Genetics

Locus heterogeneity

, genes at more than one locus may cause the disorder. Example: Osteogenesis imperfecta whereby collagen a-1 (I) chain protein and collagen a-2(I) chain protein are encoded by the COL1A1 gene on chromosome 17q21.3-q22 and COL1A2 gene on chromosome 7q22.1, respectively (i.e., two separate genes located on different chromosomes). A mutation in either gene will cause osteogenesis imperfecta

Autosomal recessive gene

-1-Antitrypsin Deficiency -Adrenogenital Syndromes -Albinism -Alpha thalassemia -Alkaptonuria -Argininosuccinic aciduria -Ataxia telangiectasia -Beta thalassemia -Bloom syndrome -Branched chain ketonuria -Childhood polycystic kidney disorder -Cystic fibrosis -Cystinuria -Dwarfism -Ehlers-Danlos syndrome (Type VI) -Erythropoietic porphyria -Fanconi anemia -Friedreich ataxia -Fructosuria -Galactosemia -Glycogen storage disorder -Von Gierke (Type Ia) -Pompe (Type II) -Cori (Type IIIa) -Andersen (Type IV) -McArdle (Type V) -Hers (Type VI) -Tarui (Type VIII) -Hemoglobin C disorder -Hepatolenticular degeneration -Histidinemia -Homocystinuria -Hypophosphatasia -Hypothyroidism -Junctional epidermolysis bullosa -Juvenile myoclonus epilepsy -Lawrence Moon syndrome -Lysosomal storage disorders -Tay Sachs -Gaucher -Niemann-Pick -Krabbe -Sandhoff -Schindler -GM1 gangliosidosis -Metachromatic leukodystrophy -Mucopolysaccharidoses -Hurler -Sanfilippo A-D -Morquio A&B -Maroteaux-Lamy Sly -Osteogenesis imperfecta (Type II & III) -Oculocutaneous albinism (Type I & II) -Peroxisomal disorders -Phenylketonuria -Premature senility -Pyruvate kinase deficiency -Retinitis pigmentosa -Sickle cell anemia -Trichothiodystrophy -Tyrosinemia -Xeroderma pigmentosa

Autosomal dominant diseases

-Achondroplasia -Acrocephalosyndactyly -Adult polycystic kidney disorder -Alport syndrome -Apert syndrome -Bor syndrome -Brachydactyly -Charcot-Marie-Tooth disorder -Cleidocranial dysplasia -Crouzon craniofacial dysplasia -Craniostenosis -Diabetes associated with defects in genes for glucokinase, HNF-1, and HNF-4 -Ehlers-Danlos syndrome (Type IV) -Epidermolysis bullosa simplex -Familial adenomatous polyposis -Familial hypercholesterolemia (Type IIa) -Goldenhar syndrome -Heart-hand syndrome -Hereditary nonpolyposis Colorectal cancer (HNPCC) -Hereditary spherocytosis -Huntington disorder -Marfan syndrome -Monilethrix -Myotonic dystrophy 1 and 2 -Neurofibromatosis -Noonan syndrome -Osteogenesis imperfecta (Type I & IV) -Pfeiffer syndrome -Piebaldism -Retinoblastoma -Treacher Collins syndrome -Spinocerebellar ataxia 1,2,3.6,7, 8,11,17 -Uncombable hair syndrome -Von Willebrand disorder -Waardenburg syndrome -Williams-Beuren syndrome

X linked recessive

-Duchenne musculardystrophy -Ectodermal dysplasia -Ehlers-Danlos (Type IX) -Fabry disorder -Fragile X syndrome -G6PD deficiency -Hemophilia A & B -Hunter syndrome -Ichthyosis -Kennedy syndrome -Kinky hair syndrome -Lesch-Nyhan syndrome -Testicular feminization -Wiskott-Aldrich syndrome

Kearns-Sayre Syndrome (KS).

. Clinical features include: chronic progressive external ophthalmoplegia (CPEO; degeneration of the motor nerves of the eye), pigmentary degeneration of the retina ("salt and pepper" appearance), heart block, short stature, gonadal failure, diabetes mellitus, thyroid disease, deafness, vestibular dysfunction, cerebellar ataxia, and onset occuring at _20 years of age. mitochondrial genetic disorder caused by partial deletions of mitochondrial DNA (delta-mtDNA) and duplication of mitochondrial DNA (dup-mtDNA).The partial deletions of mtDNA have been associated with a marked reduction in the enzymatic activity of NADH dehydrogenase (Complex I), succinate dehydrogenase (Complex II), ubiquinonecytochrome c oxidoreductase (Complex III), and cytochrome oxidase (Complex IV). 2. Heteroplasmy is common and expression of the disease is highly variable. 3. Prevalence. The prevalence of KS is not known, although a conservative estimate for the prevalence of all mitochondrial diseases is 1/8,500.

Smith-Lemli-Opitz (SLO) Syndrome

. Clinical features include: prenatal and postnatal growth retardation, microcephaly, moderate to severe mental retardation, cleft palate, cardiac defects, underdeveloped external genitalia and hypospadias in males, postaxial polydactyly, Y-shaped 2 to 3 toe syndactyly, downslanting palpebral fissures, epicanthal folds, anteverted nares, and micrognathia. an autosomal recessive genetic disorder caused by _70 different mutations in the DHCR7 gene on chromosome 11q12-q13 for 7-dehydrocholesterol reductase which catalyzes the last step in cholesterol biosynthesis 7-dehydrocholesterol → cholesterol. 2. SLO syndrome is commonly caused either by a missense mutation which results in a normal threonine →methionine substitution at position 93 (T93M), a nonsense mutation which results in a normal tryptophan S nonsense at position 151 (W151X) causing a premature STOP codon, or a intron 8 splice acceptor mutation, all of which account for _50% of all cases. 3. Prevalence. The prevalence of SLO is 1/20,000 to 40,000 births.

Xeroderma pigmentosum (XP)

. Clinical features include: sunlight (UV radiation) hypersensitivity with sunburnlike reaction, severe skin lesions around the eyes and eyelids, and malignant skin cancers (basal and squamous cell carcinomas and melanomas) whereby most individuals die by 30 years of age. XP is an autosomal recessive genetic disorder caused by mutations in nucleotide excision repair enzymes, which results in the inability to remove pyrimidine dimers and individuals who are hypersensitive to sunlight (UV radiation). b. The XPA gene and the XPC gene are two of the genes involved in the cause of XP. XPA gene located on chromosome 9q22.3 encodes for a DNA repair enzyme. The XPC gene located on chromosome 3p25 also encodes for a DNA repair enzyme c. Prevalence. The prevalence of XP is 1/250,000 in the U.S. population

Type 3 VWD.

. Type 3 VWD is an autosomal recessive genetic disorder. b. Type 3 VWD results from a reduced synthesis of vWF and factor VIII. c. Type 3 VWD is a rare disease but the most severe form of VWD. d. Clinical features include: nose bleeding (epistaxis); severe skin bleeding; severe bleeding from mucosal surfaces; muscle hematomas; and severe joint bleeding.

Type 2 VWD.

2. Type 2 VWD. a. Type 2 VWD is an autosomal dominant or autosomal recessive genetic disorder. b. Type 2 VWD results from a reduced functionality of vWF. c. There are four subtypes of Type 2 VWD: 2A, 2B, 2M, and 2N. d. Type 2A VWD accounts for 10% to 15% of the cases. e. Clinical features include: can be diagnosed at any age, lifelong easy bruising, nose bleeding (epistaxis), skin bleeding, prolonged bleeding from mucosal surfaces, heavy menstrual bleeding, and moderate to moderately severe bleeding.

Noonan Syndrome (NS)

4. Clinical features include: short stature, congenital heart defects, broad or webbed neck, unusual chest shape (e.g., superior pectus carinatum, inferior pectus excavatum), apparently low-set nipples, cryptorchidism in males, characteristic facial appearance (e.g., lowset, posteriorly rotated ears; vivid blue irides; widely-spaced eyes; epicanthal folds; and thick, droopy eyelids). 1. NS is an autosomal dominant genetic disorder caused by mutations in the following genes: a. The PTPN11 gene on chromosome 12p12.1 which encodes for tyrosine-protein phosphatase non-receptor type 11 in _50% of NS cases. This is an extracellular protein that plays a key role in the cellular response to growth factors, hormones, and cell adhesion molecules. b. The RAF1 gene on chromosome 3p25 which encodes for RAF proto-oncogene serine/ threonine-protein kinase in 3-17% of NS cases. This protein plays a key role in the signal transduction pathway for epidermal growth factor (EGF) action. c. The SOS1 gene on chromosome 2p22 - p21, which encodes for son-of-sevenless homolog 1 in _10% of NS cases. This protein plays a key role in the signal transduction pathway for receptor tyrosine kinase action. 2. Many NS individuals have de novo mutations. However, an affected parent is recognized in 30% to 75% of families. In simplex cases (i.e., those with no known family history), the mutation is inherited from the father. 3. Prevalence. The prevalence of NS is 1/1,000 to 2,500 births.

. Friedreich Ataxia (FRDA).

6. Clinical features include: degeneration of the posterior columns and spinocerebellar tracts, loss of sensory neurons in the dorsal root ganglion, slowly progressive ataxia of all four limbs with onset at 10 to 15 years of age, optic nerve atrophy, scoliosis, bladder dysfunction, swallowing dysfunction, pyramidal tract disease, cardiomyopathy (arrhythmias), and diabetes. is an autosomal recessive genetic disorder caused by a 600 to 1,200 unstable repeat sequence of (GAA)n in intron 1 of the FXN gene on chromosome 9q13-a21.1 for the frataxin protein, which is located on the inner mitochondrial membrane and plays a role in the synthesis of respiratory chain complexes I through III , mitochondrial iron content, and antioxidation defense. 2. A longstanding hypothesis is that FRDA is a result of mitochondrial accumulation of iron, which may promote oxidative stress injury. 3. Normal FXN alleles have _5 to 33 repeats. They are stably transmitted without any decrease or increase in repeat number. 4. Premutation FXN alleles have _34 to 65 repeats. They are not stably transmitted. Expansion of the permutation FXN alleles occurs during meiosis during the production of both sperm (paternal transmission) and ova (maternal transmission) because _96% of FRDA individuals are homozygous for the 600 to 1,200 unstable repeat sequence of (GAA)n. 5. Prevalence. The prevalence of FRDA is 1/50,000.

Cystic Fibrosis (CF).

6. Clinical features include: production of abnormally thick mucus by epithelial cells lining the respiratory resulting in obstruction of pulmonary airways, recurrent respiratory bacterial infections, and end-stage lung disorder; pancreatic insufficiency with malabsorption; acute salt depletion, chronic metabolic alkalosis; and males are almost always sterile due to the obstruction or absence of the vas deferens 1. CF is an autosomal recessive genetic disorder caused by _1,000 mutations (almost all are point mutations or small deletions 1-84 bp) in the CFTR gene on chromosome 7q31.2 for the cystic fibrosis transmembrane conductance regulator which functions as a chloride ion (Cl_) channel. The Cl_ ion channel normally transports Cl_ out of the cell and H2O follows by osmosis. The H2O maintains the mucus in a wet and less viscous form. 2. CF is most commonly (_70% of cases in the North American population) caused by a three base deletion which codes for the amino acid phenylalanine at position 508 (delta F508) such that phenylalanine is missing from CFTR. However, there are a large number of deletions, which can cause CF, and parents of an affected child can carry different deletions of CFTR gene. These mutations result in absent/near absent CFTR synthesis, a block in CFTR regulation, or a destruction of Cl_ transport. 3. The poly T tract/TG tract is associated with CFTR-related disorders. The poly T tract is a string of thymidine bases located in intron 8 with the 5T, 7T, and 9T the most common variants. The TG tract is a repeat of thymidine and guanine bases just 5' of the poly T tract with repeats that commonly number 11, 12, or 13. 4. Sweat chloride test. The pilocarpine iontophoresis for sweat chloride is the primary diagnostic test for CF. [Cl_] _60 Eq/L on two separate occasions is diagnostic. 5. Prevalence. The prevalence of CF is 1/3,200 in the Caucasian population with a heterozygote carrier frequency of 1/20. CF is less common in the African American population (1/15,000) and in the Asian American population (1/31,000).

