Clinical Genetics and Genomics: Pedigrees, Inheritance, and Counseling
Core concepts
The clinical domain rewards systematic pedigree reasoning and clear-eyed risk communication.
- Inheritance patterns. Autosomal dominant (vertical transmission, male-to-male possible), autosomal recessive (consanguinity, affected siblings, carrier parents), X-linked recessive (males affected, carrier females, no male-to-male transmission), X-linked dominant (affected fathers transmit to all daughters, no sons), mitochondrial (maternal transmission, variable heteroplasmy, no transmission from affected males).
- Penetrance and expressivity. Reduced penetrance and variable expressivity make an unaffected parent compatible with dominant inheritance; age-dependent penetrance changes risk estimates.
- Anticipation and dynamic mutations. Trinucleotide repeat disorders (e.g., Huntington disease, fragile X) show expansion across generations; fragile X premutation carriers can have FXTAS or POI.
- Bayesian risk. Combine prior probability with conditional information (unaffected siblings, normal testing, age) to update carrier or recurrence risk.
- Counseling ethics. Informed consent, confidentiality, duty to warn limits, and the difference between diagnostic, predictive, and carrier testing.
Traps
Watch for male-to-male transmission excluding X-linked, an affected father with an X-linked dominant condition passing it to all daughters and no sons, and a family history that looks recessive but is actually a de novo dominant event. Also beware conflating recurrence risk in a sibling with risk in the proband's offspring.
Rule of thumb
Draw the pedigree before answering. Assign genotypes to every affected person first, then propagate. If a parent is unaffected but has an affected child with a dominant condition, consider reduced penetrance, gonadal mosaicism, or a de novo event.
Worked example
Two affected brothers, unaffected parents, no consanguinity: autosomal recessive is most likely, but gonadal mosaicism for a dominant condition is possible. Recurrence risk for a future sibling is 25% under recessive inheritance, but counseling should acknowledge both possibilities until testing clarifies.