Pedigree with incomplete penetrance
A family shows a rare autosomal dominant condition. Individual II-3 is affected and has an affected father (I-1) and an unaffected mother (I-2). II-3 has two children with an unaffected partner: III-1 is unaffected and III-2 is affected. III-2 has an affected child, IV-1. Genetic testing shows II-3 carries the pathogenic variant, but III-1 does not. The variant is estimated to have 80% penetrance. A counsellor tells III-1 that because they are unaffected, their children cannot inherit the condition.
1. