Modes of Inheritance & Genetic Disorders — USMLE Step 1 Notes

How to read a pedigree — the five modes

• Autosomal dominant (AD): one mutant allele suffices. Vertical transmission through every generation, both sexes affected, males and females transmit, ~50% of offspring affected. Often structural proteins or receptors; features include variable penetrance and expressivity. Examples: Huntington disease, Marfan, neurofibromatosis, familial hypercholesterolaemia, ADPKD.
• Autosomal recessive (AR): two mutant alleles needed. Tends to skip generations, appears in siblings, linked to consanguinity; both parents are usually unaffected carriers (25% affected, 50% carriers per pregnancy). Often enzyme deficiencies. Examples: cystic fibrosis, most inborn errors of metabolism, sickle cell, Friedreich ataxia.
• X-linked recessive (XLR): mostly affects males; no male-to-male transmission; carrier mothers pass it to 50% of sons. Examples: Duchenne/Becker muscular dystrophy, haemophilia A/B, G6PD deficiency, Lesch-Nyhan, Fragile X (with caveats).
• X-linked dominant (XLD): affected fathers pass it to all daughters and no sons; affected mothers pass it to ~50% of each. Some are male-lethal (few affected boys). Examples: Rett syndrome, X-linked hypophosphataemic rickets, Alport (most), incontinentia pigmenti.
• Mitochondrial: maternal transmission to all children (sperm mitochondria are not inherited); variable severity from heteroplasmy. Examples: MELAS, MERRF, Leber hereditary optic neuropathy, Leigh syndrome.

Key genetic concepts

• Anticipation: trinucleotide-repeat disorders worsen and start earlier across generations (Huntington, myotonic dystrophy, Fragile X, Friedreich ataxia).
• Imprinting: parent-of-origin expression — Prader-Willi (paternal 15q deletion) vs Angelman (maternal).
• Mosaicism: two cell lines from a post-zygotic mutation (e.g. some Down syndrome, McCune-Albright).
• X-inactivation (Lyonisation): random silencing of one X in females explains variable expression in carriers.
• Penetrance = proportion of genotype-carriers who show the phenotype; expressivity = how severely.

Cystic fibrosis (AR)

• Genetics: autosomal recessive; CFTR gene on chromosome 7; commonest mutation is Phe508del (F508del).
• Pathophysiology: defective CFTR chloride channel → thick, dehydrated secretions in lungs, pancreas, gut, sweat ducts and vas deferens; impaired chloride/water transport.
• Diagnosis: raised sweat chloride (≥60 mmol/L), newborn screening (raised immunoreactive trypsinogen), and genetic testing.
• Treatment: airway clearance and mucolytics (dornase alfa, hypertonic saline), inhaled antibiotics for chronic Pseudomonas, pancreatic enzyme replacement with fat-soluble vitamins, and CFTR modulators (e.g. elexacaftor-tezacaftor-ivacaftor).
• Complications: bronchiectasis and respiratory failure, chronic Pseudomonas/Staph/Burkholderia infection, pancreatic insufficiency and CF-related diabetes, meconium ileus, malabsorption, infertility (congenital absence of the vas deferens).

Duchenne & Becker muscular dystrophy (XLR)

• Genetics: X-linked recessive dystrophin (DMD) gene mutations. Duchenne = frameshift (no functional dystrophin); Becker = in-frame (partly functional, milder).
• Pathophysiology: loss of dystrophin destabilises the muscle membrane during contraction → progressive myofibre necrosis and fibrofatty replacement.
• Diagnosis: very high creatine kinase, genetic testing (first-line), muscle biopsy if needed; Gower sign and calf pseudohypertrophy. Duchenne presents ~2-5 years; Becker later.
• Treatment: corticosteroids slow decline; multidisciplinary care (physiotherapy, respiratory and cardiac surveillance); newer exon-skipping/gene therapies for selected mutations.
• Complications: loss of ambulation by ~teens (Duchenne), dilated cardiomyopathy, respiratory failure, scoliosis; cardiac disease can dominate in Becker.

Myotonic dystrophy (AD)

• Genetics: autosomal dominant CTG trinucleotide repeat in DMPK (type 1); shows anticipation.
• Pathophysiology: toxic RNA gain-of-function disrupting splicing of multiple genes.
• Diagnosis: myotonia (delayed muscle relaxation, e.g. cannot release a handshake), distal weakness, and multisystem clues; confirm by repeat-length testing.
• Treatment: supportive; treat myotonia if disabling; cardiac monitoring is essential.
• Complications: cardiac conduction block/arrhythmia (a major cause of death), cataracts, frontal balding, testicular atrophy, insulin resistance, and anaesthetic sensitivity.