Duchenne Muscular Dystrophy (DMD

6. Clinical features include: symptoms appear in early childhood with delays in sitting and standing independently; progressive muscle weakness (proximal weakness _distal weakness) often with calf hypertrophy; progressive muscle wasting; waddling gait; difficulty in climbing; wheelchair bound by 12 years of age; cardiomyopathy by 18 years of age; death by _30 years of age due to cardiac or respiratory failure. 1. DMD is an X-linked recessive genetic disorder caused by various mutations in the DMD gene on chromosome Xp21.2 for dystrophin which anchors the cytoskeleton (actin) of skeletal muscle cells to the extracellular matrix via a transmembrane protein (_-dystrophin and (_-dystrophin) thereby stabilizing the cell membrane. The DMD gene is the largest known human gene. 2. DMD is caused by small deletion, large deletion, deletion of the entire gene, duplication of one of more exons, insertion, or single-based change mutations. These mutations result in absent/near absent dystrophin synthesis. 3. Serum creatine phosphokinase (CK) measurement. The measurement of serum CK is one of the diagnostic tests for DMD. [serum CK] _ 10 times normal is diagnostic. 4. Skeletal muscle biopsy. A skeletal muscle biopsy shows histological signs of fiber size variation, foci of necrosis and regeneration, hyalinization, and deposition of fat and connective tissue. Immunohistochemistry shows almost complete absence of the dystrophin protein. 5. Prevalence. The prevalence of DMD is 1/5,600 live male births. DMD has a 1/4,000 carrier frequency in the U.S. population, although it is difficult to calculate because _33% of DMD cases are new mutations.

Fragile X Syndrome (Martin-Bell Syndrome)

7. Clinical features include: mental retardation (most severe in males), macroorchidism (postpubertal), speech delay, behavioral problems (e.g., hyperactivity, attention deficit), prominent forehead and jaw, joint laxity, and large, dysmorphic ears. is the second leading cause of inherited mental retardation (Down syndrome is the number one cause). Fragile X syndrome is an X-linked recessive genetic disorder caused by a 200 to 1,000_ unstable repeat sequence of (CGG)n outside the FMR1 gene on chromosome X for the Fragile X mental retardation 1 protein (FMRP1, a nucleocytoplasmic shuttling protein that binds several mRNAs found abundantly in neurons. 2. The 200 to 1,000_unstable repeat sequence of (CGG)n creates a fragile site on chromosome X, which is observed when cells are cultured in a folate-depleted medium. The 200 to 1,000_ unstable repeat sequence of (CGG)n has also been associated with hypermethylation of the FMR1 gene so that FMRP1 is not expressed, which may lead to the phenotype of Fragile X. 3. Fragile X syndrome involves two mutation sites. Fragile X site A involves a 200 to 1,000_ unstable repeat sequence of (CGG)n located in a 5' UTR of the FMR 1 gene on chromosome Xq27.3. Fragile X site B involves a 200_ unstable repeat sequence of (CCG)n located in a promoter region of the FMR 1 gene on chromosome Xq28. 4. Normal FMR1 alleles have _5 to 40 repeats. They are stably transmitted without any decrease or increase in repeat number. 5. Premutation FMR1 alleles have _59 to 200 repeats. They are not stably transmitted. Females with permutation FMR1 alleles are at risk for having children with Fragile X syndrome. 6. Prevalence. The prevalence of Fragile X syndrome is 1/4,000 males. The prevalence of Fragile X syndrome is 1/2,000 females

Chimerism

A person may become a chimera by the fusion of two genetically different zygotes to form a single embryo (i.e., the reverse of twinning) or by the limited colonization of one twin by cells from a genetically different (i.e., nonidentical; fraternal) co-twin.

Cancer

Cancers are genetic disorders, but most of them are not strictly inherited. The fact that cancers tend to cluster in families demonstrates that there is a genetic component to the disorders as a group. 2. For example, the risk of developing breast cancer doubles for first-degree relatives of women diagnosed with the disorder. The risk also increases if more than one first-degree relative has breast cancer and increases even more if the cancers developed relatively early (before 45 years of age). However, the genetic components of many cancers are poorly understood. The genes known to be involved in hereditary cancers will be discussed in Chapter 16. 3. The role of environmental factors is also recognized in the etiology of many cancers (e.g., the role of tobacco use in lung cancer). The role of infectious agents is also recognized in the etiology of _15% of cancers (e.g., the role of human papilloma virus [HPV] in cervical cancer).

Fanconi anemia (FA)

Clinical features include: DNA crosslinking agent hypersensitivity, short stature, hypopigmented spots, café-au-lait spots, hypogonadism microcephaly, hypoplastic or aplastic thumbs, renal malformation including unilateral aplasia or horseshoe kidney, acute leukemia, progressive aplastic anemia, head and neck tumors, medulloblastoma, and is the most common form of congenital aplastic anemia. . FA is an autosomal recessive genetic disorder caused by mutations in DNA recombination repair, which results in individuals who are hypersensitive to DNA crosslinking agents. b. The FA-A gene (involved in 65% of FA cases) is one of the genes involved in the cause of FA. The FA-A gene located on chromosome 16q24 encodes for a protein that normalizes cell growth, corrects sensitivity to chromosomal breakage in the presence of mitomycin C, and generally promotes genomic stability. c. Prevalence. The prevalence of FA is 1/32,000 in the Ashkenazi Jewish population.

Glycogen Storage Disease Type I (GSDI; von Gierke).

Clinical features include: accumulation of glycogen and fat in the liver and kidney resulting in hepatomegaly and renomegaly, severe hypoglycemia, lactic acidosis, hyperuricemia, hyperlipidemia, hypoglycemic seizures, doll-like faces with fat cheeks, relatively thin extremities, short stature, protuberant abdomen, and neutropenia with recurrent bacterial infections. an autosomal recessive genetic disorder caused by _85 different mutations in the G6PC gene on chromosome 17q21 for glucose-6-phosphatase, which catalyzes the reaction glucose-6-phosphate →glucose _ phosphate. 2. GSDIb is an autosomal recessive genetic disorder caused by _78 different mutations in the SLC37A4 gene on chromosome 11q23 for glucose-6-phosphate translocase, which transports glucose-6-phosphate into the lumen of the endoplasmic reticulum. 3. GSDIa is commonly (32% of cases in the Caucasian population and 93% to 100% of cases in the Jewish population) caused by a missense mutation which results in a normal arginine S cysteine substitution at position 83 (R83C). GSDIb is commonly (15% of cases in the Caucasian population and 30% of cases in the German population) caused by a missense mutation which results in a normal glycine Scysteine substitution at position 339 (G339C). 4. Prevalence. The prevalence of GSDI is 1/100,000 births.

Galactosemia (GAL).

Clinical features include: feeding problems in the newborn; failure to thrive, hypoglycemia, hepatocellular damage, bleeding diathesis, jaundice, and hyperammonemia; sepsis with E. coli, shock, and death may occur if the galactosemia is not treated; galactosemia is one of the conditions tested for on newborn screens in most states. . GAL is an autosomal recessive genetic disorder caused by various missense mutations in the GALT gene on chromosome 9p13 for galactose-1-phosphate uridylyltransferase (GALT) which catalyzes the reaction galactose-1-phosphate →glucose-1-phosphate. 2. The various missense mutations result either in a normal glutamine S arginine substitution at position 188 (Q188R) prevalent in northern Europe; a normal serine Sleucine substitution at position 135 (S135L) prevalent in Africa; or a normal lysine Sasparagine substitution at position 285 (K285N) prevalent in Germany, Austria, and Croatia. 3. The Duarte variant allele is caused by a missense mutation which results in a normal asparagine →aspartate substitution at position 314 (N314D) which imparts instability to GALT whereby affected individuals have 5% to 20% GALT activity compared to normal individuals. 4. Prevalence. The prevalence of GAL is 1/30,000 births

Huntington Disease (HD)

Clinical features include: age of onset is 35 to 44 years of age, mean survival time is 15 to 18 years after onset, a movement jerkiness most apparent at movement termination, chorea (dancelike movements), memory deficits, affective disturbances, personality changes, dementia, diffuse and marked atrophy of the neostriatum due to cell death of cholinergic neurons and GABA-ergic neurons within the striatum (caudate nucleus and putamen) and a relative increase in dopaminergic neuron activity, and neuronal intranuclear aggregates. The disorder is protracted and invariably fatal. In HD, homozygotes are not more severely affected by the disorder than heterozygotes, which is an exception in autosomal dominant disorders. an autosomal dominant genetic disorder caused by a 36 S 100_ unstable repeat sequence of (CAG)n in the coding sequence of the HD gene on chromosome 4p16.3 for the Huntington protein, which is a widely expressed cytoplasmic protein present in neurons within the striatum, cerebral cortex, and cerebellum, although its precise function is unknown. 2. Because CAG codes for the amino acid glutamine, a long tract of glutamines (a polyglutamine tract) will be inserted into the Huntington protein and cause protein aggregates to form within certain cells (such as implicated in other neurodegenerative disorders). 3. Normal HD alleles have _26 repeats. They are stably transmitted without any decrease or increase in repeat number. 4. Premutation HD alleles have 27 to 35 repeats. They are not stably transmitted. Individuals with permutation HD alleles are at risk for having children with HD. A child with HD inherits the expanded repeat from the father. 5. An inverse correlation exists between the number of CAG repeats and the age of HD onset: 60 to 100 CAG repeats _juvenile onset of HD and 36 to 55 CAG repeats _adult onset of HD. 6. Prevalence. The prevalence of HD is 3 to 7/100,000 in populations of western European descent. HD is less common in Japan, China, Finland, and Africa.

vwf

Clinical features include: can be diagnosed at any age; lifelong easy bruising; nose bleeding (epistaxis); skin bleeding; prolonged bleeding from mucosal surfaces; heavy menstrual bleeding; and mild to moderately severe bleeding symptoms, while some patients are asymptomatic. A. VWD is a genetic disorder caused by a mutation in the VWF gene on chromosome 12p13.3 for von Willebrand factor (vWF). B. VWD is the most common inherited bleeding disorder. However, only a small number of patients come to medical attention because of bleeding symptoms. C. vWF participates in the intrinsic pathway of hemostasis (blood clotting) in the following way: vWf acts as a carrier protein for factor VIII; forms a bridge between vascular subendothelial connective tissue and platelets by binding to the platelet receptor Gp1b at sites of endothelial damage. D. The majority of mutations causing VWD are still undefined. A database of mutations is available at http://www.ragtimedesign.com/vwf/mutations. A mutation that has been reported in a number of patients is a missense mutation, which results in a normal cysteine Sarginine at position 386 (C386R). E. VWD is defined by a reduced synthesis or reduced functionality of vWF. F. Prevalence. The prevalence of VWD is 1/10,000 worldwide. The prevalence of VWD is 1/1,200 births in the Veneto region in northern Italy. G. There are three clinically significant forms of VWD: 1. Type 1 VWD. a. Type 1 VWD is an autosomal dominant genetic disorder. b. Type 1 VWD results from a reduced synthesis of vW. c. Type 1 VWD accounts for 75% of the cases (i.e., the most common type of VWD).

pcd

Clinical features include: chronic cough; chronic rhinitis; chronic sinusitis; chronic/ recurrent ear infections; recurrent sinus/pulmonary infections due to a defect of cilia in the respiratory pathways; neonatal respiratory distress; digital clubbing; sterility in males (retarded sperm movement); situs inversus totalis (mirror-image reversal of all visceral organs with no apparent consequences; PCD with situs inversus totalis is called Kartagener syndrome); heterotaxy (discordance of right and left patterns of ordinarily asymmetrical structures with significant malformations; for example asplenia or polysplenia); the gold standard diagnostic test is the appearance of ciliary ultrastructural defects obtained by electron microscopy of a respiratory epithelium biopsy. autosomal recessive genetic disorder caused by missense, nonsense, splice site, insertion, and deletion mutations where at least two different genes have been implicated thus far: a. DNAH5 gene on chromosome 5p15-p14 for ciliary dynein axonemal heavy chain 5. This mutation occurs in 28% of the cases. b. DNAI1 gene on chromosome 9p21-p13 for dynein axonemal intermediate chain 1. This mutation occurs in 10% of the cases. c. _60% of PCD affected individuals do not have mutations in the DNAH5 gene or DNAI1 gene. It is speculated that mutations in other genes on chromosomes 15q24-25, 15q13.1-q15.1, 16p12.1-p12.2, and 19q13.42-q13.43 for dynein light chains, spoke head proteins, and other axonemal proteins may be causative. 2. These mutations result in defective outer dynein arms that results in cilia that are immotile (ciliary immotility), beat abnormally (ciliary dyskinesia), or are absent (ciliary aplasia). 3. PCD affected individuals inherit the mutant genes from the parents who are obligate asymptomatic heterozygotes. 4. Prevalence. The prevalence of PCD is 1/12,000 to 17,000 births in the US population.

Hereditary Tyrosinemia Type I (TYRI).

Clinical features include: diagnosis is based on detection of elevated plasma succinylacetone concentration; elevated plasma tyrosine, methionine, and phenylalanine concentrations; elevated urinary tyrosine metabolite (e.g., hydroxyphenylpyruvate) concentration; elevated urinary _-aminolevulinic acid; cabbage-like odor; untreated children with HTI show severe liver dysfunction, renal tubular dysfunction, growth failure, and rickets. autosomal recessive genetic disorder caused by a mutation in the FAH gene on chromosome 15q23-q25 for fumarylacetoacetate hydrolase, which catalyzes the reaction fumarylacetoacetic acid →fumarate _ acetoacetate. 2. TYRI is caused by either a missense mutation, which results in a normal proline Sleucine substitution at position 261 (P261L) or RNA splicing mutations. The P261L mutation accounts for 100% of cases in the Ashkenazi Jewish population. The P261L and some RNA splicing mutations account for 60% of cases in the US population. 3. Prevalence. The prevalence of TYRI is 1/120,000 births.

Angelman syndrome (AS; happy puppet syndrome)

Clinical features include: gait ataxia (stiff, jerky, unsteady, upheld arms), seizures, happy disposition with inappropriate laughter, severe mental retardation (only 5 to 10 word vocabulary), developmental delays are noted at _6 months, and age of onset _1 year of age. AS is caused by a microdeletion of the AS/PWS region on chromosome 15q11.2-13 derived from the mother. b. AS is an example of genomic imprinting (see above). The counterpart of AS is Prader-Willi syndrome. c. The maternally inherited UBE3A allele which encodes for ubiquitin-protein ligase E3A is most likely one of the genes that is deleted in AS and results in many of the clinical features of AS. The loss of ubiquitin-protein ligase E3A disrupts the protein degradation pathway. d. Prevalence. The prevalence of AS is 1/12,000 to 20,000 births.

HFE-Associated Hereditary Hemochromatosis (HHH).

Clinical features include: excessive storage of iron in the liver, heart, skin, pancreas, joints, and testes; abdominal pain, weakness, lethargy, weight loss, and hepatic fibrosis; without therapy, symptoms appear in males at 40 to 60 years of age and in females after menopause autosomal recessive genetic disorder caused by _28 different mutations in the HFE gene on chromosome 6p21.3 for hereditary hemochromatosis protein, which is a cell surface protein, expressed as a heterodimer with ß2-microglobulin, binds the transferrin receptor 1, and reduces cellular iron uptake although the exact mechanism is unknown. 2. HHH is most commonly caused by two missense mutations that result in a normal cysteine S tyrosine substitution at position 282 (C282Y), resulting in decreased cell surface expression or that result in a normal histidine S asparagine substitution at position 63 (H63D), resulting in pH changes that affects binding to the transferrin receptor 1. 3. ≈87% of HHH affected individuals in the European population are homozygous for the C282Y mutation or are compound heterozygous (i.e., two different mutations at the same gene locus) for the C282Y and H63D mutations. 4. These mutations result in elevated transferrin-iron saturation, elevated serum ferritin concentration, and hepatic iron overload assessed by Prussian blue staining of a liver biopsy. 5. If a person has HHH decides to have a child, then the carrier risk factor becomes important. The risk that a partner of European descent is a heterozygote (Hh) is 11% (1 out of 9 individuals), due the high carrier rate in the general European population for HHH. 6. Prevalence. The prevalence of HHH is 1/200 to 500 births.

Glycogen Storage Disease Type V (GSDV; McArdle Disease).

Clinical features include: exercise-induced muscle cramps and pain, "second wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest, episodes of myoglobinuria, increased resting basal serum creatine kinase (CK) activity, onset typically occurs around 20 to 30 years of age; clumsiness, lethargy, slow movement, and laziness in preadolescents. an autosomal recessive genetic disorder caused by _46 different mutations in the PYGM gene on chromosome 11q13 for muscle glycogen phosphorylase, which initiates glycogenlinical features include: asymptomatic presence of fructose in the urine. breakdown by removing _1,4glucosyl residues from the outer branches of glycogen with liberation of glucose-1-phosphate. 2. GSDV is commonly caused by either a nonsense mutation which results in a normal arginine →nonsense at position 49 (R49X) causing a premature STOP codon (90% of cases in European and US populations) or a missense mutation which results in a normal glycine →serine substitution at position 204 (G204S; 10% of cases in European and US populations). 3. Prevalence. The prevalence of GSDV is 1/100,000 births.

22q11.2 Deletion syndrome (DS)

Clinical features include: facial anomalies resembling first arch syndrome (micrognathia, low-set ears) due to abnormal neural crest cell migration, cardiovascular anomalies due to abnormal neural crest cell migration during formation of the aorticopulmonary septum (e.g., Tetralogy of Fallot), velopharyngeal incompetence, cleft palate, immunodeficiency due to thymic hypoplasia, hypocalcemia due to parathyroid hypoplasia, and embryological formation of pharyngeal pouches 3 and 4 fail to differentiate into the thymus and parathyroid glands. DS is caused by a microdeletion of the DiGeorge chromosomal critical region (DGCR) on chromosome 22q11.2. _90% of DS individuals have a de novo deletion b. The TBX1 gene, which encodes for T-box transcription factor TBX10 protein is most likely one of the genes that is deleted in DS and results in some of the clinical features of DS. c. DS encompasses the phenotypes previously called DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, Opitz g/BBB syndrome, and Cayler cardiofacial syndrome. d. Prevalence. The prevalence of DS is 1/6,000 births in the U.S. population.

Williams syndrome (WS)

Clinical features include: facial dysmorphology (e.g., prominent lips, wide mouth, periorbital fullness of subcutaneous tissues, short palpebral tissues, short upturned nose, long philtrum), cardiovascular disease (e.g., elastin arteriopathy, supravalvular aortic stenosis, pulmonic valvular stenosis, hypertension, septal defects), endocrine abnormalities (e.g., hypercalcemia, hypercalciuria, hypothyroidism, early puberty), prenatal growth deficiency, failure to thrive in infancy, connective tissue abnormalities (e.g., hoarse voice, hernias, rectal prolapse, joint and skin laxity), and mild mental deficiency with uneven cognitive disabilities is caused by a microdeletion of the Williams-Beuren syndrome critical region (WBSCR) on chromosome 7q11.23. _90% of WS individuals have a de novo deletion b. The ELN gene (elastin) which encodes for the elastin protein is most likely one of the genes that is deleted in WS and results in some of the clinical features of WS. c. The LIMK1 gene, which encodes for a brain-expressed lim kinase 1 protein is another likely gene that is deleted in WS and results in some of the clinical features of WS. d. Prevalence. The prevalence of WS is 1/7,500 in a Norway population.

Asymptomatic Fructosuria (AF; or Essential Fructosuria).

Clinical features include: failure to thrive, fructosuria, hepatomegaly, jaundice, aminoaciduria, metabolic acidosis, lactic acidosis, low urine ketones, recurrent hypoglycemia and vomiting at the age of weaning when fructose or sucrose (a disaccharide that is hydrolyzed to glucose and fructose) is added to the diet; infants and adults are asymptomatic until they ingest fructose or sucrose. autosomal recessive genetic disorder caused by a mutation in the KHK gene on chromosome 2p23.3-p23.2 for ketohexokinase (or fructokinase) which catalyzes the reaction fructose →fructose-1-phosphate. 2. C C. Hereditary Fructose Intolerance (HFI; Fructosemia). 1. HFI is an autosomal recessive genetic disorder caused by a mutation in the ALDOB gene on chromosome 9q21.3-q22.2 for fructose 1-phosphate aldolase B, which catalyzes the reaction fructose 1-phosphate →dihydroxyacetone phosphate _ D-glyceraldehyde. 2. The most likely mechanism causing the clinical features of HFI is that the PO4 3_ group gets sequestered on fructose and therefore is not available for ATP synthesis. 3. Prevalence. The prevalence of HFI is 1/20,000 births.

Trisomy 18 (Edwards syndrome; 47,_18)

Clinical features include: mental retardation, congenital heart defects, small facies and prominent occiput, overlapping fingers, cleft lip and/or palate, and rocker-bottom heels. is a trisomic disorder caused by an extra chromosome 18. b. Prevalence. The prevalence of trisomy 18 is 1/5,000 live births. Live births usually die by _2 month of age. Most trisomy 18 conceptions spontaneously abort.

. Medium-Chain Acyl-coenzyme A Dehydrogenase (MCAD) Deficiency

Clinical features include: hyperketotic hypoglycemia, vomiting, and lethargy triggered by either a common illness (e.g., viral gastrointestinal or upper respiratory tract infections) or prolonged fasting (e.g., weaning the infant from nighttime feedings) which may quickly progress to coma and death; hepatomegaly and acute liver disease; children are normal at birth and present between 3 and 24 months of age; later presentation into adulthood is possible. autosomal recessive genetic disorder caused by _45 different mutations in the ACADM gene on chromosome 1p31 for medium-chain acyl-coenzyme A dehydrogenase (MCAD) which catalyzes the initial dehydrogenation of acyl-CoAs with a fatty acid chain length of 4 to 12 carbon atoms. 2. The ACADM gene is a nuclear gene that codes for MCAD enzyme, which is active in the mitochondria and part of the mitochondrial fatty acid ß-oxidation pathway. A defect in MCAD leads to an accumulation of medium-chain fatty acids, which are further metabolized to glycine-esters, carnitine-esters, and dicarboxylic acids (all of which are detectable in blood, urine, and bile). 3. The mitochondrial fatty acid _-oxidation pathway normally fuels hepatic ketogenesis, which is a major source of energy when hepatic glycogen stores are depleted during prolonged fasting or high energy demands. 4. MCAD deficiency is caused by a missense mutation which results in a normal lysine S glutamate substitution at position 304 (K304E) prevalent in the Northern European population. 5. Prevalence. The prevalence of MCAD is 1/15,700 births in the US population. MCAD is especially prevalent in Caucasians of Northern European descent.

Bloom syndrome (BS)

Clinical features include: hypersensitivity to DNA-damaging agents, long, narrow face, erythema with telangiectasias in butterfly distribution over the nose and cheeks, highpitched voice, small stature, small mandible, protuberant ears, absence of upper lateral incisors, well-demarcated patches of hypopigmentation and hyperpigmentation, immunodeficiency with decreased IgA, IgM, and IgG levels, and predisposition to several types of cancers. a. BS is an autosomal recessive genetic disorder caused by mutations DNA repair enzymes on chromosome 15q26 which results in individuals who are hypersensitive to DNAdamaging agents. b. The BLM gene is one of the genes involved in the cause of BS. The BLM gene located on chromosome 15q26 encodes for RecQ helicase, which unwinds the DNA double helix during repair and replication. c. Prevalence. The prevalence of BS is high in the Ashkenazi Jewish population.

mtDNA-associated Leigh Syndrome (mtDNA-LS).

Clinical features include: hypotonia, spasticity, movement disorders, cerebellar ataxia, periphery neuropathy, signs of basal ganglia disease, hypertrophic cardiomyopathy, raised lactic acid concentration in blood and cerebrospinal fluid, death occurs by 2 to 3 years of age, and onset occurs at 3 to 12 months of age, often following a viral infection a mitochondrial genetic disorder most commonly caused by a mutation in the MT-ATP6 gene for the Fo ATP synthase 6 subunit whereby a T S G transition occurs at nucleotide position 8993 (T8993G), which changes a highly conserved leucine to an arginine (L156R), or a T S C transition occurs at nucleotide position 8993 (T8993C), which changes a highly conserved leucine to a proline (L156P). 2. A hypothesis is that these amino acid changes in the Fo ATP synthase 6 subunit block proton (H_ ion) translocation from the intermembrane space to the mitochondrial matrix and thereby block ATP synthesis. 3. Prevalence. The prevalence of mtDNA-LS is 1/140,000

Menkes Disease (MND).

Clinical features include: infants initially appear normal up to 2 to 3 months of age but then develop hypotonia; seizures; failure to thrive; loss of developmental milestones; changes in hair (short, coarse, twisted, lightly pigmented, "steel wool" appearance); jowly facial appearance with sagging cheeks; temperature instability; hypoglycemia; urinary bladder diverticulae; and gastric polyps. Without early treatment with parenteral copper, MND progresses to severe neurodegeneration and death by 7 months →3 years of age. MND is an X-linked recessive genetic disorder caused by various mutations in the ATP7A gene on chromosome Xq12-q13 for Copper-Transporting ATPase 1, which is a P-type ATPase that transports copper across cell membranes thereby controlling copper homeostasis. 2. MND is commonly caused by small insertion and deletion mutations (35%), nonsense mutations (20%); RNA splicing mutations (15%), and missense mutations (8%). 3. These mutations result in low serum concentration of copper (0 to 60 g/dL vs. 70 to 150 g/dL normal), low serum concentration of ceruloplasmin (30 to 150 mg/dL vs. 200 to 450 mg/dL normal), a decreased intestinal absorption of copper, an accumulation of copper in some tissues, and a decreased activity of copper-dependent enzymes (e.g., dopamine ß-hydroxylase critical for catecholamine synthesis or lysyl oxidase). 4. Prevalence. The prevalence of MND is 1/1,000,000 births.

Ataxia-telangiectasia (AT)

Clinical features include: ionizing radiation hypersensitivity, cerebellar ataxia with depletion of Purkinje cells, progressive nystagmus, slurred speech, oculocutaneous telangiectasia initially in the bulbar conjunctiva followed by ear, eyelid, cheeks, and neck, immunodeficiency, and death in the second decade of life. A high frequency of structural rearrangements of chromosomes 7 and 14 is the cytogenetic observation with this disease. autosomal recessive genetic disorder caused by mutations in DNA recombination repair enzymes on chromosome 11q22-q23, which results in individuals who are hypersensitive to ionizing radiation. b. The ATMgene (AT mutated) is one of the genes involved in the cause of AT. The ATMgene located on chromosome 11q22 encodes for a protein where one region resembles a PI-3 kinase (phosphatidylinositol-3 kinase) and another region resembles a DNA repair enzyme/cell cycle checkpoint protein. c. Prevalence. The prevalence of AT is 1/20,000 to 100,000 in the U.S. population.

Miller-Dieker syndrome (MD; agyria; lissencephaly)

Clinical features include: lissencephaly (smooth brain, i.e., no gyri), microcephaly, a high and furrowing forehead, death occurs early. Lissencephaly should not be mistakenly diagnosed in the case of premature infants whose brains have not yet developed an adult pattern of gyri (gyri begin to appear normally at about week 28). . MD is caused by a microdeletion on chromosome 17p13.3. b. The LIS1 gene (lissencephaly) which encodes for the LIS1 protein is most likely one of the genes that is deleted in MD and results in some of the clinical features of MD. The LIS1 protein contains a coiled-coil domain and a tryptophan-aspartate repeat domain both of which interact with microtubules and multiprotein complexes within migrating neurons. c. The 14-3-3_ gene, which encodes for the 14-3-3_ protein is another likely gene deleted in MD and results in some of the clinical features of MD. The 14-3-3_ protein phosphorylated serine and phosphorylated threonine domains both of which interact with microtubules and multiprotein complexes within migrating neurons. d. Prevalence. The prevalence of MD is unknown

Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome (MELAS).

Clinical features include: mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. MELAS is a mitochondrial genetic disorder caused by a mutation in the tRNALeu gene whereby an A S G transition occurs at nucleotide position 3243 (A3243G). 2. The mutated tRNALeu causes a reduction in the amount and the aminoacylation of the mutated tRNALeu, a reduction in the association of mRNA with ribosomes, and altered incorporation of leucine into mitochondrial enzymes. 3. Mitochondrial enzymes with a large number of leucine residues will have a low probability of being completely synthesized. In this regard, cytochrome oxidase (Complex IV) has been shown to be synthesized at very low rates. 4. Heteroplasmy is common and expression of the disease is highly variable. 5. Prevalence. The prevalence of MELAS is 1/6,250 in northern Finland

Trisomy 21 (Down syndrome; 47,_21)

Clinical features include: moderate mental retardation (the leading cause of mental retardation), microcephaly, microphthalmia, colobomata, cataracts and glaucoma, flat nasal bridge, epicanthal folds, protruding tongue, simian crease in hand, increased nuchal skin folds, appearance of an "X" across the face when the baby cries, and congenital heart defects. Alzheimer neurofibrillary tangles and plaques are found in trisomy 21 patients after 30 years of age. A condition mimicking acute megakaryocytic leukemia (AMKL) frequently occurs in children with trisomy 21 and they are at increased risk for developing acute lymphoblastic leukemia (ALL). Trisomy 21 is a trisomic disorder caused by an extra chromosome 21. Trisomy 21 is linked to a specific region on chromosome 21 called the DSCR (Down syndrome critical region). Trisomy 21 may also be caused by a specific type of translocation, called a Robertsonian translocation that occurs between acrocentric chromosomes. b. Prevalence. The prevalence of trisomy 21 is 1/2,000 conceptions for women _25 years of age, 1/300 conceptions for women _35 years of age, and 1/100 conceptions in women _40 years of age. Trisomy 21 frequency increases with advanced maternal age.

Myotonic Dystrophy Type 1

Clinical features include: muscle weakness and wasting, myotonia (delayed muscle relaxation after contraction), cataracts, cardiomyopathy with conduction defects, multiple endocrinopathies, age of onset is 2 to 30 years of age, and low intelligence or dementia. . DM1 is an autosomal dominant genetic disorder caused by a _35 to 1,000 unstable repeat sequence of (CTG)n in the 3'UTR region of the DMPK gene on chromosome 19q13.2-q13.3 for myotonin-protein kinase which is a serine-threonine protein kinase associated with intercellular conduction and impulse transmission in the heart and skeletal muscle. 2. A hypothesis is that DM1 is caused by a gain-of-function RNA mechanism in which the alternate splicing of other genes (e.g., Cl_ ion channels, insulin receptor) occurs. 3. Normal DMPK alleles have _5 to 35 repeats. They are stably transmitted without any decrease or increase in repeat number. 4. Premutation DMPK alleles have _35 to 49 repeats. They are not stably transmitted. Individuals with permutation DMPK alleles are at risk for having children with DM1. A child with severe DM1 (i.e., congenital DM1) most frequently inherits the expanded repeat from the mother. 5. Prevalence. The prevalence of DM1 is 1/100,000 in Japan, 1/10,000 in Iceland, and 1/20,000 worldwide.

Myoclonic epilepsy with ragged red fibers syndrome (MERRF

Clinical features include: myoclonus (muscle twitching), seizures, cerebellar ataxia, dementia, and mitochondrial myopathy (abnormal mitochondria within skeletal muscle that impart an irregular shape and blotchy red appearance to the muscle cells, hence the term ragged red fibers). a mitochondrial genetic disorder caused by caused by a mutation in the tRNALys gene whereby an A S G transition occurs at nucleotide position 8344 (A8344G). 2. The mutated tRNALys causes a premature termination of translation of the amino acid chain (the amount and the aminoacylation activity of the mutated tRNALys is not affected). 3. Mitochondrial enzymes with a large number lysine residues will have a low probability of being completely synthesized. In this regard, NADH dehydrogenase (Complex I) and cytochrome oxidase (Complex IV) both of which have a large number of lysine residues have been shown to be synthesized at very low rates. 4. Heteroplasmy is common and expression of the disease is highly variable. 5. Prevalence. The prevalence of MERRF is 1/100,000 in northern Finland, 1/400,000 in northern England, and 1/400,000 in western Sweden.

Type 1 Diabetes

Clinical features include: neuropathy, retinopathy leading to blindness, and nephropathy leading to kidney failure. The characteristic dysfunction in this disorder is an autoimmune destruction of pancreatic beta cells that produce insulin. This results clinically in hyperglycemia, ketoacidosis, and exogenous insulin dependence. 2. Type 1 diabetes demonstrates an association with the highly polymorphic HLA (human leukocyte antigen) class II genes, which play a role in immune responsiveness and account for _40% of familial clustering of Type 1diabetes. The specific loci involved in Type 1 diabetes are called HLA-DR3 and HLA-DR4 loci located on chromosome 6p. HLA-DR3 and HLADR4 loci code for MHC Class II cell-surface glycoproteins that are expressed on antigenpresenting cells (e.g., macrophages). _90% of Type 1 diabetic patients carry either the HLA DR3-DQ2 allele or the HLA DR4-DQ8 allele. 3. It is hypothesized that alleles closely linked to HLA-DR3 and HLA-DR4 loci somehow alter the immune response such that the individual has an immune response to an environmental antigen (e.g., virus). The immune response "spills over" and leads to the destruction of pancreatic beta cells. Markers for immune destruction of pancreatic beta cells include autoantibodies to glutamic acid decarboxylase (GAD65), insulin, and tyrosine phosphatases IA-2 and IA-2_. At present, it is not known whether the autoantibodies play a causative role in the destruction of the pancreatic beta cell, or whether the autoantibodies form secondarily after the pancreatic beta cells have been destroyed

Hereditary nonpolyposis colorectal cancer (HNPCC)

Clinical features include: onset of colorectal cancer at a young age, high frequency of carcinomas proximal to the splenic flexure, multiple synchronous or metachronous colorectal cancers, and presence of extracolonic cancers (e.g., endometrial and ovarian cancer, adenocarcinomas of the stomach, small intestine, and hepatobiliary tract), and accounts for 3% to 5% of all colorectal cancers. autosomal dominant genetic disorder caused by mutations in DNA mismatch repair enzymes, which results in the inability to remove single nucleotide mismatches or loops that occur in microsatellite repeat areas. b. The four genes involved in the cause of HNPCC include: i. MLH1 gene located on chromosome 3p21.3 which encodes for DNA mismatch repair proteinMlh1. ii. MSH2 gene located on chromosome 2p22-p21, which encodes for DNA mismatch repair protein Msh2 iii. MSH6 gene located on chromosome 2p16 which encodes for DNA mismatch repair protein Msh6 iv. PMS2 gene located on chromosome 7p22 which encodes for PMS1 protein homolog 2. c. These genes are the human homologues to the Escherichia coli mutS gene and mutl gene that code for DNA mismatch repair enzymes. d. Prevalence. HNPCC accounts for 1% to 3% of colon cancers and _1% of endometrial cancers.

Acute promyelocytic leukemia (APL) t(15;17)(q22;q21)

Clinical features include: pancytopenia (i.e., anemia, neutropenia, and thrombocytopenia), including weakness and easy fatigue, infections of variable severity, and/or hemorrhagic findings (e.g., gingival bleeding, ecchymoses, epistaxis, or menorrhagia), and bleeding secondary to disseminated intravascular coagulation. A rapid cytogenetic diagnosis of this leukemia is essential for patient management because these patients are at an extremely high risk for stroke. . APL t(15;17)(q22;q21) is caused by a reciprocal translocation between chromosomes 15 and 17 with breakpoints at bands q22 and q21, respectively. b. This results in a fusion of the promyelocyte gene (PML gene) on 15q22 with the retinoic acid receptor gene (RAR_ gene) on 17q21, thereby forming the PML/RAR_ oncogene. c. The PML/RAR_ oncoprotein (a transcription factor) blocks the differentiation of promyelocytes to mature granulocytes such that there is continued proliferation of promyelocytes.

Prader-Willi syndrome (PW)

Clinical features include: poor feeding and hypotonia at birth, but then followed by hyperphagia (insatiable appetite), hypogonadism, obesity, short stature, small hands and feet, behavior problems (rage, violence), and mild-to-moderate mental retardation. PW is caused by a microdeletion of the Prader-Willi critical region (PWCR) on chromosome 15q11.2-13 derived from the father. b. PW illustrates the phenomenon of genomic imprinting which is the differential expression of genes depending on the parent of origin. The mechanism of inactivation (or genomic imprinting) involves DNA methylation of cytosine nucleotides during gametogenesis resulting in transcriptional inactivation. c. The counterpart of PW is Angelman syndrome. Other examples that highlight the role of genomic imprinting include complete hydatidiform moles and Beckwith-Wiedemann syndrome (BWS) (see Chapter 1IV). d. The paternally inherited SNRPN allele, which encodes for a small nuclear ribonucleoprotein- associated N protein is most likely one of the genes that is deleted in PW and results in some of the clinical features of PW. d. Prevalence. The prevalence of PW is 1/10,000 to 25,000 births.

Familial Hypercholesterolemia (FH).

Clinical features include: premature heart disease as a result of atheromas (deposits of LDL-derived cholesterol in the coronary arteries); xanthomas (cholesterol deposits in the skin and tendons); arcus lipoides (deposits of cholesterol around the cornea of the eye); homozygote and heterozygote phenotypes are known; homozygotes develop severe symptoms early in life and rarely live past 30 years of age; heterozygotes have plasma cholesterol level twice that of normal. autosomal dominant genetic disorder caused by _400 different mutations in the LDLR gene on chromosome 19p13.1-13.3 for the low-density lipoprotein receptor which binds LDL and delivers LDL into the cell cytoplasm. 2. Mutations in the LDLR gene are grouped into 6 classes: a. Class 1 mutations prevent LDLR synthesis. b. Class 2 mutations prevent LDLR transport to the cell membrane. c. Class 3 mutations prevent LDL binding to LDLR. d. Class 4 mutations prevent LDL internalization into the cell cytoplasm by coated pits. e. Class 5 mutations prevent LDLR recycling back to the cell membrane after LDL _LDLR dissociation. f. Class 6 mutations prevent LDLR targeting to the apical membrane adjacent to the blood capillaries. 3. Other genes associated with FH include: a. FH is also an autosomal dominant genetic disorder caused by a mutation in the APOB gene on chromosome 2p23-p24 for apolipoprotein B-100 which is a component of LDL and the ligand for LDLR. The prevalence of APOB gene homozygotes is 1/1,000,000 births. The prevalence of APOB gene heterozygotes is 1/1,000 births in Caucasians of European descent. b. FH is also an autosomal dominant genetic disorder caused by a missense, gain-offunction mutations in the PCSK9 gene on chromosome 1p32-p34.1 for proprotein convertase subtilisin/kexin type 9. The increased PCSK9 protease activity degrades LDLR leading to hypercholesterolemia. This type of FH is very rare. c. The Tyr142Stop and Cys679Stop nonsense mutations in the PCSK9 gene are loss-of-function mutations. The decreased PCSK9 protease activity has been associated with a 40% reduction in LDL cholesterol (i.e., hypocholesterolemia) and a 90% reduced risk of coronary artery disease in 2.6% of the African American population. d. The Arg46Leu mutation in the PCSK9 gene is a loss-of-function mutation. The decreased PCSK9 protease activity has been associated with a 15% reduction in LDL cholesterol (i.e., hypocholesterolemia) and 50% reduced risk of coronary artery disease in 3.2% of whites in the US population. 4. Prevalence. The prevalence of LDLR gene homozygotes is 1/1,000,000 births. The prevalence of LDLR gene heterozygotes is 1/500 births. Most cases of hypercholesterolemia and hyperlipoproteinemia in the general population are of multifactorial origin.

Trisomy 13 (Patau syndrome; 47,_13)

Clinical features include: profound mental retardation, congenital heart defects, cleft lip and/or palate, omphalocele, scalp defects, and polydactyly. a. Trisomy 13 is a trisomic disorder caused by an extra chromosome 13. b. Prevalence. The prevalence of trisomy 13 is 1/20,000 live births. Live births usually die by _1 month of age. Most trisomy 13 conceptions spontaneously abort.

Spinocerebellar Ataxia Type 3 (SCA3, Machado-Joseph Disease).

Clinical features include: progressive cerebellar ataxia, dysarthria, bulbar dysfunction, extrapyramidal features including rigidity and dystonia, upper and lower motor neuron signs, cognitive impairments, age of onset is 20 to 50 years of age, individuals become wheelchair bound, and nuclear inclusions are found. autosomal dominant genetic disorder caused a 52 to 86 repeat sequence of (CAG)n in coding sequence of the ATXN3 gene on chromosome 14q24.3-q31 for the ataxin 3 protein, which is a ubiquitin-specific protease that binds and cleaves ubiquitin chains and thereby participates in protein quality control pathways in the cell. 2. A hypothesis is that SCA3 is caused by impaired protein clearance because mutant ataxin 3 forms nuclear inclusions that contain elements of the refolding and degradation machinery of the cell (i.e., chaperone and proteosome subunits). 3. Normal ATXN3 alleles have _44 repeats. 4. Premutation ATXN3 alleles have not been reported to date. 5. Prevalence. The prevalence of SCA3 in not known. Using a system based on genetic loci, numerous autosomal dominant ataxias have been classified (SCA1-26) and the numbers continue to grow. In general, all autosomal dominant ataxias are rare.

Spinal and Bulbar Muscular Atrophy (SBMA, Kennedy Syndrome

Clinical features include: progressive loss of anterior motor neurons, proximal muscle weakness, muscle atrophy, muscle fasciculations, difficulty in swallowing and speech articulation, late-onset gynecomastia, defective spermatogenesis with reduced fertility, testicular atrophy, and a hormonal profile consistent with androgen resistance. X-linked recessive genetic disorder caused by a _38 repeat sequence of (CAG)n in the coding sequence of the AR gene on chromosome Xq11-q12 for the androgen receptor which is a member of the steroid-thyroid-retinoid superfamily of nuclear receptors and expressed in the brain, spinal cord, and muscle. 2. A hypothesis is that SBMA is caused by a gain-of-function mutation because there is a well-known syndrome called complete androgen insensitivity that is caused by a loss-offunction mutation in the AR gene. 3. Normal AR alleles have _34 repeats. 4. Premutation AR alleles have not been reported to date. 5. Prevalence. The prevalence of SBMA is _1/50,000 live males in the Caucasian and Asian population. SBMA occurs only in males

Leber's Hereditary Optic Neuropathy (LHON).

Clinical features include: progressive optic nerve degeneration that results clinically in blindness, blurred vision, or loss of central vision; telangiectatic microangiopathy; disk pseudoedema; vascular tortuosity; onset occurs at _20 years of age with precipitous vision loss; and males are affected far more often than females for some unknown reason. LHON is a mitochondrial genetic disorder caused by 3 mtDNA missense mutations, which account for 90% of all cases worldwide and are therefore designated as primary LHON mutations. 2. The primary LHON mutations include the following: a. A mutation in the ND4 gene (which encodes for subunit 4 of NADH dehydrogenase; Complex I) whereby an A S G transition occurs at nucleotide position 11778 (A11778G). This is the most common cause (_50% of all LHON cases) of LHON. b. A mutation in the ND1 gene (which encodes for subunit 1 of NADH dehydrogenase; Complex I) whereby a G S A transition occurs at nucleotide position 3460 (G3460A). c. A mutation in the ND 6 gene (which encodes for subunit 6 of NADH dehydrogenase; Complex I) whereby a T S C transition occurs at nucleotide position 14484 (T14484C). 3. All 3 primary LHON mutations decrease production of ATP such that the demands of a very active neuronal metabolism cannot be met and suggest a common disease-causing mechanism. 4. Heteroplasmy is rare and expression of the disease is fairly uniform. Consequently, the family pedigree of LHON demonstrates a typical mitochondrial inheritance pattern. 5. Prevalence. Little data exist on the absolute prevalence of LHON. However, the prevalence of LHON is 1/33,000 in northern England

Chromosome 4p deletion (Wolf-Hirschhorn syndrome; WHS

Clinical features include: prominent forehead and broad nasal root ("Greek warrior helmet"), short philtrum, down-turned mouth, congenital heart defects, growth retardation, and severe mental retardation. is caused by a deletion of the Wolf-Hirschhorn critical region (WHCR) on chromosome 4p16.3 _75% of WHS individuals have a de novo deletion, 13% inherited an unbalanced chromosome rearrangement from a parent, and 12% have a ring chromosome 4. b. Prevalence. The prevalence of Wolf-Hirschhorn syndrome is 1/50,000 births, with a 2:1 female/male ratio.

