Pedigree With Incomplete Penetrance
A couple seeks genetic counseling. The woman's father has a dominantly inherited condition caused by a known pathogenic variant, and she tested positive for the same variant. She is 30 and asymptomatic. Her husband has no family history and tests negative. They have one unaffected 5-year-old son. The woman's brother, who also carries the variant, is 45 and unaffected. The counselor notes the condition shows incomplete penetrance and variable age of onset, with about 60 percent of carriers affected by age 50. The couple asks whether their son is 'safe' because he is unaffected, and whether any future child has a 50 percent chance of being affected.
1. Explain why the woman's brother being unaffected does not mean he cannot pass the variant to his children.
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The condition is dominant at the genotype level, but penetrance is incomplete: only about 60 percent of carriers show symptoms by age 50. Being unaffected therefore does not mean the variant is absent or harmless; it means the genotype has not produced detectable disease, possibly because of age, modifier genes, or environment. A carrier who is unaffected can still transmit the variant to offspring with a 50 percent probability per child, because the variant is present in half of his gametes. The judgement is to separate genotype (carrier status) from phenotype (symptoms), which is exactly what incomplete penetrance forces counselors to do.
2. The couple asks whether their unaffected son is 'safe' and whether a future child has a 50 percent chance of being affected. How should the counselor answer?
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The son is not proven safe. He has a 50 percent chance of having inherited the variant from his mother, and because penetrance is incomplete, being unaffected at age 5 says little. Genetic testing could clarify his genotype, though predictive testing in a child raises ethical and consent issues that should be discussed. For a future child, the chance of inheriting the variant is 50 percent, but the chance of actually developing the condition is lower-roughly 60 percent of carriers affected by age 50-so 'affected' and 'inheriting the variant' are not the same probability. The counselor should present both numbers and explain that onset may occur later.