Was not previously recognized as an enhancer for that gene orbeing involved with hair follicle gene expression. Enhancer is activated in a tissue specific manner by developmental transcription factor, LEF1. SNP alters a sequence that binds LEF1, but the site is not even a consensus LEF1 site to begin with. Only causes ~20% reduction in enhancer activity, yet profound difference in hair color. -sequence-dependent epigenetic mechanism

Describe MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes)

-Clinical features: mitochondrial myopathy, seizures, mental retardation, lactic acidosis, stroke-like episodes, short stature, recurrent vomiting -some families with the same mutation have diabetes and deafness, other cardiomyopathy, other CPEO -.5-1.5% of diabetes mellitus in general population attributed to same mutation -sporadic and pedigrees with maternal inheritance, heteroplasmy -point mutation in tRNAleu

What does FMRP (Fragile X RNA or protein) normally do?

-FMRP binds RNA and inhibits translation of specific mRNAs in dendritic spines where synapses will form. Allows for high spatial and temporal regulation of translation required for synaptic maturation -FMRP also found in nucleus. May shuttle specific RNAs out of the nucleus. FMRP has both a nuclear localization signal and nuclear export signal

Describe Hb S disease

-HBB c.20A>T, p.Glu7Val -change from glutamic acide (GAG) to valine (GTG) at codon 7 of beta-globin gene -homozygosity: Hb S (sickle cell) disease a. incidence: 1 in 600 African americans; carrier frequency 8% of African Americans -vaso-occlusive crises: acute/chronic pain, organ damage -chronic hemolysis: anemia, vascular dysfunction -infection -splenic sequestration -acute chest syndrome

What is Hb C?

-Hb S modifier -p.Glu7Lys (GAG -> AAG) (acidic to basic change) a. HbSC - milder hemolysis/anemia -S Beta-thalassemia -modifiers of gamma-globin expression: increased Hb F production, BCL11A, MYB - polymorphisms, hydroxyurea

Describe Recurrence risk for multifactorial disorders

-RR is an empiric average risk and varies among families -RR increases with number of affected individuals -Risk increases with severity -an affected proband of the less frequently affected gender - offspring and silbings haf a higher RR

What is Brugada syndrome

-ST segment elevation on precordial leads - can lead to ventricular fibrillation -may cause up to 20% of sudden cardiac deaths in young people with structurally normal hearts -mutations in SCN5A (mostly missence) found in 25-30% of BRugada syndrome patients - encodes a sodium channel -may also be sporadic or drug-induced

Describe Angelman syndrome (AS)

-UDP syndrome -unique behavior (inappropriately happy demeanor with frequent laughing, smiling, and excitability) -ataxic gait with jerky arm movements, seizures, and severe intellectual disability with severe speech impairment -often microcephalic Etiology: 1. Maternal deletion in the region of 15q11-13 (70%). There is no functional gene expression from the AS region of 15q. On the paternal 15, this area is noramlly methylated and silenced 2. paternal uniparental disomy - 2 copies of the paternal chromosome 15 and no copy of the maternal chromosome (7%). There is absence of a gene (UBE3A or E6-AP ubiquitin protein ligase) expressed from the maternal allele only in the brain 3. imprinting center defect - biparental inheritance of chromosome 15 with no deletion and with a normal methylation pattern (3%) 4. UBE3A mutation on maternal 15q11-13 - biparental inheritance of chromosome 15 with no deletion and with a normal methylation pattern (10%) 5. UBE3a silencing by other mechanisms - biparental inheritance of chromsome 15 with no deletion and with a normal methylation pattern (10%)

Describe X-linked dominant diseases with male lethality

-X-linked dominant pedigree with male lethality with no affected males (only affected females) - may also see an increased number of miscarriages (affected males) -affected females produce affected daughters, normal daughters, normal sons in 1:1:1 ratio Examples: incontinentia pigmenti, Rett syndrome

What is heterogeneity?

-a condition with more than one cause (chromosomal, Mendelian, polygenetic, multifactorial, environmental, etc) -example: congenital deafness

Describe locus heterogeneity in autosomal recessive conditions

-a single mutation in one of several genes (loci) produces the same clincial phenotype -example: fanconi anemia, Bardet-Biedl syndrome

What is locus heterogeneity in autosomal dominant disorders

-a single mutation in one of several genes (loci/locations) produces the same clinical phenotype -example: tuberous sclerosis complex is caused by mutations in either TSC1 or TSC2

Describe how aging affects somatic mtDNA mutations

-accumulation of mtDNA mutations. Inversely proportional to replicative potential of its cells. Proportional to metabolic rate -Example: neurons with no replicative capacity and increased metabolic rate have increased susceptibility to increasing mtDNA mutations with age -declining OXPHOS activity (mt function) with age

What are different types of heterogeneity that appear in autosomal dominant conditions?

-allelic heterogeneity -locus heterogeneity

How does tissue-specific OXPHOS expression relate to mitochondrial genetics?

-bioenergetic expression thresholds forhuman organs, in decreasing order: CNS, heart and skeletal muscle, renal, endocrine, and liver -disease is often in muscle and brain: myopathies, encephalopathies -severity of OXPHOS defect and clinical manifestations varies with % of normal vs mutant mtDNAs

What are characteristics of X-linked Dominant inheritance?

-both males and females affected a. variable expression in males and females -no male-to-male transmission (otherwise looks like autosomal dominant) -all daughters of affected males are affected - usually more mild -an affected female has a 50% chance of passing the disorder to each child (boy or girl)

Describe Prader-Willi syndrome (PWS)

-can be a UDP syndrome -hypotonia and poor weight gain in infancy -rapid weight gain at 2-4 years leading to obesity, hypogonadism, and mild to moderate intellectual disability Etiology: 1. Paternal deletion in the region of 15q11-13 (70%). There is no functional gene expression from the PWS region of 15q. On the maternal 15, this area is normally methylated and silenced 2. maternal uniparental disomy - 2 copies of the maternal chromosome 15 and no copy of the parental chromosome (30%). Here the individual with PWS has two amternal chromosomes 15 which normally have the PWS critical region methylated or silenced. They do not have the portion of 15 which has expression of the father's PWS region 3. imprinting center mutation - controls imprinting - biparental inheritance of chromosome 15 wihtout a detectable deletion (1-2%). This mutation causes the PWS critical region to become methylated or silenced so that the paternal 15 has an abnormal methylation pattern (which resembles that of the maternal 15)

What is CPVT?

-catecholaminergic polymorphic ventricular tachycardia -normal hear, normal resting EKG -ventricular tachycardia is triggered by emotional or physical stress -mutations in RYR2 (ryanodine receptor) or CASQ2 a. bothi nvolved in intracellular calcium release

What are sequence dependent epigenetic mechanisms?

-chromatin affected by DNA mutations -mutation in enhancer alters transcription factor binding -expansion of triplet repeat causing change in DNA methylation

What are sequence independent epigenetic mechanisms?

-chromatin affected by signals -signals from within the cell, extracellular, or environmental signals -examples is stress-induced changes in DNA methylation in specific genes in hypothalamic nuclei -early epigenetic differences in twins. Differences in methylation increase with age in twins. Changes can occur very early - believedthat random chance, plus small differences in uterine environments give rise to divergent epigenetic patterns

How often do new mutations occur?

-depends on the disorder, reproductive fitness, gene size -the more severe the disorder, the more likely a new mutation - when a mutation is spontaneous, if it is passed to the next generation, you know it is a new mutation

What is allelic heterogeneity in autosomal dominant disorders?

-different mutations at the same locus (alleles) are responsible for the disorder -examples: Marfan syndrome, Neurofibromatosis type 1

What is X-linked inheritance?

-differential expression in males and females

What is genomic imprinting?

-differential expression of alleles of a gene depending on whether it was inherited from the father or the mother -involves differentital methylation of genes during male and female gametogenesis -results in transcriptional inactivation. Gene carries a "tag" or imprint that acts to silence an allele from one parent. An absence of the gene from the other parent results in abnormal development -about 80 imprinted genes in humans -many involved in embryonic and placental growth

What is the parental conflict hypothesis?

-differing interests of each parent -father's interest: growth of offspring at expense of mother. Paternally expressed genes tend to be growth promoting a. Hydatidiform mole - human placental tumor with 2 paternally derived haploid sets of chromosomes and no maternal chromosomes (2 sperm essentially) -mother's interest: conserve resources and provide nourishment to current and subsequent litters. Maternally expressed genes tend to be growth limiting a. ovarian teratoma - benign tumor with 2 maternally derived haploid sets of chromosomes and no paternal chromosomes (2 eggs essentially) - can form hair or teeth

What are mitochondrial disorders?

-disorders affecting both males and females but transmitted mostly through females -associated with variety of degenerative disorders. Delayed onset; progressive course -involve high energy systems, primarily: brain, eyes, ears, heart, muscle, liver, kidney

Describe heterodisomy

-due to an error in meiosis I. -two different homologous chromosomes from one parent (inherited from both grandparents) -heterodisomy can result from: 1. fertilization of a disomic gamete by a nullisomic gamete 2. fertilization of a disomic gamete by a monosomic gamete with subsequent chromosome loss

Describe isodisomy

-due to an error in meiosis II -two identical copies of a single homolog of a chromosome from one parent (inherited from one grandparent) -isodisomy can result from: 1. a disomic gamete fertilizing a monosomic gamete with loss of the chromosome 2. a nullisomic gamete fertilizing a monosomic gamete with chromosome duplication 3. a disomic gamete fertilizing a nullisomic gamete

Describe threshold expression for mitochondrial genetics

-each tissue requires a minimum level (threshold) of mitochondrial ATP production to sustain cellular functions -as the percentage of mutant mtDNAs increases, energy production declines -energy output falls below minimum necessary for normal tissue function and clinical manifestations result (threshold expression)

What is the Hardy-Weinberg Law?

-estimate the frequency of: 1. autosomal dominant and recessive alleles in a population 2. carriers of deleterious recessive alleles in a population -for a population, p + q = 1 (p = frequency of the dominant allele A, q = frequency of the recessive allele a) -for a population p^2 + 2pq + q^2 = 1 1. 1 = 100% of genotypes in the new generation 2. p^2 = frequency of homozygous dominant (AA) genotype in the population 3. q^2 = frequency of homozygous recessive (aa) genotypes in the population 4. 2pq = frequency of the heterozygous genotype (Aa) in the population

Describe Lever's hereditary optic neuropathy (LHON)

-first mitochondrial disease identified -clinical features: rapid optic nerve death, leading to bilateral loss of central vision usually between 12 and 30 years of age -complex I missesne mutations -maternal inheritance (generally homoplasmic), but evidence that also multifactorial: both alcohol and tobacco use are associated with icnreased probability of blindness in carriers of mutations

Describe individuals that are homozygous for dominant mutations

-for most conditions, homozygous affected individuals are much more severe than heterozygotes -example: achondroplasia (lethal double dominant) -exception: Huntington disease (homozygotes are indistinguishable from heterozygotes)

How are small non coding RNAs (miRNA, siRNA, snoRNA) epigenetic regulators?

-generally inhibitory -some miRNAs critical for stem cell pluripotency

Describe the dynamic process of imprinting

-germline cells erase imprint -imprint re-established according to sex of individual

What is Ehlers-Danlos syndrome

-group of related connective tissue disorders -loose (hypermobile) joints and stretchy skin -hypermobility type: most common and least severe a. joint hypermobility - recurrent dislocations, chronic pain b. minimal skin involvement c. other systemic symptoms - constipation, headaches, easy bruising, postural orthostatic tachycardia, menorrhagia -up to 1/3 of children will have aortic dilatation - decreases to ~15% of adults -vascular type a. susceptible to arteiral, intestinal, uterine rupture b. caused by mutaton in COL3A1

What are myocardial disorders?

-heart is structurally/functionally abnormal -cannot be explained by coronary artery disease, hypertension, valvular heart disease, congenital heart disease

What does it mean to say that there is gene expression above the genome?

-in general, all cells contain the same nuclear DNA complement even after terminal differentiation in the adult (major exceptions are the immune cells) -hence selective expression must occur to generate different cell types, often at level of transcription 1. most adult cells have the potential to be any cell (basis of induced pluripotent stem cells) 2. regulation must occur at some level other than just DNA sequence. In other words, above the genome via regulation of gene expression

Describe gain of function due to genomic variation

-increased levels of gene product (example, translocation of MYC gene to immunoglobulin locus leads to overexpression of an oncogene, causing Burkitt lymphoma) -constitutive (unregulated) activity - (example: mutations in RET tyrosine kinase in either regulatory domain (MEN2A) or catalytic domain (MEN2B) cause inherited endocrine cancer syndrome. Loss of RET causes different disorder, Hirschsprung disease (megacolon), so different variations can affect gene differently

Describe variations in enhancers activated by NF-kB transcription factor

-key immune regulator, activated during inflammatory response -genome wide study of NF-kB DNA binding sites -10% of binding sites of NF-kB differ between individuals (measured using lymphoblastoid cell lines), many due to single-nucleotide polymorphisms, correlated with differences in gene expression -sequence-dependent epigenetic mechanism

What is hypertrophic cardiomyopathy?

-left ventricular hypertrophy -1 in 500 adults -most commonly caused by mutations in cardiac sarcomere protein genes a. autosomal dominant b. e.g. beta-myosin heavy chain (MYH7), myosin-binding protein C (MYBPC3), cardiac troponoin T (TNNT2) c. variable expressivity and incomplete penetrance -metabolic cardiomyopathies (Pompe disease) -mitochondrial cardiomyopathies -diagnosis: gene sequencing panel

How are Long Noncoding RNAs (lncRNAs) epigenetic regulators?

-linear and circular forms -some lncRNAs linked to human heart disease, but functions mostly not known. Some are antisense of mRNAs and thought to be inhibitory -XIST (X-inactive specific transcript): a. expressed from X chromosome that will be inactivated, coats chromosome and recruits silencing complex, including DNA methylation enzymes b. essential for X inactivation, which is necessary for dosage equivalence between male and female c. mutations in XIST result in familial skewed X inactivation in which instead of random inactivation of either X during development, the same X is inactivated in nearly all cells

What are FX associated disorders POI and FXTAS?

-linked to "grey zone" -both disorders involve FMR1 premutations (55-200 triplets) -FMR1 RNA expressed at higher levels, so considered gain of function, but can actually have a mild decrease in FMRP protein levels -premutation carriers previously regarded as clinically uninvolved, only recognized in last decade -premature ovarian insufficiency (POI): premature dysfunction or cessation of menstruation, absent or irregular periods, infertility, variable severity a. occurs in 20-25% of premutation females (mothers of FXS boys). Inolves hormonal imbalances, but not well understood b. can also include mild cognitive and/or behavioral deficits on the fragile X spectrum, but not clear. In some premutation carriers (5-8% over age 50), also exhibit symptoms of FXTAS -Fragile X-associated tremor/ataxia syndrome (FXTAS) a. delayed neurodegenrative disorder of older adult carriers with gait ataxia (falling), cosgnitive (difficulty knowing appropriate behaviro), intention tremor. Additinal radiological findings of symmetric white matter lesions or generalized brain atrophy. Significant variability in progression of symptoms b. mostly in male carriers, usually greater than 50 years of age for onset. Occurs in more than 50% of premutation men over 70 (maternal grandfathers of FXS boys), about 75% of those over 80. Less common in females, but does occur. May be most common neurodegenerative disease linked to a single gene

What are characteristics of X-linked recessive inheritance?

-males affected -passed through healthy carrier females -no male-to-male transmission -all daughters of affected males are obligate carriers

What are the functions of the genome?

1. Transfer genetic information from generation to generation (meiosis) 2. Transfer genetic information from parent cell to daughter cells (mitosis) 3. Control cellular phenotype and functions (cell fate)

How are enhancer-encoded small RNAs (eRNAs) (a type of noncoding RNAs) epigenetic regulators?

-many enhancers are themselves transcribed into small RNAs, function not known -implication is that variations in enhancer sequences may not be limited to binding of transcription factors

Describe maternal inheritance of mitochondrial genetics

-mitochondrial located in cell cytoplasm Mature sperm have little cytoplasm and few mitochondria -females transmit mtDNA mutations to all offspring of either sex -males do not transmit mtDNA mutations

How is an imprint epigenetic?

-modifications are to structure of DNA rather than sequence -DNA rich in cytosine and guanine are preferentially methylated (CpG islands) - silence the gene

Describe ventricular septal defect (VSD)

-most common congenital heart malformation -prevalence of 300 per 100,000 live births (.3%) (depends on technology used to calculate numbers. Could actually be 2-5%) Only 60 of the 300 detected will require closure -most often isolated - but can be part of larger heart malformations -chromosomal abnormalities: trisomy 13/18/21 -some syndromes

Describe alpha-thalassemia

-most people have 4 alpha chains -homologous pairing and unequal crossover can lead to deletions -can have anywhere from 0 to 4 functional alpha genes (0 - hydrops fetalis - are often miscarries or have signficant disease in infancy) If the individual has 1, 2, or 3 functional alpha genes, they have more sever to silent carrier versions of the hemolytic anemia

Why is there a high mutation rate in mitchondrial DNA?

-mtDNA mutation rate is about 10 times greater than nDNA mutation rate -may be secondary to: generation of mutagenic oxygen radicals and limited DNA repair capacity -phenotypic effect of mutations depends on the severity of damage to the protein specified by the gene

Describe replicative segregation of mitochondrial genetics

-mtDNA replicates autonomously from nDNA -mitochondria segregate independently of nuclear chromosomes -proportion of mitochondria with mtDNA mutation differs among cells and tissues -heteroplasmy: heterogeneity in numbers of normal and mutant mtDNA. Variable presentation due to relative proportion of normal and mutant mtDNA -homoplasmy: either pure mutant or normal mtDNA -accounts for variability of clinical or phenotypic expression due to relative proportion of normal and mutant mtDNA

What are thalassemias?

-mutations that cause a reduction of synthesis or stability in alpha or beta-globin chains -most commonly: alpha-thalassemia - result from gene deletions beta-thalassemia - result from point mutations

What are congenital heart malformations?

-occur in 7-8 per 1,000 live births (.7-.8%) -account for 10% of all infant deaths in Western countries -25% have additional noncardiac malformations -13% have chromosomal abnormalities detectable by standard karyotyping -Includes: Ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of Fallot, and transposition of the great arteries)

Describe new recessive X-linked mutations

-occur with varying frequency -reproductive fitness issues: if reproductive fitness is low, and the frequency of the gene remains constant in the population, an isolated case ina family may be due to a new mutation. Haldane's rule: mother of an affected son has a 2/3 chance of being a carrier -example: Duchenne Muscular Dystrophy

Describe tetralogy of fallot

-one of the two most common cyanotic heart diseases of infancy -30 per 100,000 live births -includes 4 parts: 1. large subaortic ventricular septal defect 2. anterior displacement of aorta (overriding aorta) 3. Right ventricular outflow tract obstruction 4. right ventricular hypertrophy -"tet spell" - increased R - L shunt from dynamic RVOT obstruction -15% of patients have 22q11.2 deletion syndrome -5% have trisomy 21

What is hemoglobin?

-oxygen-carrying molecule in red blood cells a. tetramer consisting of two alpha-like and two beta-like chains b. main adult hemoglobin: Hb A (alpha2beta2) -alpha-globin cluster: 16p13.3 a. alph1, alpha2, zeta -beta-globin cluster: 11p15.4 a. beta, delta, Ggamma, Agamma, epsilon

What is somatic mosaicism?

-post zygotic mutation in a somatic (non-germline) cell -suggested bby: skin findings following the lines of Blaschko, segmental abnormalities -Example: Cancer, placental mosaicism (aneuploidy and uniparental disomy), mendelian disorders (NF1-segmental)

What is the mechanism of FXTAS?

-premutation mystery 1. gain of function due to increased FMR1 gene transcription - intermediate # triplets are not methylated and actually increase FMR1 gene transcription 2. but, FMR1 mRNA poorly translated because triplets impede translation, so see small decrease in protein level 3. Clinical data did not support FXTAS simply being less FMRP (FXS patients do not show ataxia or tremor) 4. For FXTAS, major problem is likely generation of toxic FMR1 RNA in nucleus that sequesters nuclear proteins leading to delayed neurodegenerative disorder -sequesters proteins within inclusion bodies, including lamins A/C, see distorted nuclei, recall progeria diseases -FMR1 RNA toxicity mechanism not fully understood 5. toxic proteins - non-AUG trnalsation of the triplet repeat: noncanonical repeat associated non-AUG (RAN) translation occurs on nonexpanded (CGG) 30-50 and premutation (CGG)59-160 repeats in 5' UTR of FMR1 gene -triplet yields polyglycine and polyalanine peptides that accumulate in nuclear inclusion bodies (similar or same as with toxic triplet RNA) -expanded triplet peptides found in uclear inclusion bodies observed in postmortem FXTAS brains, but not control brains. -suggests polyglycine and polyalanine products might have natural and pathogenic roles -non-AUG translation of triplets now also found in other triplet disorders: myotonic dystrophy, spinocerebellar ataxia type 8, one type of ALS -conceptually similar to polyglutamine toxicity from triplets embedded wtihin protein coding regions (Huntingtons)

What are common characteristics of tirnucleotide repeat mutations?

-premutations/full mutations -instability - meiotic and mitotic: a. size of repeat correlates with severity and age of onset of the disorder b. may be due to slippage at DNA replication c. repeat is transmitted with expansion or contraction below some threshold length d. expansion is more common e. size of the expansion influenced by the sex of the transmitting parent -anticipation: occurrence of a genetic disease at a progressively earlier age of onset or with increasing severity in successive generations a. expansion of the trinucleotide repeats is the cause of anticipation

How are proteins epigenetic regulators?

-proteins that bind methylated DNA - leads to condensed chromatin - represses gene expression. Occurs on C's of CpG dinucleotides (often found in CpG islands, but also near islands on CpG shores) a. specific methyl cytosine binding proteins recognize methylated DNA. Example: MeCP2 (mutations in Rett Syndrome - X-linked lethal for males) -homeodomain proteins can open or close chromatin structures -proteins can act as HATs or HDACs

Describe histone acetylation

-relaxes chromatin - activates gene expression -acetylation occurs on lysine residue of core histone tails, neutralization of positive charge weakens the nucleosome structure -Histone acetyltransferases (HAT) and deacetylases (HDAC) - enzymes regulate acetylation state -drugs that regualte HATs and HDACs are used to treat variety of diseases (Cancer - Vorinostat inhibits HDACs, induces growth arrest, differentiation, or apoptosis in tumor cells; inflammatory lung diseases - glucocorticoids inhibit HATs, reduced NfKB and inflammatory response; epilepsy - valproate inhibits HDACs)

Describe trinucleotide repeats

-repeating series of 3 nucleotide bases within a gene -may occur in coding sequence (exon), intron, 5' UTR, or 3' UTR -normal repeat size stably transmitted -expanded repeat size - unstable and can change size on transmission from parent to offspring

What are different hemoglobinopathies?

-structural variantes: Hb S, Hb C -Thalassemias: result from quantitative defect in a globin chain a. alpha-thalassemia, beta-thalassemia, Hb H, Hb Bart's -hereditary persistence of fetal hemoglobin

What are the characteristics of autosomal dominant inheritance?

-the presence of one mutant allele is sufficient to cause disease -affects both sexes equally -multiple generations (vertical inheritance) -an affected individual has 50% risk for having an affected child; two affected individuals have a 25% risk of having an UNaffected child

What is Uniparental Disomy?

-the presence of two copies of a specific chromosome or chromosome segment inherited from a single parent, instead of the normal biparental inheritance -discovered in 1991 in girl with cystic fibrosis and short stature. She had two copies of maternal chromosome 7 and no copies from dad -most UDP have no phenotypic anomalies. But, can lead to the manifestation of rare recessive disorders of the parent is a carrier of a recessive mutation -UDP of imprinted genes can result in abnormal phenotypes: Prader-Willi syndrome, Angelman syndrome, Beckwith-Weidemann, and russell-Silver syndromes

What are triplet repeats within epigenetics?

-triplet (trinucleotide) is a short tandem repeat. It is a series of 3 bases in DNA or RNA. Triplet repeats are normally stably transmitted. However, expansion of triplet repeat is unstable and responsible for at least 15 diseases -triplet repeat diseases result fromseveral molecular mechanisms that are generally grouped into two classes: 1. polyglutamine coding triplets (CAG repeat): 2-3-fold small-scale increases in repeat length in coding sequences. -Huntington disease: expansion of polyglutamine tract results in a misfolded protein that gains a toxic function by forming aggregates 2. noncoding triplets: small and large scale (up to 20-fold) increases in repeat length, in non-coding sequences -Myotonic dystrophy (3' non-coding): accumulation of nuclear RNA with triplet repeat the binds and sequesters RNA-binding proteins -Fragile X syndrome (5' non-coding): hypermethlation of DNA shuts off gene transcription

What are the characteristics of autosomal recessive inheritance?

-two mutant alleles for the same gene are required to cause disease -males and females affected equally (autosomal) -one generation (siblings) affected (horizontal inheritance) -heterozygotes/carriers - clinically normal - an unaffected sibling has 2/3 chance to be a carrier -recurrence risks: 25% for parents of affected; offspring of affected: dependent on population frequency and consanguinity

Describe beta-thalassemia

-typically only symptomatic after birth -thalassemia major: two beta-thalassmeia mutant alleles a. beta-0-thalassema - no Hb A present (most severe form) b. beta-+-thalassemia - Hb A is detectable -thalassemia minor: one beta-thalassemia mutant allele: slight anemia; increased Hb A2 (alpha-2-delta-2) on electrophoresis

What are different syndromes associated with heart malformations?

1. 22q11.2 deletion syndrome (DiGeorge) - testing using FISH, chromosomal microarray 2. Turnery syndrome - testing using karyotype and aneuploidy FISH 3. Noonan syndrome - testing using single gene sequencing or gene panel 4. Williams syndrome - testing using FISH or CMA

Describe Fragile X

1. Fragile X syndrome (FXS) has two associated disorders: FXTAS, POI, which affect different steps of gene expression -transcriptional - FXFS, FXTAS, POI -RNA transport, localization- FXTAS, POI -translational control - FXTAS, POI 2. Fragile X syndrome (FXS) -name from a "fragile site" on chromsome X identified by cytogenetic analysis -X-linked intellectual disability disorder a. most common inherited mental disability; delayed speech and language disability, physical traits (lax ligaments, large heads, long face with typical facial features, large testes after early childhood), autism spectrum behavior) b. mainly affects boys (XY), girls less profound phenotype (XX) -Etiology: caused by an unstable CGG repeat in the 5' untranslated region of the fragile X mental retardation (FMR 1) gene on the X chromosome a. normal = 5-55 repeats b. premutation 55-200 repeats c. full mutation = greater than 200 repeats (up to 1000). Leads to high level of methylation of CpG's in repeat, which blocks transcription of FMR1 gene. No Fragile X RNA or protein (FMRP) made

What is an allele?

A variant of a gene or a repetitive element at a certain locus (place) in the genome. - Heterozygosity is good. Loss of heterozygosity occurs in cancer or uniparental disomy.

Types of phenotypic consequences of genomic variation

1. Loss of function 2. Gain of function 3. Acquisition of a novel property 4. Dominant negative effect 5. Ectopic gene expression

What are forces that change allele frequencies?

1. Mutation -generate new alleles, but has little impact on allele frequency and has a minimal impact on the genetic variability present in a population -average mutation rate per gene: 1/100,000; random; non-directional -allele frequency is determined by natural effects of small populations and selection 2. natural effects of small populations: -drift = random loss of alleles due to failed matings -migration = small groups move in and out of the population -non-random mating = selective reproduction lessens heterozygosity -founder effects = small group founds new population (example: Amish - Ellis-van Creveld syndrome) -bottleneck = natural disasters leave survivors who are not representative of whole population 3. selection - primary force that leads to evolutionary divergence (natural or applied) -acts on genetic diversity in populations through survival and differential reproduction; better-adapted individuals have an increased chance of leaving more offspring -fitness; measure of relative survival and reproductive success of a specific individual or genotype

What are examples of non-coding DNA?

1. Regulatory elements like enhancers, promotors, and silencers 2. Repetitive elements like transposons, simple repeats, and segmental repeats. 3. Conserved elements (evolutionary conserved regions) 4. Pseudogenes

Describe translocations resulting in Trisomy 21

1. Robertsonian (14/21 common) - De novo (75%); recurrence risk <1% - Familial (25%); recurrence risk mother 16%, recurrence risk father 5% 2. Isochromosome 21 - Mitotic nondisjunction; recurrence risk <1% - Parental isochromosome; recurrence risk 100%

What are some common aneuploidy syndromes

1. Sex chromosome aneuploidy: Turner's syndrome (45, X), Klinefelter syndrome (46,XXY) 2. Autosomal aneuploidy: Down syndrome (47, +21), Edwards syndrome (47, +18), Patau syndrome (47, +13)

Examples of repetitive gene elements

1. Simple repeats - AKA tandem repeats - they are short repetitive elements that exist directly adjacent to one another 2. Transposons - AKA interspersed repeats - they are mobile elements where a repeated segment is inserted in another place in the DNA 3. Segmental duplications - long blocks of duplicated DNA that can be interspersed or in tandem - 1000 to 200000 base pairs in length

What are the different types of gene variations?

1. Single nucleotide polymorphisms (SNPs) and variations (SNVs) 2. Insertions/Deletions (indels) - they are generally smaller than CNVs and are less common than SNPs 3. Segmental Duplications that yield structural and copy number variations. - Structural variations (inversions, insertions, translocations) - Copy number variations (CNVs) include duplications and deletions - They are generally large DNA fragments

Holes in the central dogma of genes

1. There are many more proteins than genes (1 gene makes many proteins) - This is largely due to alternative splicing - occurs in more than 90% of genes 2. Most RNA does not make protein - There are more non-coding RNA genes than coding genes

What is germline mosaicism?

1. a mutation during embryonic life affects the precursors of gametes - a proportion of gametes then carry the mutation -man insufficient number of somatic cells are affected so there are no clinical features of the condition, parents still have ability to pass on the mutation 2. this is in contrast to sporadic mutations where only one gamete had a spontaneous mutation 3. suspect when there are multiple affected children with clinically normal parents 4. counseling issues - two affected siblings does not make a recessive disease; "new" mutations may not be new; recurrence risk can be as high as 3-4%

Explain how Huntington Disease is caused by triplet repeats

1. autosomal dominant with variable age of onset and variable severity -expansion of a CAG repeat in the HTT gene: normal: 10-30 repeats mutations: 36-121 repeats -new mutaiton in up to 10% of cases 2. parent of origin effect -expands through male germline -90% of juvenile Huntington patients inherit the mutation from their father 3. average age of onset: 37 years -penetrance: 100% by age 80 4. signs and symtpoms: personality changes, memory loss, chorea 5. model for general approach to presymptomatic testing for other adult-onset diseases with complex ethical issues raised -symptoms often evident after reproductive years -accurate molecular genetic diagnosis, but no treatment or cure, and disease carries serious prognosis -should asymptomatic, at-risk individual have testing? What are psychosocial, medical, insurance, employment implications?S

Describe Myotonic dystrophy (DM)

1. autosomal dominant, with variable age of onset and variable severity. -due to a CTG repeat in the 3' UTR of the DMPK gene 2. Clinical features: -myotonia with progressive weakness and wasting; myotonia on grip testing (inability to relax your muscles) -involvement of facial and jaw muscles: ptosis, atrophy of the sternocleidomastoid muscles -cataracts, testicular atrophy and diabetes mellitus, intellectual disability, premature balding in males 3. severity varies with the number of CTG repeats normal: 5-30 repeats mildly affected: 50-80 repeats severely affected: greater than 2000 repeats -parent of origin effect: maternal expansion -anticipation and congenital DM in offspring of an affected mother. a. Congenital DM: marked hypotonia, respiratory distress, may cause neonatal death

Wha are the categories of genetic diseases?