Chromosome 5p deletion (Cri du chat; cat cry syndrome)

Clinical features include: round facies, a catlike cry, congenital heart defects, microcephaly, and mental retardation. a deletion of the cri du chat critical region (CDCCR) on chromosome 5p15.2 and the catlike critical region (CLCR) on chromosome 5p15.3. _80% of cri du chat individuals have a de novo deletion. In _80% of the cases, the deletions occur on the paternal chromosome 5. b. Prevalence. The prevalence of cri du chat syndrome is 1/50,000 births

Turner syndrome (Monosomy X; 45,X)

Clinical features include: short stature, low-set ears, ocular hypertelorism, ptosis, low posterior hairline, webbed neck due to a remnant of a fetal cystic hygroma, congenital hypoplasia of lymphatics causing peripheral edema of hands and feet, shield chest, pinpoint nipples, congenital heart defects, aortic coarctation, female hypogonadism, ovarian fibrous streaks (i.e., infertility), primary amenorrhea, and absence of secondary sex characteristics. Monosomy X is a monosomic sex chromosome disorder caused by a loss of part or all of the X chromosome. _66% of monosomy X females retain the maternal X chromosome and 33% retain the paternal X chromosome. _50% of monosomy X females are mosaics [e.g., 45,X/46,XX or 45,X/46, _i(Xq)]. b. Monosomy X is the only monosomic disorder compatible with life and is found only in females. c. The SHOX gene (short stature homeobox-containing gene on the X chromosome) which encodes for the short stature homeobox protein is most likely one of the genes that is deleted in Monosomy X and results in the short stature of these females. d. Prevalence. The prevalence of monosomy X is _1/2,000 live female births. There are _50,000 to 75,000 monosomy X females in the U.S. population, although true prevalence is difficult to calculate because monosomy X females with mild phenotypes remain undiagnosed. _3% of all female conceptions results in monosomy X making it the most common sex chromosome abnormality in female conceptions. However, most monosomy X female conceptions spontaneously abort.

Wilson Disease (WND

Clinical features include: symptoms occur in individuals from 3 to 50 years of age; recurrent jaundice; hepatitislike illness; fulminant hepatic failure; tremors; poor coordination; loss of fine motor control; chorea; masklike facies; rigidity; gait disturbance; depression; neurotic behaviors; Kayser-Fleischer rings (deposition of copper in Descemet's membrane of the cornea); blue lunulae of the fingernails; and high degree of copper storage in the body. autosomal recessive genetic disorder caused by _260 mutations in the ATP7B gene on chromosome 13q14.3-q21.1 for Copper-Transporting ATPase 2, which is a P type ATPase expressed mainly in the kidney and liver that plays a key role in incorporating copper into ceruloplasmin and in the release of copper into bile. 2. WND is commonly caused by either a missense mutation which results in a normal histidine S glutamine substitution at position 1069 (H1069Q), a missense mutation which results in a normal arginine Sleucine substitution at position 778 (R778L), or a 15 base pair deletion in the promoter region. 3. The H1069Q mutation accounts for 45% of cases in the European population. The R778L mutation accounts for 60% of cases in the Asian population. The 15 base pair deletion mutation is common in the Sardinian population. 4. These mutations result in high hepatic concentration of copper (_250 g/g dry weight vs. _55 g/g dry weight normal); high urinary excretion of copper (_0.6 umol/24 hours); and damage of various tissues due to excessive accumulation of copper. 5. Prevalence. The prevalence of WND is 1/30,000 in most populations. The prevalence is 1/10,000 in Chinese and Japanese populations.

Chronic myeloid leukemia (CML) t(9;22)(q34;q11.2)

Clinical features include: systemic symptoms (e.g., fatigue, malaise, weight loss, excessive sweating), abdominal fullness, bleeding episodes due to platelet dysfunction, abdominal pain may include left upper quadrant pain, early satiety due to the enlarged spleen, tenderness over the lower sternum due to an expanding bone marrow, and the uncontrolled production of maturing granulocytes, predominantly neutrophils, but also eosinophils and basophils. t(9;22)(q34;q11.2) is caused by a reciprocal translocation between chromosomes 9 and 22 with breakpoints at q34 and q11.2 respectively. The resulting der(22) is referred to as the Philadelphia chromosome. b. This results in a fusion of the ABL gene on 9q34 with the BCR gene on 22q11.1, thereby forming the ABL/BCR oncogene. c. The ABL/BCR oncoprotein (a tyrosine kinase) has enhanced tyrosine kinase activity that transforms hematopoietic precursor cells. d. Prevalence. The prevalence of CML is 1/100,000 per year with a slight male predominance.

X linked Dominant

Hypophosphatemic rickets Rett syndrome Goltz syndrome Incontinentia pigmenti Orofaciodigital syndrome

Maple Syrup Urine Disease (MSUD).

Clinical features include: untreated children with MSUD show maple syrup odor in cerumen 12 to 24 hours after birth, elevated plasma branched-chain amino acid concentration, ketonuria, irritability, poor feeding by 2 to 3 days of age, deepening encephalopathy including lethargy, intermittent apnea, opisthotonus, and stereotyped movements like "fencing" and "bicycling" by 4 to 5 days of age; acute leucine intoxication (leucinosis) associated with neurological deterioration due to the ability of leucine to interfere with the transport of other large neutral amino acids across the blood-brain barrier, thereby reducing the amino acid supply to the brain. autosomal recessive genetic disorder cause by _60 different mutations in either the BCKDHA gene on chromosome 19q13.1-q13.2 for the E1_ subunit of the branchedchain ketoacid dehydrogenase complex (BCKD), the BCKDHB gene on chromosome 6q14 for the E1ß subunit of BCKD, or the DBT gene on chromosome 1p31 for the E2 subunit of BCKD all of which catalyze the second step in the degradation of branched-chain amino acids (e.g., leucine, isoleucine, and valine). 2. The BCKD enzyme is an enzyme complex found in the mitochondria. 3. Prevalence. The prevalence of MSUD is 1/185,000 births.

Hemophilia A

Clinical features include: usually diagnosed before 1 year of age, prolonged oozing after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, large "goose eggs" after minor head bumps, abnormal bleeding after minor injuries, deep muscle hematomas, episodes of spontaneous joint bleeding are frequent, and 2 to 5 spontaneous bleeding episodes/month without adequate treatment. X-linked recessive genetic disorder caused by a mutation in the F8 gene on chromosome Xq28 for coagulation factor VIII. B. Factor VIII participates in the intrinsic pathway of hemostasis (blood clotting) in the following way: factor VIII binds to von Willebrand factor (vWF) in the circulation for stabilization (vWF acts as a carrier protein for factor VIII); factor VIII is cleaved by thrombin, released from vWF, and binds to activated platelet membranes where it interacts with factor IX; the factor VIII and factor IX interaction activates factor X (which is a critical step in early hemostasis). C. Hemophilia A is most commonly (45% of cases) caused by the F8 intron 22-A gene inversion ("flip" inversion) mutation. The remainder of cases are caused by missense, complete or partial deletions, RNA splicing, nonsense, large insertion, sequence duplications, and frameshift mutations. D. Hemophilia A is defined by a reduced factor VIII clotting activity in the presence of normal vWF levels. E. Prevalence. The prevalence of hemophilia A is 1/10,000 births in the US population. F. There are three clinically significant forms of hemophilia A: 1. Severe hemophilia A. a. Severe hemophilia A results from _1% of factor VIII clotting activity

Moderately severe hemophilia A.

Clinical features include: usually diagnosed before 5 to 6 years of age, prolonged oozing after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, abnormal bleeding after minor injuries, episodes of spontaneous joint bleeding are rare, and one bleeding episode/month →one bleeding episode/year. Moderately severe hemophilia A results from 1% to 5% of factor VIII clotting activity

Mild hemophilia A.

Clinical features include: usually diagnosed later in life, prolonged oozing after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, abnormal bleeding after major injuries, episodes of spontaneous joint bleeding are absent, and 1 bleeding episode/year →1 bleeding episode/10years. Mild hemophilia A results from 6% to 35% of factor VIII clotting activity.

Klinefelter syndrome (47, XXY)

Clinical features include: varicose veins, arterial and venous leg ulcer, scant body and pubic hair, male hypogonadism, sterility with fibrosus of seminiferous tubules, marked decrease in testosterone levels, elevated gonadotropin levels, gynecomastia, IQ slightly less than that of siblings, learning disabilities, antisocial behavior, delayed speech as a child, tall stature, and eunuchoid habitus. is a trisomic sex chromosome disorder caused by an extra X chromosome. The most common karyotype is 47,XXY but other karyotypes (e.g., 48,XXXY) and mosaics (47,XXY/ 46,XY) have been reported. b. Klinefelter syndrome is found only in males and is associated with advanced paternal age. c. Prevalence. The prevalence of Klinefelter syndrome is 1/1,000 live male births.

Mucopolysaccharidosis Type I (MPS I).

Clinical features of MPS IH (Hurler syndrome) include: infants initially appear normal up to ≈9 months of age but then develop symptoms; coarsening of facial features, thickening of alae nasi, lips, ear lobules, and tongue; corneal clouding; severe visual impairment; progressive thickening heart valves leading to mitral and aortic regurgitation; dorsolumbar kyphosis; skeletal dysplasia involving all the bones; linear growth ceases by 3 years of age; hearing loss; chronic recurrent rhinitis; severe mental retardation; and zebra bodies within neurons. autosomal recessive genetic disorder caused by _57 different mutations in the IDUA gene on chromosome 4p16.3 for _-L-iduronidase that catalyzes the reaction that removes _-L-iduronate residues from heparan sulfate and dermatan sulphate during lysosomal degradation. 2. MPS I is the prototypical mucopolysaccharidoses disorder. MPS I presents as a continuum from severe to mild clinical symptoms, and MPS I affected individuals are best described as having either severe symptoms (MPS IH; Hurler syndrome); intermediate symptoms (MPS IH/S; Hurler-Scheie syndrome); or mild symptoms (MPS IS; Scheie syndrome). 3. MPS IH (Hurler syndrome) is most commonly caused by two nonsense mutations which result in a normal tryptophan Snonsense substitution at position 402 (W402X) or in a normal glutamine Snonsense substitution at position 70 (Q70X). 4. The W402X mutation accounts for 55% of cases in the Australasian population. The Q70X mutation accounts for 65% of cases in the Scandinavian population. 5. These mutations result in elevated heparan sulphate and dermatan sulphate excretion in the urine, reduced/absent _-L-iduronidase activity, and heparan sulfate and dermatan sulfate accumulation. 6. Prevalence. The prevalence of MPS IH is 1/100,000 and of MPS IS is 1/500,000.

