Achondroplasia
GENE/DEFECT: FGFR3 — constitutively active gain-of-function mutation
INHERITANCE: Autosomal dominant. New mutations common; low recurrence risk.
CLINICAL FEATURES: Short limbs relative to trunk, prominent forehead, low nasal root, redundant skin folds on arms and legs.
Cystic Fibrosis
GENE/DEFECT: CFTR — impaired chloride ion channel function
INHERITANCE: Autosomal recessive. Most common genetic disorder in North American Caucasians.
CLINICAL FEATURES: Pancreatic insufficiency, pulmonary obstruction (thick mucus), recurrent infections (S. aureus, P. aeruginosa).
Duchenne Muscular Dystrophy
GENE/DEFECT: Dystrophin (DMD) — deletions
INHERITANCE: X-linked recessive.
CLINICAL FEATURES: Progressive degeneration of skeletal muscle; impaired cardiac and respiratory musculature.
Familial Hypercholesterolemia
GENE/DEFECT: LDL receptor — haploinsufficiency
INHERITANCE: Autosomal dominant.
CLINICAL FEATURES: Impaired LDL uptake, elevated LDL, cardiovascular disease and stroke. More severe in homozygotes.
Fragile X Syndrome
GENE/DEFECT: FMR1 — CGG repeat expansion in 5’ UTR (expansion via mother)
INHERITANCE: X-linked dominant; females less affected. Shows anticipation.
CLINICAL FEATURES: Long face, prominent jaw, large ears, intellectual disability in boys. Increasing penetrance across generations.
Gaucher’s Disease
GENE/DEFECT: Beta-glucosidase deficiency causing glucocerebroside accumulation
INHERITANCE: Autosomal recessive.
CLINICAL FEATURES: Lysosomal storage disease: splenomegaly, hepatomegaly, bone marrow infiltration. Neurological symptoms uncommon.
G6PD Deficiency
GENE/DEFECT: Glucose-6-phosphate dehydrogenase — reduced activity
INHERITANCE: X-linked recessive. Common in Mediterranean and African descent.
CLINICAL FEATURES: Hemolytic anemia triggered by oxidizing agents (sulfonamides, dapsone) or fava beans.
Hemochromatosis
GENE/DEFECT: Unknown gene on short arm of chromosome 6
INHERITANCE: Autosomal recessive. Women less affected due to menstrual iron loss.
CLINICAL FEATURES: Enhanced iron absorption; hemosiderin deposits in organs. Cirrhosis, cardiomyopathy, diabetes, skin pigmentation, arthritis.
Holoprosencephaly
GENE/DEFECT: Sonic Hedgehog (SHH) — haploinsufficiency
INHERITANCE: Autosomal dominant.
CLINICAL FEATURES: Absent/reduced interhemispheric fissure, dysmorphic facial features, intellectual disability.
Huntington Disease
GENE/DEFECT: HTT — CAG repeat expansion in exon 1 (expansion via father)
INHERITANCE: Autosomal dominant (gain-of-function). Shows anticipation.
CLINICAL FEATURES: Progressive motor, cognitive, psychiatric decline. Chorea in ~90% of patients.
Klinefelter Syndrome
GENE/DEFECT: 47,XXY karyotype
INHERITANCE: ~50% due to paternal meiosis I error.
CLINICAL FEATURES: Sterile males: long limbs, small genitalia, gynecomastia, feminine contours, learning disabilities.
Marfan Syndrome
GENE/DEFECT: Fibrillin-1 (FBN1) — dominant negative effect
INHERITANCE: Autosomal dominant.
CLINICAL FEATURES: Tall stature, scoliosis, aortic dilation/dissection, mitral valve prolapse, joint hypermobility. Death often from CHF.
MERRF
GENE/DEFECT: Mitochondrial tRNALys mutation; heteroplasmy
INHERITANCE: Maternal transmission. Onset varies with fraction of mutant mtDNA.
CLINICAL FEATURES: Myopathy (ragged red fibers on biopsy), dementia, myoclonic seizures, ataxia, deafness.
Myotonic Dystrophy
GENE/DEFECT: DMPK — CTG repeat expansion in 3’ UTR
INHERITANCE: Autosomal dominant. Shows anticipation.
CLINICAL FEATURES: Muscle weakness, arrhythmias, cataracts, testicular atrophy. Congenital form: open triangle-shaped mouth.
Neurofibromatosis Type 1
GENE/DEFECT: Microdeletion 17q11.2 — NF1 (neurofibromin)
INHERITANCE: Autosomal dominant.
CLINICAL FEATURES: Peripheral neurofibromas. Minority: neurofibrosarcoma, astrocytoma, Schwann cell tumors, childhood CML.
Osteogenesis Imperfecta
GENE/DEFECT: Alpha-1 or alpha-2 chains of type I collagen — null or missense mutations
INHERITANCE: Usually autosomal dominant. Null = milder; missense = often perinatal lethal.
CLINICAL FEATURES: Deformed, undermineralized, fracture-prone bones. Severity varies by mutation type.
Phenylketonuria (PKU)
GENE/DEFECT: Phenylalanine hydroxylase (PAH) — loss of function
INHERITANCE: Autosomal recessive.
CLINICAL FEATURES: Intellectual disability if untreated. Detectable on newborn screen; treatable with dietary restriction.
Polycystic Kidney Disease
GENE/DEFECT: PKD1 (polycystin-1) or PKD2 (polycystin-2)
INHERITANCE: Autosomal dominant. Two-hit model.
CLINICAL FEATURES: Multiple renal cysts, hematuria, end-stage renal disease, kidney failure.
Prader-Willi / Angelman Syndrome
GENE/DEFECT: Deletion 15q11-q13 or uniparental disomy chr 15. Imprinting determines phenotype.
INHERITANCE: Maternal deletion = Angelman. Paternal deletion = Prader-Willi.
CLINICAL FEATURES: Angelman: severe ID, spasticity, seizures, characteristic gait. Prader-Willi: obesity, hyperphagia, small hands/feet, hypogonadism, mild-mod ID.
Tay-Sachs Disease
GENE/DEFECT: Beta-hexosaminidase A (HEXA) — GM2 ganglioside accumulation
INHERITANCE: Autosomal recessive. Common in Ashkenazi Jews and French Canadians.
CLINICAL FEATURES: Hypotonia, spasticity, seizures, blindness, death by age 2. Cherry-red spot on retina is early sign.
Thalassemias
GENE/DEFECT: Alpha- or beta-globin mutations — reduced/absent chain synthesis
INHERITANCE: Autosomal recessive.
CLINICAL FEATURES: Severe hemolytic anemia. Severity scales with number of affected alleles.
Turner Syndrome
GENE/DEFECT: 45,X karyotype (monosomy X)
INHERITANCE: Usually paternal sex chromosome transmission error.
CLINICAL FEATURES: Short stature, webbed neck, widely spaced nipples, primary amenorrhea, sterility, fetal lymphedema. Intelligence typically normal.
Xeroderma Pigmentosum
GENE/DEFECT: Any of 9 nucleotide excision repair genes (locus heterogeneity)
INHERITANCE: Autosomal recessive; variable expressivity.
CLINICAL FEATURES: UV photosensitivity, premature skin aging, BCC/SCC/melanoma (5%). 10-20x increased internal neoplasm risk.