1. chromosomal disorders 2. single gene mendelian disorders 3. polygenic/multifactorial non-mendelian disorders

Explain twin studies

1. concordance of MZ and DZ twins -the raction of individuals of a specific type that share a trait -monozygotic twins share all genes -dizygotic twins share 50% of their genes 2. hertiability: the proportion of the total variance of a trait in a population that is caused by genetic variation -h^2 = (variance in DZ - variance in MZ)/ variance in DZ -h^2 = 0 = exclusively environmental -h^2 = 1 = exclusively genetic

What are the 2 types of uniparental disomy (UDP)?

1. isodisomy 2. heterodisomy

What are the roles of chromatin proteins?

1. package DNA in the nucleus (into a really really small space) 2. regulate transcription - genes are activated or inhibited depending on chromatin condensation state, which is the degree of DNA packing -higher order folding of chromatin into loops can organize genes into expression domains so they are expressed together (chromosomes are not linear molecules in vivo) (remember heterochromatin are near the outer edge with the lamina) -regulation involves both proteins and noncoding RNAs)

What are trinucleotide repeat mechanisms that cause disease?

1. polyglutamine tract (CAG repeat) - 2- 3-fold small-scale increases in repeat length. Example: Huntington disease 2. nonpolyglutamine tract - small and large scale (up to 20-fold) increases in repeat length. Example: fragile X, myotonic dystrophy

What are common characteristics of trinucleotide repeat mutations?

1. premutation 2. instability 3. anticipation

What is the normal etiology for chromosome 15?

1. the maternal copy of chromosome 15 is active in the AS critical region and methylated in the PWS critical region 2. the paternal copy of chromsome 15 is active in the PWS critical region and methylated in the AS critical region (normal: one expression on each chromosome)

What assumptions does the Hardy-Weinberg law make?

1. the population is infinitely large 2. all genotypes are equally able to reproduce a. each allele is equally viable (no lethals) 3. mating in the population is random 4. factors that change allele frequency (forces of evolution) are ignored (mutation, migration, selection) 5. defines the ideal case for a NON-evolving population

What is gene expression?

1. typical gene expression - occurs from both alleles simultaneously 2. atypical gene expression - occurs from only one allele -dependent upon parental origin -"imprinting" - typically due to methylation -small proportion (less than 1%) of genes -example: IGF2 is only expressed from the allele inherited from the father

What is euploid?

Any exact multiple of n chromosomes - Ex) diploid = 2n (number of chromosomes in a normal somatic cell, 46 in humans) - Triploid = 3n (lethal in humans)

Describe Williams syndrome

A chromosomal disorder in which there is an interstitial deletion of the long arm of chromosome 7 at q11, which deletes the elastin gene. - Clinical manifestation includes facial dysmorphisms (stellate iris, periorbital fullness, prominent lips), hypercalcemia, cardiac defects (supravalvular aortic stenosis, peripheral pulmonary artery stenosis), mild intellectual disability, characteristic behaviors (loquacious).

What is a high carrier frequency?

A complication of some recessive diseases where there are lots of heterozygous carriers in the general population - homozygous to heterozygous matings suggest autosomal dominant inheritance (pseudo dominance) - since there is high carrier frequency, the inheritance mimics dominant disorders, looks vertical but it isn't truly. -example: hereditary hemochromatosis

What is a malforamtion?

A defect of organ differentiation

Describe alpha thalassemia

A disease with high carrier frequency where there are more than 2 alleles for a gene Clinical: decreased production of alpha globin; anemia (mild to severe) - 1 to 3 mutations - hydrops fetalis (Hb Bart) - 4 mutations Etiology: mutations in HBA1 and/or HBA2 - HBA1 and HBA2 are in tandem on chromosome 16 - mutations can be in cis or trans - there is more than 1 copy of HBA1 or HBA2 gene

What are duplications?

A gain of a chromosome segment, equivalent to a partial trisomy. - Clinical consequences depend on segment size and number and function of genes in segment. - They are usually less serious than deletions of same size, but also depends on genes involved in the duplication

What is a syndrome?

A grouping of clinical features (phenotype) due to a single etiology - Ex) chromosomal, single gene, teratogens (environment), and complex inheritance

What is a karyotype?

A laboratory technique developed to observe chromosomes - Primarily obtained from blood lymphocytes but may be obtained from other sources according to availability and need. - Ex) bone marrow = fastest growing, skin fibroblasts for mosaicism, and amniocytes for prenatal diagnosis - Can't use RBCs because they do not contain nuclei

What is the genome?

A totality of all the DNA of an individual organism - The human haploid genome is 22 autosomes (non-sex) and X/Y - Nuclear DNA is seen in karyotypes of mitotic chromosomes - Mitochondrial DNA is also part of the genome

What are translocations?

A transfer of genetic material from one chromosome to another.

What are satellites

A type of simple (tandem) repeat variation in DNA ~100's of bp in length - large heterochromatic tandem repeats - They are found throughout chromosomes, but mostly in centromeres and telomeres

What are microsatellites?

AKA short tandem repeats (STRs) ~2-10 bp - STR polymorphisms (STRPs) - there is a variable number of STRs amongst people - Commonly used for criminal forensics - They often control expression of nearby genes

What are interspersed repeats?

AKA transposons, they are transposable genetic elements that have multiplied in our genome by replicating themselves and inserting the new copies in different places. - They are very abundant >40% of genome - They are similar to RNA and DNA viruses like retrotransposons and DNA transposons

What are manifesting heterozygotes?

Affected females in a recessive X-linked disease 1. chromosomal explanations - Turner syndrome (45, X) - X-autosome translocation - can't inactivate the translocated X -structural abnormalities of X chromosome (rings) - ring chromosomes escape X inactivation and normal X is inactivated 2. Mendelian explanations -homozygous female (carrier mother and affected father) -skewed X-inactivation -environmental stresses precipitate symptoms (G6PD deficiency, ornithine transcrabamylase (OTC) deficiency)

What are variations?

All variations are due to mutations in DNA - Not all mutations/variations cause disease state - variation is normal and the most common source is small nucleotide polymorphisms which are differences in a single nucleotide.

What is Chromosomal Microarray (CMA)?

Also known as comparative genomic hybridization (CGH). This uses millions of tiny probes across all chromosomes to detect copy number variants. It can detect gains and losses of 1-5kb. DNA from the patient and from a control are labeled different colors and hybridized to a slide containing hundreds or thousands of defined DNA probes. - This technique can detect variants below the detection of both karyotype and FISH - It does not detect rearrangements or location of extra chromosomal material - This is a first-line test for patients with intellectual disability and/or autism spectrum disorder or a patient with dysmorphic features not fitting a particular syndrome

Describe deletion 22q11.2 syndrome?

Also known as velo-cardio-facial syndrome or diGeorge syndrome. This occurs due to interstitial delection of the long arm of chromosome 21 at q11. This deletes the TBX1 gene (transcription factor active in the heart). - Clinical manifestations include facial dysmorphisms (long face, square nasal root), cleft palate, immunodeficiency, hypocalcemia, cardiac defects (tetralogy of fallot, truncus arteriosus), IQ generally 70-90, and psychiatric disorders. - About 93% occur de novo and 7% are inherited.