Hexosaminidase A Deficiency (HAD). . Acute infantile HAD (Tay-Sachs disease; TSD

Clinical features of TSD include: infants initially appear normal up to 3 to 6 months of age but then develop symptoms; progressive weakness and loss of motor skills; decreased attentiveness; increased startled response; a cherry red spot in the fovea centralis of the retina; generalized muscular hypotonia; later, progressive neurodegeneration, seizures, blindness, and spasticity occur followed by death at _2 to 4 years of age. prototypical HAD. HAD presents as a group of neurodegenerative disorders caused by lysosomal accumulation of GM2 ganglioside. 2. TSD is an autosomal recessive genetic disorder caused by mutations in the HEXA gene on chromosome 15q23-q24 for hexosaminidase _-subunit, which catalyzes the reaction that cleaves the terminal ß-linked N-acetylgalactosamine from GM2 ganglioside. 3. TSD is most commonly caused by either a 4-bp insertion in exon 11 mutation (_TATC1278) which produces a frameshift and a premature STOP codon or a RNA splicing mutation in intron 12 (_1IVS12) which produces unstable mRNAs, which are probably rapidly degraded. 4. The _TATC1278 and the _1IVS12 mutations account for _95% of cases in the Ashkenazi Jewish population. These mutations result in absent/near absent hexosaminidase A activity and GM2 ganglioside accumulation. 5. Prevalence. The prevalence of TSD is 1/324,000 births in the Ashkenazi Jewish population since the advent of population-based carrier screening. The prevalence of TSD was 1/3,600 births in the Ashkenazi Jewish population before the advent of population-based carrier screening.

Gaucher Disease (GD).

Clinical features of Type I GD include: bone disease (e.g., focal lytic lesions, sclerotic lesions, osteonecrosis) is the most debilitating pathology of Type I GD; hepatomegaly; splenomegaly; cytopenia and anemia due to hypersplenism, splenic sequestration, and decreased erythropoiesis; and pulmonary disease (e.g., interstitial lung disease, alveolar/ lobar consolidation; pulmonary hypertension); no primary CNS involvement. 1. GD is an autosomal recessive genetic disorder caused by mutations in the GBA gene on chromosome 1q21 for _-glucosylceramidase, which hydrolyzes glucocerebroside into glucose and ceramide. 2. GD is the most common lysosomal storage disorder. GD presents as a continuum of clinical symptoms and is divided into three major clinical types (Types 1, 2, and 3) which is useful in determining prognosis and management of the individual. 3. GD is most commonly caused by either a missense mutation which results in a normal asparagine S serine substitution at position 370 (N370S), a missense mutation which results in a normal leucine S proline substitution at position 444 (L444P), a 84GG mutation, or a IVS2+1 mutation. 4. The N370S, L444P, 84GG, and IVS2_1 mutations account for 95% of cases in the Ashkenazi Jewish population. These mutations result in absent/near absent ß-glucosylceramidase activity and glucosylceramide (and other glycolipids) accumulation. 5. If one parent has GD (gg), the risk that a partner of Ashkenazi Jewish descent is a heterozygote is _5% (1 out of 18 individuals) due the high carrier rate in the general Ashkenazi Jewish population. 6. Prevalence. The prevalence of Type I GD is 1/855 in the Ashkenazi Jewish population

Phenylalanine Hydroxylase (PAH) Deficiency (or PKU).

Clinical features of classic PKU include: no physical signs are apparent in neonates with PAH deficiency; diagnosis is based on detection of elevated plasma phenylalanine concentration (_1,000 umol/L for classic PKU) and normal BH4 cofactor metabolism; a dietary phenylalanine tolerance of _500 mg/day; untreated children with classic PKU show impaired brain development, microcephaly, epilepsy, severe mental retardation, behavioral problems, depression, anxiety, musty body odor, and skin conditions like eczema. PAH deficiency is an autosomal recessive genetic disorder caused by a mutation in the PAH gene on chromosome 12q23.2 for phenylalanine hydroxylase which catalyzes the reaction phenylalanine →tyrosine. 2. PAH deficiency is caused by missense (most common; 62% of cases); small deletion (13% of cases); RNA splicing (11% of cases); silent (6% cases); nonsense (5% of cases); or insertion (2% of cases) mutations. 3. PAH deficiency results in an intolerance to the dietary intake of phenylalanine (an essential amino acid). This produces a variability in metabolic phenotypes including classic phenylketonuria (PKU), non-PKU hyperphenylalaninemia, and variant PKU. This variability in metabolic phenotypes is caused primarily by different mutations in the PAH gene that result in variations in the kinetics of phenylalanine uptake, permeability of the blood-brain barrier, and protein folding. 4. Classic PKU is associated with the complete absence of PAH and is the most severe of the three types of PAH deficiency. 5. Prevalence. The prevalence of PAH deficiency is 1/10,000 births in the Caucasian population and 1/200,000 in the Ashkenazi Jewish population. Since the advent of universal newborn screening, symptomatic classic PKU is rarely seen.

Lactose Intolerance (LI; Lactase Nonpersistence; Adult-Type Hypolactasia

Clinical findings of lactose intolerance include: diarrhea, crampy abdominal pain localized to the periumbilical area or lower quadrant, flatulence, nausea, vomiting, audible borborygmi, stools that are bulky, frothy, and watery, and bloating after milk or lactose consumption. . LI is an autosomal recessive genetic disorder associated with short tandem repeat polymorphisms (STRPs) in the promoter region that affects transcriptional activity of the LCT gene on chromosome 2q21 for lactase-phlorizin hydrolase which catalyzes the reaction lactose →glucose _ galactose. 2. These STRPs in the human population lead to two distinct phenotypes: lactase persistent individuals and lactase nonpersistent individuals. 3. All healthy newborn children up to the age of _5 to 7 years of age have high levels of lactase- phlorizin hydrolase activity so that they can digest large quantities of lactose present in milk. 4. Northern European adults (particularly Scandinavian) retain high levels of lactasephlorizin activity and are known as lactase persistent and therefore lactose tolerant. 5. However, a majority of the world's adults (particularly in Africa and Asia) lose the high levels of lactase-phlorizin activity and are known as lactase nonpersistent and therefore lactose intolerant.

Heart Disease

Some genes known to play a role in heart disease are involved with the regulation of lipoproteins in the circulation. There are a number of risk factors for heart disease (e.g., cigarette smoking, obesity, hypertension, high cholesterol, and a positive family history). The risk of developing heart disease increases in an individual who has: 1. A first-degree affected male relative (recurrence risk _ _2_ the general population risk) 2. A first-degree affected female (least affected sex) relative (recurrence risk _2_the general population risk) 3. Many affected relatives (recurrence risk _2_ the general population risk) 4. Affected relative or relatives who were diagnosed with heart disease at _55 years of age (recurrence risk _2_ the general population risk)

Other urea cycle disorders

These include: carbamoylphosphate synthetase I (CPSI) deficiency; argininosuccinic acid synthetase (ASS) deficiency (or citrullinemia type I); argininosuccinic acid lyase (ASL) deficiency (or argininosuccinic aciduria); arginase (ARG) deficiency (or hyperargininemia); and N-acetyl glutamate synthetase (NAGS) deficiency.

Other Glycogen Storage Diseases

These include: glycogen storage disease type II (GSDII; Pompe); glycogen storage disease type IIIa (GSDIIIa; Cori); glycogen storage disease type IV (GSDIV; Andersen); glycogen storage disease type VI (GSDVI; Hers); and glycogen storage disease type VII (GSDVII; Tarui).

Type 2 Diabetes

Type 2 diabetes accounts for _90% of all cases of diabetes. In contrast to Type 1 diabetes, there is almost always some insulin production. Type 2 diabetics develop insulin resistance, a condition where the cells have reduced ability to use insulin. 2. The disorder typically occurs in adults over 40 with the greatest risk factors being obesity and a family history. Type 2 diabetes can usually be treated effectively by a combination of diet modification and exercise. A regular exercise regimen can substantially reduce the risk of developing the disorder, even in those with a family history. This is because regular exercise helps prevent weight gain but it also aids in preventing the development of insulin resistance. 3. There is a strong genetic component to Type 2 diabetes because the concordance rate in MZ twins is _90%. The recurrence risk for first-degree relatives is high (15% →40%). Populations that have adopted Western diet and activity patterns show an increased incidence of the disorder, most likely due to an increase in obesity. 4. A number of genes have been linked to Type 2 diabetes but the genetic component of the disorder is not completely understood.

WAGR syndrome

Wilms tumor, aniridia (absence of the iris), genitourinary abnormalities (e.g., gonadoblastoma), and mental retardation. Wilms tumor is the most common renal malignancy of childhood, which usually presents between 1 to 3 years of age. WT presents as a large, solitary, well-circumscribed mass that on cut section is soft, homogeneous, and tan-gray in color. WT is interesting histologically in that this tumor tends to recapitulate different stages of embryological formation of the kidney so that three classic histological areas are described: a stromal area, a blastemal area of tightly packed embryonic cells, and a tubular area. In 95% of the cases, the WT tumor is sporadic and unilateral. a microdeletion on chromosome 11p13. _90% of WAGR individuals have a de novo deletion. b. The WT1 gene (Wilms tumor gene 1) which encodes for the WT1 protein (a zinc finger DNA-binding protein) is most likely one of the genes that is deleted in WAGR and results in the genitourinary clinical features of WAGR. WT1 protein is required for the normal embryological development of the genitourinary system. WT1 protein isoforms synergize with SF-1 (steroidogenic factor-1) which is a nuclear receptor that regulates the transcription of a number of genes involved in reproduction, steroidogenesis, and male sexual development. c. The PAX6 gene (paired box), which encodes for the PAX6 protein (a paired box transcription factor) is another likely gene that is deleted in WAGR and results in the aniridia and mental retardation clinical features of WAGR. d. Prevalence. The prevalence of WAGR syndrome is unknown. However, the prevalence of Wilms tumor is 1/125,000 in the U.S. population.

Hemophilia B

X-linked recessive genetic disorder caused by a mutation in the F9 gene on chromosome Xq27.1-q27.2 for coagulation factor IX. B. Factor IX participates in the intrinsic pathway of hemostasis (blood clotting) in the following way: factor VIII is cleaved by thrombin, released from vWF, and binds to activated platelet membranes where it interacts with factor IX; the factor VIII and factor IX interaction activates factor X (which is a critical step in early hemostasis). C. Hemophilia B is caused by a wide variety of mutations, which include: missense, complete or partial deletions, RNA splicing, nonsense, and frameshift mutations. D. Hemophilia B is defined by a reduced factor IX clotting activity in the presence of normal vWF levels. E. Prevalence. The prevalence of hemophilia B is 1/25,000 in the US population. F. There are three clinically significant forms of hemophilia B: 1. Severe hemophilia B. a. Severe hemophilia B results from _1% of factor IX clotting activity. b. Clinical features include: usually diagnosed before 1 year of age, prolonged oozing after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, large "goose eggs" after minor head bumps, abnormal bleeding after minor injuries, deep muscle hematomas, episodes of spontaneous joint bleeding are frequent, and 2 to 5 spontaneous bleeding episodes/month without adequate treatment. 2. Moderately severe hemophilia B. a. Moderately severe hemophilia B results from 1% to 5% of factor IX clotting activity. b. Clinical features include: usually diagnosed before 5 to 6 years of age, prolonged oozing after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, abnormal bleeding after minor injuries, episodes of spontaneous joint bleeding are rare, and one bleeding episode/month →one bleeding episode/year. 3. Mild hemophilia B. a. Mild hemophilia B results from 5% to 30% of factor IX clotting activity. b. Clinical features include: usually diagnosed later in life, prolonged oozing after injuries, renewed bleeding after initial bleeding has stopped, delayed bleeding, abnormal bleeding after major injuries, episodes of spontaneous joint bleeding are absent, and 1 bleeding episode/year →1 bleeding episode/10 years.

