Clinical Genetics and Risk Assessment
Core concepts
Candidates must move fluently among inheritance patterns: autosomal dominant (vertical transmission, 50% per child, reduced penetrance, variable expressivity, new mutations), autosomal recessive (carrier parents, 25% recurrence, consanguinity), X-linked (no male-to-male transmission, carrier females), mitochondrial (maternal transmission, heteroplasmy, variable threshold), and multifactorial (empiric recurrence risks). Pedigree symbols and standard notation are fair game.
Calculating risk
Bayesian analysis updates carrier probability with test results and family history. Know when to apply it: an unaffected woman with a family history of an X-linked or recessive condition whose testing is incomplete or whose relatives' status is uncertain. Also know age-related and penetrance adjustments, and that empiric risks for multifactorial conditions are approximations, not Mendelian fractions.
Traps
Common errors: applying a 50% risk to a sibling when the proband's mutation is de novo (siblings are usually at population risk unless gonadal mosaicism is suspected); ignoring that a negative test in an unaffected relative changes risk differently depending on whether the tested person is affected; confusing carrier frequency with recurrence risk; and forgetting that penetrance modifies risk expression, not transmission probability. Another trap is treating a variant of uncertain significance as pathogenic when calculating family risk.
Worked example
A woman's brother has an X-linked condition and her son is unaffected. Her carrier risk starts at 2/3 (she has one affected brother; parents assumed carriers). A negative carrier test with 95% sensitivity reduces her risk to (1/3 x 0.05) / [(1/3 x 0.05) + (2/3 x 1)] = about 1/41, roughly 2.4%. Rule of thumb: always state the prior, the test's sensitivity, and the result before multiplying.