Chromosomal & Mendelian
Disorders

• Down syndrome (trisomy 21)
  • Karyotype: 47,XX,+21 (95% nondisjunction; 4% Robertsonian; 1% mosaicism)
  • Maternal age ↑ risk: 1:25 at ≥45 years
  • Features: intellectual disability, flat facies, epicanthal folds, Brushfield spots, hypotonia, simian crease
  • Congenital heart: endocardial cushion defect → AV canal
  • GI: duodenal atresia (“double-bubble”), Hirschsprung
  • ↑ risk ALL (15–20×), early Alzheimer (by age 40)
  • Median survival ~47 years
• Edwards syndrome (trisomy 18)
  • Nondisjunction; severe malformations: low-set ears, micrognathia, overlapping fingers, rocker-bottom feet, heart defects; poor prognosis
• Patau syndrome (trisomy 13)
  • Nondisjunction; cleft lip/palate, holoprosencephaly, polydactyly, renal/cardiac defects; very poor survival
• Microdeletion syndromes
  • Cri-du-chat: del 5p → catlike cry, microcephaly, ID, heart disease
  • 13q14 → retinoblastoma (tumor suppressor)
  • 11p13 (WAGR): Wilms tumor, aniridia, GU anomalies, ID
• Sex chromosome
  • Klinefelter (47,XXY): hypogonadism, tall, gynecomastia, azoospermia; ↑FSH/LH, ↓testosterone
  • Turner (45,X): short stature, webbed neck, shield chest, coarctation, bicuspid AV, streak gonads, primary amenorrhea; 45,X/46,XY mosaicism → gonadoblastoma risk

• Autosomal recessive – early onset, enzyme defects, both alleles mutated
  • Cystic fibrosis: CFTR (chr7), ΔF508 most common; thick mucus → lung infections, pancreatic insufficiency, meconium ileus, biliary cirrhosis; sweat Cl⁻ ↑; common pathogens: S. aureus, H. influenzae, P. aeruginosa
  • PKU: phenylalanine hydroxylase deficiency → phenylalanine ↑, tyrosine ↓; intellectual disability if untreated; screen at birth; diet restrict Phe (avoid aspartame)
  • Alkaptonuria: homogentisic acid oxidase deficiency → black urine on standing, ochronosis (cartilage discoloration), early arthritis
  • Albinism: tyrosinase deficiency → no melanin; ↑ skin cancer risk
  • Glycogen storage: von Gierke (G6Pase → hypoglycemia, hepatomegaly); Pompe (acid maltase → cardiomegaly, hypotonia); McArdle (muscle phosphorylase → cramps)
  • Tay-Sachs: hexosaminidase A deficiency → GM2 ganglioside accumulation; cherry-red spot, neurodegeneration; common in Ashkenazi Jews
  • Niemann-Pick: sphingomyelinase → sphingomyelin; cherry-red spot, hepatosplenomegaly, neurodegeneration (type A)
  • Gaucher: glucocerebrosidase → glucocerebroside; most common lysosomal; type I: hepatosplenomegaly, bone pain, cytopenias; Gaucher cells (tissue-paper cytoplasm)
  • MPS: Hurler (α-L-iduronidase) severe; Hunter (iduronate sulfatase) X-linked milder
• Autosomal dominant – structural proteins, variable onset, one allele sufficient
  • Familial hypercholesterolemia: LDLR mutation → LDL ↑, xanthomas, premature atherosclerosis; homozygotes MI in teens
  • Marfan: fibrillin-1 defect → tall, arachnodactyly, lens dislocation, aortic dissection, mitral prolapse
  • Ehlers-Danlos: collagen defect → hyperextensible skin/joints, vascular rupture (vascular type)
  • Neurofibromatosis type 1: NF1 (17q) → neurofibromas, café-au-lait spots, Lisch nodules, pheochromocytoma risk
  • NF2: merlin defect → bilateral acoustic neuromas, meningiomas
  • von Hippel-Lindau: VHL (3p) → hemangioblastomas (retina, cerebellum), renal cell carcinoma, pheochromocytoma

• X-linked recessive – males affected; carrier females
  • Lesch-Nyhan: HGPRT deficiency → hyperuricemia, self-mutilation, intellectual disability
  • Bruton agammaglobulinemia: Btk defect → no antibodies, recurrent infections
  • Menkes: ATP7A → copper deficiency, failure to thrive
  • Testicular feminization: androgen insensitivity (XY) → female phenotype
• X-linked dominant – males & females affected
  • Alport syndrome (also other patterns): nephritis + deafness
• Triplet repeat
  • Fragile X: CGG repeat in FMR1 → ID, elongated face, large ears, macroorchidism
  • Huntington: CAG repeat (HTT) → caudate atrophy, chorea, dementia (adult onset)
• Genomic imprinting
  • Prader-Willi: paternal 15q deletion → obesity, hypotonia, hypogonadism
  • Angelman: maternal 15q deletion → seizures, ataxia, inappropriate laughter

• Mitochondrial DNA – maternal inheritance only
  • Leber hereditary optic neuropathy: retinal ganglion cell loss → central vision loss
  • MERRF: myoclonic epilepsy, ragged-red fibers (Gomori trichrome), ataxia, dementia
• Multifactorial – multiple genes + environment
  • Neural tube defects, type 2 diabetes, hypertension

• Karyotypic sex – XX or XY; SRY on Y → testes
• Gonadal sex – ovarian/testicular/ovotestis
• Ductal sex – Müllerian (female) vs Wolffian (male)
• Phenotypic sex – external genitalia
• 46,XX DSD – ovarian development issues, androgen excess, vaginal atresia
• 46,XY DSD – testicular development defects, androgen synthesis disorders, hypospadias
• Ovotesticular disorder: both ovarian and testicular tissue; most common karyotype 46,XX

• Most common genetic cause of intellectual disability: Down syndrome and Fragile X
• CFTR ΔF508: most common CF mutation; affects protein folding & trafficking
• Maternal PKU: dietary phenylalanine restriction before conception
• Neurofibromatosis type 1: NF1 on 17q; neurofibromin inhibits Ras
• VHL: ubiquitin ligase for HIF-1α; loss → ↑ VEGF, hemangioblastomas
• Huntington: autosomal dominant, anticipation (CAG expansion)
• Fragile X: X-linked dominant with reduced penetrance in females
• Turner: most common cause of female hypogonadism; preductal coarctation
• Klinefelter: most common cause of male hypogonadism; tall, eunuchoid