Master Genetics
for USMLE Step 1

What the USMLE Step 1 Tests in Genetics

USMLE Step 1 Genetics tests the ability to recognise inheritance patterns (autosomal dominant/recessive, X-linked, mitochondrial), calculate recurrence risks using Hardy–Weinberg and Bayesian reasoning, and identify classic dysmorphic syndromes (e.g., Down, Turner, Noonan). Candidates must interpret pedigree diagrams, distinguish between genomic imprinting (Prader–Willi vs Angelman) and uniparental disomy, and apply tumour suppressor gene concepts (RB1 in retinoblastoma, APC in FAP). Clinical decision-making includes selecting first-line genetic tests (karyotype, FISH, CMA, targeted sequencing), recognising indications for newborn screening (e.g., phenylketonuria, cystic fibrosis), and counselling for prenatal screening (nuchal translucency, quad screen). Knowledge of pharmacogenomics (e.g., TPMT in azathioprine, CYP2C19 in clopidogrel) and common trinucleotide repeat disorders (Huntington, fragile X) is essential.

High-Yield Concepts

• Autosomal Dominant Inheritance: Affects males and females equally; vertical transmission; 50% recurrence risk for offspring. Examples: Huntington disease (CAG repeat >40, onset age 30–50), neurofibromatosis type 1 (NF1 gene, café-au-lait spots ≥6, Lisch nodules), familial adenomatous polyposis (APC gene, >100 colorectal polyps by age 20).
• Autosomal Recessive Inheritance: Affects males and females equally; often consanguineous; 25% recurrence risk. Examples: cystic fibrosis (CFTR ΔF508 mutation, sweat chloride >60 mmol/L), phenylketonuria (PAH deficiency, newborn screen elevated phenylalanine, dietary restriction), sickle cell disease (HbS, Hb electrophoresis shows HbS >50%, hydroxyurea for crises).
• X-Linked Recessive Inheritance: Affects mainly males; carrier females usually asymptomatic; no male-to-male transmission. Examples: Duchenne muscular dystrophy (dystrophin deletion, elevated CK, Gowers sign, loss of ambulation by age 12), haemophilia A (factor VIII deficiency, PTT prolonged, treat with desmopressin or factor VIII concentrate), glucose-6-phosphate dehydrogenase deficiency (X-linked, favism, haemolytic anaemia triggered by sulfonamides or fava beans).
• Mitochondrial Inheritance: Maternally transmitted; all offspring of affected females inherit, but only females pass on. Examples: MELAS (mitochondrial encephalopathy, lactic acidosis, stroke-like episodes, m.3243A>G mutation), Leber hereditary optic neuropathy (LHON, acute vision loss in young adults, G11778A mutation).
• Genomic Imprinting and Uniparental Disomy: Prader–Willi syndrome: paternal deletion of 15q11-q13 (or maternal uniparental disomy) → hyperphagia, obesity, hypotonia. Angelman syndrome: maternal deletion of same region (or paternal uniparental disomy) → severe intellectual disability, ataxia, frequent laughter. Key: deletion of active allele determines phenotype.
• Trinucleotide Repeat Disorders: Anticipation (worsening in successive generations) due to repeat expansion. Huntington disease: CAG repeat >40, autosomal dominant, chorea, dementia. Fragile X syndrome: CGG repeat >200 in FMR1, X-linked, macroorchidism, long face, intellectual disability. Myotonic dystrophy: CTG repeat >50 in DMPK, autosomal dominant, myotonia, cataracts, cardiac conduction defects.
• Tumour Suppressor Genes and Two-Hit Hypothesis: Knudson hypothesis: both alleles must be inactivated. Retinoblastoma: RB1 gene on 13q14, hereditary (first hit germline) → bilateral, early onset; sporadic (both hits somatic) → unilateral. Li–Fraumeni syndrome: TP53 mutation, increased risk of sarcomas, breast cancer, leukaemia. APC in FAP: loss of both alleles leads to colorectal cancer.
• Pharmacogenomics: Key Examples: TPMT deficiency: autosomal recessive, risk of severe myelosuppression with azathioprine/6-mercaptopurine; measure TPMT activity before starting. CYP2C19 poor metabolisers: reduced activation of clopidogrel, increased risk of stent thrombosis; consider alternative antiplatelet. G6PD deficiency: avoid primaquine, sulfonamides, dapsone to prevent haemolysis.

Common Traps in Genetics Questions

• Confusing autosomal dominant with X-linked dominant: X-linked dominant shows no male-to-male transmission, and affected males may have more severe disease (e.g., Rett syndrome is lethal in males).
• Assuming all trinucleotide repeats show anticipation: Friedreich ataxia (GAA repeat) does not show anticipation; it shows founder effect.
• Forgetting that mitochondrial disorders can present in both sexes but are only transmitted by females; a male with a mitochondrial mutation cannot pass it to offspring.
• Misinterpreting a pedigree with multiple affected siblings and unaffected parents as autosomal dominant with incomplete penetrance, when it could be autosomal recessive with carrier parents.
• Overlooking that uniparental disomy can cause imprinting disorders even without deletion; e.g., Prader–Willi from maternal UPD of chromosome 15.

How to Revise Genetics for the USMLE Step 1

Prioritise pedigree interpretation and recurrence risk calculations using Hardy–Weinberg for carrier frequency and Bayesian analysis for updated risks. Focus on classic syndromes with pathognomonic features (e.g., Down syndrome: trisomy 21, nuchal translucency >3.5 mm, AVSD; Turner: 45,X, webbed neck, coarctation). Practise identifying mode of inheritance from pedigrees quickly—look for male-to-male transmission to rule out X-linked. Review first-line tests: karyotype for aneuploidy, FISH for microdeletions, CMA for copy number variants, and targeted sequencing for single-gene disorders. Questions often integrate genetics with biochemistry (e.g., lysosomal storage diseases) or pharmacology (e.g., warfarin resistance due to VKORC1 polymorphism). Drill calculations: autosomal recessive carrier frequency = 2√(disease incidence), and Bayesian tables for Huntington predictive testing.

Practise it: MedLumen has 30 Genetics questions for the USMLE Step 1, each with a full explanation and references.