Rett syndrome (X-linked dominant)

• Genetics: X-linked dominant MECP2 mutation; typically affects girls (often lethal in males).
• Pathophysiology: loss of MeCP2 (a transcriptional regulator) impairs neuronal maturation.
• Diagnosis: normal early development then regression (6-18 months) with loss of purposeful hand use, stereotyped hand-wringing, deceleration of head growth (acquired microcephaly), gait problems.
• Treatment: supportive and multidisciplinary; treat seizures and breathing/behavioural issues.
• Complications: intellectual disability, epilepsy, scoliosis, breathing dysregulation, autonomic dysfunction.

Fragile X syndrome (X-linked)

• Genetics: CGG trinucleotide expansion in FMR1 (X chromosome) with hypermethylation silencing the gene; anticipation. The commonest inherited cause of intellectual disability.
• Pathophysiology: loss of FMRP, an RNA-binding protein needed for synaptic regulation.
• Diagnosis: molecular testing for the CGG repeat; clinical clues of long face, large ears, macro-orchidism (post-pubertal), joint hypermobility.
• Treatment: supportive — educational, behavioural and speech/occupational therapy; treat comorbid ADHD/anxiety/seizures.
• Complications: intellectual disability and autism spectrum features; premature ovarian insufficiency and FXTAS (tremor/ataxia) in premutation carriers.

Huntington disease (AD)

• Genetics: autosomal dominant CAG expansion in HTT (chromosome 4); anticipation, worse with paternal transmission.
• Pathophysiology: mutant huntingtin causes neuronal loss, especially caudate/putamen (striatal) atrophy with reduced GABA and acetylcholine.
• Diagnosis: chorea, behavioural/psychiatric change and progressive dementia, usually 30-50 years; caudate atrophy on imaging; confirm by CAG repeat testing (with genetic counselling).
• Treatment: no cure; symptomatic — tetrabenazine/deutetrabenazine or antipsychotics for chorea, and psychiatric support.
• Complications: progressive disability, depression and high suicide risk, aspiration and death typically ~15-20 years after onset.

Friedreich ataxia (AR)

• Genetics: autosomal recessive GAA trinucleotide expansion in FXN (frataxin); the exception that is recessive despite being a repeat disorder.
• Pathophysiology: frataxin deficiency impairs mitochondrial iron handling → oxidative damage in dorsal root ganglia, spinocerebellar and corticospinal tracts, and the heart.
• Diagnosis: childhood-onset progressive ataxia, loss of proprioception/vibration and reflexes with upgoing plantars, dysarthria, pes cavus and scoliosis; confirm genetically.
• Treatment: supportive multidisciplinary care; monitor and treat cardiomyopathy and diabetes.
• Complications: hypertrophic cardiomyopathy (leading cause of death), diabetes mellitus, wheelchair dependence.

Down syndrome — trisomy 21

• Genetics: trisomy 21, usually meiotic non-disjunction (risk rises with maternal age); ~5% from a robertsonian translocation, some mosaic.
• Pathophysiology: a gene-dosage effect from the extra chromosome 21.
• Diagnosis: antenatal screening (low PAPP-A, raised beta-hCG, increased nuchal translucency; low AFP/oestriol with high hCG and inhibin on the quad test); confirm with cell-free DNA and karyotype/amniocentesis. Features: hypotonia, upslanting palpebral fissures, epicanthic folds, single palmar crease, flat facial profile, Brushfield spots.
• Treatment: supportive; surveillance for the complications below.
• Complications: intellectual disability, atrioventricular septal defect and other cardiac defects, duodenal atresia, Hirschsprung disease, hypothyroidism, atlantoaxial instability, increased risk of ALL/AML and early-onset Alzheimer disease.

Edwards syndrome — trisomy 18

• Genetics: trisomy 18 (non-disjunction); second commonest autosomal trisomy.
• Diagnosis/features: clenched fists with overlapping fingers, rocker-bottom feet, micrognathia, prominent occiput, low-set ears, cardiac and renal defects; low levels of all quad-screen markers is a clue.
• Prognosis/complications: most die within the first year; profound disability.

Patau syndrome — trisomy 13

• Genetics: trisomy 13 (non-disjunction).
• Diagnosis/features: holoprosencephaly, cleft lip/palate, microphthalmia, polydactyly, cutis aplasia, midline and cardiac defects.
• Prognosis/complications: most die within the first year.

Cri-du-chat syndrome — 5p deletion

• Genetics: deletion of the short arm of chromosome 5 (5p-), usually de novo.
• Diagnosis/features: a distinctive high-pitched, cat-like cry in infancy, microcephaly, round 'moon' face, hypertelorism, epicanthal folds, low-set ears and intellectual disability.
• Treatment/complications: supportive; intellectual disability, feeding and speech difficulties, and sometimes cardiac defects.

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