Genetics for USMLE Step 1

A 32-year-old woman has a father affected by Huntington disease with onset at 55. She herself is asymptomatic. Her paternal grandfather was affected with onset at 62. Which genetic phenomenon best explains the earlier age of onset in successive generations?

1. Mosaicism The presence of two genetically distinct cell lines from a postzygotic mutation. It does not explain inheritance patterns across generations of this kind.
2. Incomplete penetrance Some individuals with the genotype never manifest the disease. Huntington is essentially fully penetrant above a threshold repeat length.
3. Anticipation due to expansion of a trinucleotide repeat correct Correct. Huntington disease is caused by an expanded CAG repeat in HTT, and the repeat is unstable during meiosis, particularly in PATERNAL transmission. Longer repeats produce earlier onset, so successive generations show progressively earlier disease.
4. Variable expressivity Different severity of the same genotype between individuals, but it does not explain a systematic generational trend.
5. Genomic imprinting The parent-of-origin silencing of a gene, as in Prader-Willi and Angelman syndromes. It does not produce progressively earlier onset across generations.

The point: Anticipation belongs to trinucleotide repeat disorders: Huntington (CAG, paternal expansion), myotonic dystrophy (CTG, maternal), Friedreich ataxia (GAA, autosomal recessive, no anticipation), fragile X (CGG, maternal). Match the repeat, the gene and which parent expands it.

Source: USMLE Content Outline — genetics NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator

A family has several affected members across three generations. Affected mothers pass the condition to ALL of their children, both sons and daughters, but no affected father transmits it to any child. Severity varies markedly between affected siblings. What is the inheritance pattern?

1. Autosomal dominant with incomplete penetrance Would show roughly equal transmission from mothers and fathers.
2. Mitochondrial correct Correct. Mitochondria come from the ovum, so transmission is exclusively maternal and every child of an affected mother is at risk. Heteroplasmy, a variable proportion of mutant mitochondria per cell, explains why severity differs so much between siblings.
3. X-linked recessive Affected fathers pass the allele to all DAUGHTERS as carriers, and sons are affected far more often than daughters. Here fathers transmit to nobody.
4. X-linked dominant Affected fathers transmit to all daughters, which contradicts the pedigree.
5. Genomic imprinting Produces a parent-of-origin effect, but on a single locus with a specific deletion, for example Prader-Willi and Angelman, rather than universal maternal transmission with variable severity.

The point: Maternal-only transmission, all children at risk, variable severity from heteroplasmy: mitochondrial. Examples worth knowing, MELAS, MERRF, Leber hereditary optic neuropathy, Leigh syndrome.

Source: USMLE Content Outline — genetics NBME / FSMB (USMLE programme) · tier 0, exam blueprint / regulator