Ornithine transcarbamylase (OTC) deficiency.

a. OTC deficiency is an X-linked recessive genetic disorder caused by a mutation in the OTC gene on chromosome Xp21.1 for ornithine transcarbamylase. b. OTC deficiency along with CPSI deficiency and NAGS deficiency are the most severe types of urea cycle disorders. Newborns with OTC deficiency rapidly develop hyperammonemia and these children are always at risk for repeated bouts of hyperammonemia. c. OTC can be distinguished from carbamoylphosphate synthetase (CPSI) deficiency by elevated levels of orotic acid in OTC individuals. d. _15% of female carriers develop hyperammonemia during their lifetime and many require chronic medical management.

Classic Rett syndrome (CRS).

d. Clinical features include: a progressive neurological disorder in girls where development from birth to18 months of age is normal; later, a short period of developmental stagnation is observed followed by rapid regression in language and motor skills; purposeful use of the hands is replaced by repetitive, stereotypic hand movements (hallmark); screaming fits; inconsolable crying; autism; and paniclike attacks a. CRS is an X-linked dominant genetic disorder caused by various mutations in the MECP2 gene on chromosome Xq28 for methyl-CpG-binding protein 2 (MECP2) which has a methyl-binding domain (binds to 5-methylcytosine rich DNA) and a transcription repression domain (recruits other proteins that repress transcription). The MECP2 protein mediates transcriptional repression of various genes and epigenetic regulation of methylated DNA by binding to 5-methylcytosine rich DNA. Although MECP2 protein is expressed in all tissues and seems to act as a global transcriptional repressor, mutations in the MECP2 gene result in a predominately neurological phenotype. b. CRS is caused by missense, nonsense, small deletion, and large deletion mutations. Most mutations in the MECP2 gene occur de novo. These mutations result in the inability of MECP to bind 5-methylcytosine rich DNA and to repress transcription. c. Prevalence. The prevalence of CRS in females is 1/18,000 by 15 years of age

Hypophosphatemic rickets (XLH).

d. Clinical features include: a vitamin D-resistance rickets characterized by a low serum concentration of PO4 3_ and a high urinary concentration of PO4 3_; short stature; dental abscesses; early tooth decay; leg deformities appeared at the time of weight-bearing; progressive departure from a normal growth rate a. XLH X-linked dominant genetic disorder caused by various mutations in the PHEX gene on chromosome Xp22.1 for phosphate regulating endopeptidase on the X chromosome (PHEX) which is a cell membrane-bound protein cleaving enzyme that degrades phosphatonins (hormonelike circulating factors that increase PO4 3_ excretion and decrease bone mineralization). b. XLH is caused by missense, nonsense, small deletion, small insertion, or RNA splicing mutations. These mutations result in the inability of PHEX to degrade phosphatonins so that high circulating levels of phosphatonins occur, which causes increased PO4 3_excretion and decreased bone mineralization. These mutations also result in the underexpression of Na_-PO4 3_ Cotransporter in the kidney, which causes a decreased PO4 3_ absorption. c. Prevalence. The prevalence of XLH is 1/20,000.

Complete hydatidiform mole

d. Clinical features include: gross, generalized edema of chorionic villi forming grapelike, transparent vesicles; hyperplastic proliferation of surrounding trophoblastic cells; absence of an embryo/fetus; preeclampsia during the first trimester; elevated hCG levels (_100,000 mIU/mL); and an enlarged uterus with bleeding; follow-up visits after a mole are essential because 3%-5% of moles develop into gestational trophoblastic neoplasia

Beckwith-Wiedemann syndrome (BWS).

d. Clinical features include: macrosomia; macroglossia; visceromegaly; embryonal tumors (e.g., Wilms tumor, hepatoblastoma, neuroblastoma, rhabdomyosarcoma); omphalocele; neonatal hypoglycemia; ear creases/pits; adrenocortical cytomegaly; and renal abnormalities. a. BWS is caused by abnormal transcription and regulation of various genes located in the imprinted domain on chromosome 11p15.5. b. The causes of BWS involve: (i) The KCNQ1OT1 gene on chromosome 11p15.5 which encodes for a paternally expressed K+ voltage-gated ion channel. In _60% of BWS cases, KCNQ1OT1 gene hypomethylation is detectable. (ii) The H19 gene on chromosome 11p15.5 which encodes for a maternally expressed H19 untranslated mRNA that functions as a tumor suppressor. In _7% of BWS cases, H19 gene hypermethylation is detectable. (iii) The CDKN1C gene on chromosome 11p15.5 which encodes for cyclin-dependent kinase inhibitor 1C that functions as a tumor suppressor. In _40% of familial BWS cases, CDKN1C gene mutations have been detected. (iv) In _20% of BWS cases, paternal uniparental disomy has been detected. c. Prevalence. The prevalence of BWS is 1/14,000 births.

Hypertension.

is a major factor in cardiovascular disorder and strokes. The heritability of hypertension is _20% to 40%. Although a number of genes have been linked to hypertension, hypertension involves complex physiological processes that involve many genes. The role of environmental factors is also recognized in the etiology of hypertension (e.g., sodium in the diet, physical activity, and weight gain).

Other Genetic Disorders Involving Degradation Pathways

mucopolysaccharidosis type II (MPS II; Hunter syndrome); mucopolysaccharidosis type IIIA (MPS IIIA; Sanfilippo A syndrome); mucopolysaccharidosis type IVA (MPS IVA; Morquio A syndrome); Niemann-Pick (NP) type 1A disorder; Fabry disorder; Krabbe disorder; and metachromatic leukodystrophy (MLD).

Pleiotropy

refers to a situation when a disorder has multiple effects on the body. Example: Marfan syndrome whereby the eye, skeleton, and cardiovascular system may be affected.

Variable Expressivity

severity of the disorder can vary greatly between individuals. Some people may have such mild disorder that they do not know they have it until a severely affected child is born. Example: Marfan syndrome whereby a parent is tall and has long fingers, but one of his children is tall, has long fingers, and has serious cardiovascular defects.

Mosaicism

■ A person may become a mosaic by postzygotic mutations that can occur at any time during postzygotic life. ■ These postzygotic mutations are actually quite frequent in humans and produce genetically different cell populations (i.e., most of us are mosaics to a certain extent). However, these postzygotic mutations are not usually clinically significant. ■ If the postzygotic mutation produces a substantial clone of mutated cells, then a clinical consequence may occur. ■ The formation of a substantial clone of mutated cells can occur in two ways: the mutation results in an abnormal proliferation of cells (e.g., formation of cancer) or the mutation occurs in a progenitor cell during early embryonic life and forms a significant clone of mutated cells. ■ A postzygotic mutation may also cause a clinical consequence if the mutation occurs in the germ-line cells of a parent (called germinal or gonadal mosaicism). For example, if a postzygotic mutation occurs in male spermatogenic cells, then the man may harbor a large clone of mutant sperm without any clinical consequence (i.e., the man is normal). However, if the mutant sperm from the normal male fertilizes a secondary oocyte, the infant may have a de novo inherited disease. This means that a normal couple without any history of inherited disease may have a child with a de novo inherited disease if one of the parents is a gonadal mosaic.

Reciprocal translocation (RC)

■ An RC is caused by the exchange of segments between two chromosomes, which forms two derivative (der) chromosomes each containing a segment of the other chromosome from the reciprocal exchange. ■ b. One of the most common inherited reciprocal translocations found in humans is the t(11;22)(q23.3;q11.2). ■ The translocation heterozygote, or carrier, would be at risk of having a child with abnormalities due to passing on only one of the derivative chromosomes. That would result in a child who would be partially trisomic for one of the participant chromosomes and partially monosomic for the other.

Robertsonian translocation (RT)

■ An RT is caused by translocations between the long arms (q) of acrocentric (satellite) chromosomes where the breakpoint is near the centromere. The short arms (p) of these chromosomes are generally lost. ■ Carriers of an RT are clinically normal because the short arms, which are lost, contain only inert DNA and some rRNA (ribosomal RNA) genes, which occur in multiple copies on other chromosomes. ■ One of the most common translocations found in humans is the Robertsonian translocation t(14q21q). ■ The clinical issue in the Robertsonian translocation t(14q21q) occurs when the carriers produce gametes by meiosis and reproduce. Depending on how the chromosomes segregate during meiosis, conception can produce offspring with translocation trisomy 21 (live birth), translocation trisomy 14 (early miscarriage), monosomy 14 or 21 (early miscarriage), a normal chromosome complement (live birth), or a t(14q21q) carrier (live birth). ■ A couple where one member is a t(14q21q) carrier may have a baby with translocation trisomy 21 (Down syndrome) or recurrent miscarriages.

inversions

■ Inversions are the reversal of the order of DNA between two breaks in a chromosome. ■ Pericentric inversion breakpoints occur on both sides of the centromere. ■ Paracentric inversion breakpoints occur on the same side of the centromere. ■ Carriers of inversions are usually normal. The diagnosis of an inversion is generally a coincidental finding during prenatal testing or the repeated occurrence of spontaneous abortions or stillbirths. ■ The risk for an inversion carrier to have a child with an abnormality or to have reproductive loss is due to crossing-over in the inversion loop that forms during meiosis as the normal and inverted chromosomes pair. ■ When the chromosomes separate, duplications and deletions of chromosomal material occur.

Isochromosome Xq [46,_i (Xq)]

■ Isochromosome Xq is caused by a duplication of the q arm and loss of p arm of chromosome X. ■ Isochromosome Xq is found in 20% of females with Turner syndrome, usually as a mosaic cell line along with a 45,X cell line [ i.e.,45,X/46, _i(Xq)].

ring chromosomes

■ Ring chromosomes are formed when breaks occur somewhere on either side of the centromere. ■ The newly created fragments (and thus the genes on them) are lost and the remaining pieces of the short and long arms join with each, forming a ring. ■ Ring chromosomes are unstable and tend to be lost during mitosis, creating a mosaic cell line. ■ A ring chromosome X is found in _15% of individuals with Turner syndrome, usually as a mosaic cell line with a 45,X cell line.

2. Isochromosome 12p [47,_i (12p)]

■ The occurrence of isochromosomes within any of the autosomes is generally a lethal situation although isochromosomes for small segments do allow for survival to term. ■ Isochromosome 12p is associated with testicular germ cell tumors. The CCND2 gene located on chromosome 12p13 encodes for cyclin D2, which regulates the cell cycle at the G1 checkpoint. Overexpression of cyclin D2 has been demonstrated in a variety of testicular germ cell tumors. ■ Isochromosome 12p is also associated with a rare polydysmorphic syndrome called Pallister-Killian syndrome. Clinical features include: mental retardation, loss of muscle tone, streaks of skin with hypopigmentation, high forehead, coarse facial features, wide space between the eyes, broad nasal bridge, highly arched palate, fold of skin over the inner corner of the eyes, large ears, joint contractures, and cognitive delays.