Describe cystic fibrosis

An example of allelic heterogeneity Clinical: chronic bronchopulmonary infection with emphysema -disruption of exocrine function of the pancreas -congenital absence of the vas deferens (infertility due to obstructive azoospermia) Etiology: over 1000 mutations in CFTR gene (allelic heterogenity) -direct DNA diagnosis available -deltaF508 deletion accounts for 70% of cases in caucasians -variable expressivity

What is globin switching?

At different points in development, dfferent hemoglobin types are used - from embryonic to fetal to adult

What are balanced translocations

Balanced translocations result in normal phenotypes and can be reciprocal translocations or Robertsonian translocations. - Reciprocal translocations (1/500 live births) occur when any 2 non-homologous chromosomes exchange fragments. The result is that all of the genetic information is maintained, although in a new arrangement. -Robertsonian translocations (1/1000 live births) occur when 2 acrocentric chromosomes fuse at the centromere and the p arms are lost. The chromosome number is 45 but all the genetic information is maintained because p arms in acrocentric chromosomes don't contain much, if any, DNA. This occurs in chromosomes 13, 14, 15, 21, and 22.

Describe the clinical presentation of mitochondrial disorders

CNS: hypotonia, ataxia, pyramidal signs, seizures, myoclonus, dementia, hearing loss Eyes: retinitis pigmentosa, opitc atrophy, cataract, nystagmus Muscle: weakness, exercise intolerance, red ragged fibers Cardiac: cardiomyopathy, arrhythmia LIver: hepatic failure Renal: renal tubular damge, Fanconi syndrome GI dysfunction Hematologic: macrocytic anemia, pancytopenia Endocrine: diabetes, short stature, exocrine pancreatic dysfunction -these all may be due to mutaion in mtDNA or nDNA

Describe gain of function mutations

Can manifest as... 1. Increased levels of gene product - Ex) translocation of MYC gene to immunoglobulin locus which leads to overexpression of an oncogene causing Burkitt lymphoma 2. Constitutive (unregulated) activity - Ex) mutations in RET tyrosine kinase causes inherited endocrine cancer sydrome They are often dominant.

Describe fanconi anemia

Clinical: progressive bone marrow failure, leukemia and other malignancies, multiple malformations: thumbs, skeletal, heart, CNS; developmental delay - an example of locus heterogeneity Etiology: 13 genes = FANC A, B, C, D1, D2, E, F, G, I, J, L, M, N -proteins from DNA repair complex FANCD1 = BRCA2 -locus heterogeneity

Describe Klinefelter syndrome (47, XXY)

Clinical features (usually become noticeable at puberty) include eunuchoid habitus (abody habitus that is tall, slim and underweight, with long legs and long arms), truncal obesity, gynecomastia (breast development), personality disturbances, behavioral problems, small testes and infertility - Occurs in 1/500 live-born males, 1/50 in males with infertility, or 1/7 in males with high grade infertility - 2/3 have 47, XXY; mostly due to maternal nondisjunction - 1/3 have Klinefelter variants (multiple X chromosomes and one Y chromosomes)

Describe Turner syndrome (45, X)

Clinical features include short stature, poorly developed lymphatic system (edema, neck webbing), heart defects (especially coarctation - narrowing of aorta as it leaves the heart), broad shield-like chest, cubitus valgus (forearm angled away from the body), amenorrhea (no menstrual cycle) and infertility Occurs in 1/2500 live-born females but even more when accounting for pregnancy losses. - About 2% of pregnancies have this mutation but 95% of them do not reach term. - About 2/3 have 45, X monosomy - most are paternal nondisjunction (sperm cell with no sex chromosome) - not related to maternal age - About 1/3 are mosaic (45,X/46,XX or 45,X/46XY)

Describe tuberous sclerosis complex

Clinical presentation: hypopigmented macules on skin, shagreen patch, facial angiofibromas, cortical tubers, subependymal nodules, seizures, renal cysts and angiomyolipomas, cardiac rhabdomyomas Etiology: mutations in TSC1 or TSC2 gene that encode the proteins hamartin and tuberin (form a complex) -new mutation: 66% -family-specific mutations (no common ones) -locus and allelic heterogeneity

Describe Glucose 6-phosphate dehydrogenase (G6PD) deficiency

Clinical: Most common enzymopathy worldwide -neonatal jaundice, hemolytic anemia -resistance to falciparum malaria in heterozygotes -environmental precipitants: drugs, illnesses, fava beans -females may by symptomatic with certain environmental stressors Etiology: enzyme eficiency - pentose-phosphate shunt -hundreds of variants -two common variants: African American and Mediterranean

Describe Marfan syndrome

Clinical: aortic dilatation, dissections, aneurysms, mitral valve prolapse, myopia, dislocated lenses, tall, thin, scoliosis, pectus, long fingers Etiology: mutations in FBN1 gene that encodes the structural protein fibrillin -new mutation: 25% -family-specific mutations (i.e. no common ones) - An example of allelic heterogeneity

Describe Neurofibromatosis type 1

Clinical: cafe au lait macules, neurofibromas, plexiform neuromas, lisch nodules (eye), learning disabilities, ADHD, increased risk of tumors Etiology: mutations in NF1 gene that encodes the tumor suppressor protein neurofibromin -new mutation: 50% -family specific mutations (no common ones) -allelic heterogeneity

Describe Rett syndrome

Clinical: females affected, lethal in hemizygous males -females normal at birth -neurologic symptoms with loss of developmental milestones at 6-18 months. Progressive deterioration Etiology: mutations in MECP2 gene -methyl-CpG binding protein (DNA binding protein) -high rate of new mutations in the paternal X chromosome

Describe incontinentia pigmenti

Clinical: females affected, lethal in hemizygous males -skin lesions: blisters - areas of hypo and hyperpigmentation -alopeica, abnormal teeth and nails -some with CNS involvement Etiology: mutations in IKBKG gene -affected males: somatic mosaic or 47 XXY (Klinefelters) -common mutation: deletion that removes exons 4 through 10 -protein protects against apoptosis

Describe Vitamin D resistant rickets (X-linked hypophosphatemia)

Clinical: males and females affected (females have milder symptoms) -lower extremity bowing (rickets) -hypophosphatemia with normal calcium and viatmin D Etiology: mutations in PHEX gene -variety of loss of function mutation -product is an endopeptidase with an unknown substrate expressed in bone lineage cells

Describe achondroplasia

Clinical: most common dwarfing condition (bone dysplasia), disproportionate, short stature due to short limbs (rhizomelia), large head (macrocephaly) Etiology: single mutation in FGFR3 gene (fibroblast growth factor receptor gene) -high new mutation rate: 80%; paternal age effect -narrow range of expressivity -no allelic or locus heterogeneity -lethal double dominant (note: other mutations in the FGFR3 in other locations produce similar but distinct phenotypes - hypochondroplasia, SADDAN, etc)

Describe Huntington disease

Clinical: neurodegenerative disorder, chorea, dementia, adult onset Etiology: trinucleotide repeat expansion in Huntington gene (HTT) -anticipation ->90% cases are inherited

Describe Duchenne Muscular Dystrophy

Clinical: progressive muscular dystrophy -onset: early childhood -non-ambulatory by teens -cardiomyopathy -1/3 have cognitive delays Etiology: due to mutations in the dystrophin gene -large deletions seen in 2/3 of patients -high new-mutation rate - appears to arise during spermatogenesis in grandfather -germline mosaicism described (consider this possibility when 2 affected males are born to a woman who is NOT identified to be a carrier for the X-linked condition. Implications for recurrence and counseling)

Describe Ornithing transcarbamylase (OTC) deficiency

Clinical: vomitine, lethargy, coma -hyperammonemia -female carriers may be symptomatic with illnesses, protein load Etiology: enzymatic defect in the urea cycle

What are examples of diseases with complete penetrance?

Complete penetrance is when all individuals who have the disease-causing mutation express the disease. - Ex) Marfan, neurofibromatosis type 1, achondroplasia

Describe the banding pattern of chromosomes

Each chromosome has a characteristic banding pattern.

