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 Wrong. Mosaicism means having two genetically different groups of cells in the body from a mutation that happened after fertilization. It does not explain this kind of pattern across generations.
2. Incomplete penetrance Wrong. Incomplete penetrance means some people with the gene change never develop the disease. Huntington disease is essentially fully penetrant, meaning almost everyone with a long enough repeat will develop it.
3. Anticipation due to expansion of a trinucleotide repeat correct Correct. Huntington disease is caused by an expanded CAG repeat, a stretch of repeated DNA letters, in the HTT gene. This repeat can grow longer when it is passed down during cell division for reproduction (meiosis), especially when passed from the FATHER. Longer repeats cause earlier onset, so each generation can get the disease sooner than the last. This pattern is called anticipation.
4. Variable expressivity Wrong. Variable expressivity means the same gene change can cause different severity in different people, but it does not explain a trend of earlier onset across generations.
5. Genomic imprinting Wrong. Genomic imprinting is when a gene is turned off depending on which parent it came from, as seen in Prader-Willi and Angelman syndromes. It does not cause the disease to start earlier in each generation.

The point: Anticipation happens in trinucleotide repeat disorders: Huntington disease (CAG repeat, grows with paternal transmission), myotonic dystrophy (CTG repeat, grows with maternal transmission), Friedreich ataxia (GAA repeat, autosomal recessive, no anticipation), and fragile X syndrome (CGG repeat, grows with maternal transmission). Learn which repeat goes with which gene, and which parent's transmission makes it grow.

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 Wrong. Autosomal dominant inheritance with incomplete penetrance would show roughly equal transmission from mothers and fathers, not this exclusively maternal pattern.
2. Mitochondrial correct Correct. Mitochondria come only from the egg (ovum), so this condition passes down only through the mother, and every child of an affected mother is at risk. Heteroplasmy, meaning each cell has a different mix of normal and mutated mitochondria, explains why severity varies so much between siblings.
3. X-linked recessive Wrong. In X-linked recessive inheritance, affected fathers pass the gene to all their DAUGHTERS, who become carriers, and sons are affected far more often than daughters. Here, affected fathers pass the condition to no one at all, which rules this out.
4. X-linked dominant Wrong. In X-linked dominant inheritance, affected fathers pass the condition to all their daughters, which does not match this family tree (pedigree).
5. Genomic imprinting Wrong. Genomic imprinting causes a parent-of-origin effect, but it affects one specific gene location with a specific deletion, as in Prader-Willi and Angelman syndromes, rather than this pattern of universal maternal transmission with widely varying severity.

The point: Transmission only through the mother, with every child at risk, and severity that varies because of heteroplasmy, points to a mitochondrial disorder. Examples worth knowing: MELAS, MERRF, Leber hereditary optic neuropathy, and Leigh syndrome.

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