Describe genetic relatedness in first, second, and third degree relatives

First degree (parents, siblings, children) - 1/2 genes shared Second degree (uncles/aunts to nieces/nephew, grandparents, grandchildren, half-siblings) - 1/4 genes shared Third degree (great-grands, first cousins) - 1/8 genes shared

What is FISH

Fluorescent in situ hybridization is a method to detect very small changes in chromosomes. - A fluorescent probes is injected into DNA and bind to sections of DNA with which it has a complimentary sequence. - Detects sequences 100-300 kb in length. - Used to diagnose microdeletion syndromes

Describe GC rich regions

GC rich DNA (Euchromatin) has greater Z DNA structure (left-handed helix) as opposed to more common right-handed B structure, that correlates with active transcription - GC rich DNA (CpG islands) means house-keeping genes are nearby that are always on, unless the DNA is methylated, which silences DNA - The chemistry of GC means fatter and more open base pairs, which is easier to transcribe from

Describe gene number in chromosomes

Gene numbers differ between chromosomes - Chromosome 1 has the most genes and chromosome Y has the fewest. - The fewest number of genes on autosomal chromosomes are 13, 18, 21

What are the two general types of genomic variations?

Gene variations and repetitive element variations - These categories are not mutually exclusive.

What is multifactorail inheritance?

Genes + Environment -underlies most common disorders a. adult onset: Alzheimer, Schizophrenia, bipolar, diabetes, hypertension, obesity b. childhood onset: pyloric stenosis, neural tube defects, congenital heart defects, cleft lip and palate, congenital hip dislocation, autism

What are issues with defining the genome?

Genes are difficult to define because.... 1. Small genes are difficult to detect. 2. Some cryptic pseudogenes turn out to be functional. 3. *2 genes can overlap.* 4. Only a small portion of the genome has protein-coding exons.

Describe the distribution of genes

Genes are not evenly distributed - Euchromatic regions are gene dense and tend to have high GC content which affects DNA structure - Giemsa stain reveals these regions as light bands because they are loosely packed -Heterochromatic regions are gene poor and tend to be AT rich - Giemsa stain reveals these regions as dark bands because they are tightly packed

What are pseudogenes?

Genes homologous to a known protein-coding gene, but are dysfunctional since they do not express the active protein - Dysfunction can be due to a lack of transcription or translation, but occasionally a non-functional protein is made - Generally thought to be residual duplicated genes that have acquired random mutations over time. Others are apparently processed mRNAs reinserted back into genome - Some have recently found to have unsuspected functions

How do epigenetics dictate cell fates?

Homeodomains -phenotypic specification by homeodomain proteins -over 300 homeodomain proteins now identified from yeast to humans (highly conserved). All members contain a 60 amino acid DNA binding domain (homeobox) -developmental switches that control cell phenotype -segmental Hox pattern controls body pattern formation -amount of homeodomain protein matters (cross-species transfer of phenotype by expression level of a homeodomain protein - same gene (Prx1) but different levels controlled at transcriptional level, yields a mouse leg or bat wing. - bats have a better enhancer of Prx1)

Compare the human genome with other organisms

Humans share most protein families with lower species like worms, flies, and plants. - Our genome is much smaller than plants but larger than parasites. - *Our genome has a greater proportion of repetitive elements* - We have *more alternative RNA splicing, so more proteins are produced per gene* - Humans have fewer protein coding genes than plants; comparable to dogs.

What is the risk assessment for X-linked recessive diseases?

If mother is a carrier: 25% risk of having an affected child; 50% risk of having an affected son Haldane's rule: Mother of a son with an X-linked recessive condition with low reproductive fitness has a 2/3 chance of being a carrier (2/3 of Xs are in women, 1/3 are in males. There's a higher liklihood that a random mutation in an X would happen in a female. In cases where recessive conditions are fatal, new mutations are required)

What are examples of diseases with incomplete penetrance?

Incomplete (reduced) penetrance is when clinical symptoms my or may not be present in all individuals who have the disease-causing mutation. - Ex) hereditary pancreatitis, most cancer syndromes

Types of transposon repeat variations

Interspersed repeats have been shown to act as gene enhancers, facilitate gene diversity, and serve as genetic markers. 1. SINEs (short interspersed elements, <500 bp) - originated from reverse transcribed small RNAs inserted back into genome. 2. LINEs (long interspersed elements) - Encodes reverse transcriptase, which can mobilize other elements, including Alu elements, most common is L1 - L1 LINE is the only autonomous element still active in humans;

What is the centromere?

It is responsible for accurate segregation during mitosis/meiosis - Placement may be metacentric (middle), submetacentric (off centered), or acrocentric (at the end of a chromosome - occurs in chromosomes 13, 14, 15, 21, 22)

What are known and suspected sites for sequence-dependent epigenetic mechanisms?

Known sites: promoters, enhancers, silencers Suspected sites: evolutionary conserved elements - intergenic non-coding sequences maintained across species; SNPs

What are different Arrhythmias?

Long QT syndrome (LQTS) Brugada syndrome Catecholaminergic polymorphic ventricular tachycardia (CPVT) -these may account for up to 35% of sudden cardiac deaths in 1- 40 year olds -channelopathies - defects in ion channels

What are minor malformations?

Malformations that are clinically insignificant - Ex) ear size & position; single palmar crease; 2/3 toe syndactyly - They can act as clues to genetic conditions (3 or more are indicative of major malformations)

What are major malformations?

Malformations that are clinically significant (medically, surgically, or cosmetically significant) - Ex) cleft lip and palate; neural tube defects; congenital heart defects

What are the maternal illnesses with highest risk of heart malformations?

Maternal rubella (german measles) phenylketonuria (PKU) diabetes - glucose is a teratogen

What are minisatellites?

More commonly called variable number tandem repeats (VNTRs), are mutations in DNA that occur adjacent to one another and are about ~10-60 bp in length. - There is a highly variable number of repeats among individuals - VNTRs are used for DNA fingerprinting, forensics, genealogy (each variant is inherited.

How are genomic variations acquired?

Mutations can occur due to... 1. Proofreading errors during DNA replications - The mutation rate from replication errors is very low, but they do occur with each cell division 2. Spontaneous mutations - From UV exposure, radiation, or chemical agents - They cause depurination, deamination, or demethylation - They often result in permanent base changes

What is aneuploid?

Numerical abnormalities with a gain or loss of 1 or more chromosomes that are the result of errors in meiosis or mitosis. - The risk for meiotic nondisjunction increases with increasing maternal age while mitotic nondisjunction occurs after the formation of a zygote and results in mosaic aneuploidy. - Ex) Monosomy is 1 copy of a chromosome, whereas trisomy is 3 copies.

What are inversions?

Occurs when a single chromosome undergoes two breaks and is reformed with a segment between the breaks inverted, basically a stretch of DNA is flipped. Carriers are normal but can produce offspring with deletions and/or duplications. - Paracentric inversion (beside the centromere) results from both breaks in one arm of the chromosome - Pericentric inversion (around the centromere) results from breaks in each arm of the chromosome

Where do autosomal trisomy disorders mainly occur?

On chromosomes with the fewest genes. - Autosomal chromsomes 13, 18, and 21

What is the Lyon hypothesis: X-inactivation?

Only one X chromosome is active in somatic cells of females, the second X remains condensed and inactive (Barr body) -inactivation occurs early in development and is complete by about 1 week post-fertilization -inactivation is random, but once made, the decision is permanent -dosage compensation so that XY = XX -variability of expression in heterozygous females -females are mosaics with respect to their X-linked genes

Describe loss of gene function

Results in partial or complete loss of protein/enzymatic function. - A relatively common mechanism for disease - Can results in loss of heterozygosity of tumor suppressor genes in cancer like p53 - Most often this is recessive but can be dominant - may depend on other gene mutations

Describe tandem repeats

Short repeats in DNA that occur adjacent to one another. - They can be direct or inverted repeats. - They are organized by size - satellites, minisatellites, and microsatellites.

Function of telomeres

Telomeres (chromosome ends), serves to stabilize, prevent fusion, allow replication without loss of DNA from the chromosome ends

What is Mendel's First Law?

The law of segregation - the two members of the factor pair segregate independently in the formation of gametes (traits occur in pairs that separate independently of each other)

What is Mendel's Second Law?

The principle of independent assortment - factors for different traits segregate independently of one another

What is penetrance?

The proportion of individuals with a disease-causing mutation (genotype) who express the associated clinically identifiable phenotype - carry gene and express disease

What is cytogenetics?

The study of chromosome structure, function, and inheritance

Describe dominant negative effect mutations

These mutations block normal protein function. - Ex) Osteogenesis imperfecta is a group of inherited bone disorders that predispose to easy fracturing and skeletal deformity. The majority of cases is caused by a dominant mutation to type 1 collagen that disrupts every normal chain of collage it binds with.

Describe ectopic gene expression mutations

These mutations result in loss of normal regulation of gene expression - either temporal or spatial. - Ex) translocation of MYC oncogene to immunoglobulin locus in Burkitt lymphoma results in high level of ectopic expression of MYC in B cells. - These mutations are often dominant.

Describe acquisition of a novel property mutation

They are mutations that result in new properties and can be either dominant or recessive. - Ex) Sickle cell anemia results in a hutation in hemoglobin S which results in a sickle celled red blood cell

What are the causes of duplications and deletions?

They occur due to unequal crossing over between misaligned sister chromatids or abnormal segregation from balanced translocation/inversions.

What are unbalanced translocations?

They result due to a misdistribution of balanced translocation. - Occurs in 1/17k newborns.

What are examples of non-coding RNA (ncRNA) genes?

This comprises the majority of transcripts - there are more non-coding RNA genes than protein-coding RNA. 1. Long ncRNA (greater than 200 nucleotides) are often intergenic but can be antisense of a protein coding gene. - thought to play a regulatory role. 2. Circular RNAs - thought to function to sequester proteins. 3. Small RNAs - micro RNA - regulate gene expression - small inhibitory RNA - regulate gene expression - small nucleolar RNA - regulate gene function - enhancer-encoded small RNAs - function unknown

Describe Wolf-Hirschhorn Syndrome

This is a disorder that occurs due to a partial deletion of the distal p arm of chromosome 4 (from p15 to p16). - Clinical manifestations include "greek helmet" facial type, cleft lip/palate, poor growth with microcephaly, heart defects, and severe intellectual disability. - About 85% are de novo and 15% are from a parent with a balanced translocation.

Describe Cri du chat Syndrome

This is a disorder that occurs due to a partial deletion of the distal p arm of chromosome 5 (p15). - Clinical manifestations include a cat-like cry, hypertelorism (wide set eyes), poor growth with microcephaly, heart defects, and severe intellectual disability. - About 85% of these changes are de novo and 15% are from a parent with balanced translocation.

What does dup21(q22.1-q22.2) mean?

This is a duplication in chromosome 21 from segment 22.1 of the q arm to chromosome 22.2 of the q arm. - This duplication is sufficient to cause down syndrome

What are copy number variations (CNVs)

This is a mutation in which an entire gene has been copied or deleted. - Generally large DNA fragments (1-2 kb)

What is ornithine transcarbamylase deficiency?

This is due to loss of function due to genomic variation and causes OTC deficiency (urea cycle) which leads to buildup of ammonia.

What is hereditary persistance of Hb F?

Throughout adult life, still make fetal hemoglobin

Describe Patau Syndrome

Trisomy 13 (47,+13) which presents as profound motor and intellectual retardation, clenched fist, rocker bottom feet, cleft lip, malformed ears, cutis aplasia, polydactyly, holoprosencephaly. - Occurs in about 1/10-12K live births (more frequent in pregnancy losses - 95% do not reach term) - 80% are full trisomy and 20% are mosaic and translocations - Recurrence is about 1% if the parent has normal chromosomes and about 2% if the parent is a translocation carrier.

Describe Edward's Syndrome.

Trisomy 18 (47,+18) which presents as profound motor and intellectual retardation, clenched fist, rocker bottom feet, small mouth, pointed ears, and short sternum. - Occurs in about 1/7500 live births (more frequent in pregnancy losses - 95% do not reach term): - 80% are full trisomy and 20% are mosaic and translocations - Recurrence is about 1% if the parent has normal chromosomes and about 2% if the parent is a translocation carrier.

Describe Down Syndrome

Trisomy 21 (47, +21) with common features such as epicanthal folds (extra fold around the eye) upslanting palpebral fissures, midface hypoplasia (eye, nose and mouth are small), low set and small ears. Associated with congenitcal heart defects (50%, AV canal defects are highly associated), intestinal atresias (12%), mild to moderate intellectual disability, hypothyroidism, leukemia, brushfield spots, short hands with single transverse palmar crease. - Occurs in 1/700 live births but more frequent in pregnancy losses: 75% do not reach term. - Most are full trisomy 21 (94%); mostly due to maternal nondisjunction - related to maternal age) - 1-3% are mosaic: recurrence risk is the same as free T21 - 3-4% are translocations - increased recurrence risk

What are repetitive element variations?

Variations in repetitive elements. - It can directly affect gene expression if it occurs at repetitive elements within a gene (CpG methylation islands, triplet repeats) - It can also affect gene expression from a large distance if it occurs in a regulatory region (SINE and L1 enhancer activity and/or chromatin structure)

What are gene variations?

Variations that occur in a gene, so if it is in a coding sequence, it can directly affect protein structure and levels - If it occurs in a non-coding sequences, it can affect RNA stability - May also affect gene expression if variation alters enhancer activity or copy number - About 99% variants are in non-gene regions, only ~1% in known genes

What are examples of X-linked Dominant disorders?

Vitamin D resistant rickets Incontinentia pigmenti Rett syndrome

What is consanguinity?

When individuals are related by descent from common ancestor. - More likely to see very rare disorders with populations with high consanguinity. - Geographically isolated populations have high consanguinity. - Communities isolated due to ethnic or religious beliefs have high consanguinity.

Describe X-linked dominant diseases without male lethality

affected male: affected female ratio is 1:2

What is Bayes' Theorem?

allows recalculation of probability based on additional information P(A:B) = P(B:A)*P(A)/P(B) P(A) = prior probability P(B:A) = conditional probability - based on specific conditions of case P(B:A)*P(A) = joint probability P(A:B) = posterior probability (the answer) P(B) = total joint probability of being affected and unaffected

What are the Mendelian inheritance patterns?

autosomal dominant autosomal recessive x-linked dominant x-linked recessive

How is epigenetics mediated?

by chromatin structure -Chromatin = DNA + DNA-binding proteins (histones)

What are classic examples of diseases inherited by autosomal recessive mutations?

cystic fibrosis hemochromatosis most inborn errors of metabolism (e.g. phenylketonuria)

Describe allelic heterogeneity in autosomal recessive conditions

different mutations at the same locus (alleles) are responsible for the disorder -example: cystic fibrosis, PKU

What are some examples of diseases that are X-linked recessive?

duchenne muscular dystrophy (males do not reproduce) G6PD deficiency OTC deficiency red-green colorblindness hemophilia

What is epigenetics?

means "above the genome" -defined as long-term transcriptional control. -the consensus now is that any stable alteration in gene transcription is an epigenetic change (does not have to be heritable)

What are classic examples of autosomal dominant inheritance diseases?

neurofibramotisis type 1 marfan syndrome achondroplasia huntington chorea osteogenesis imperfecta most familial cancer syndromes

Describe familial aggregation for multifactorail disorders

relative risk = prevalence of disease in relatives/prevalence of disease in population Relative Risk = 1 for nonhertiable diseases (family members are not more likely than population to have the disease) Relative risk > 1 for heritable disease (family members are more likely than population to have the disease

What is variable expressivity?

varying signs and symptoms (range of phenotypes) that can occur in different people with the same genetic condition (Marfan syndrome, Neurofibromatosis type 1)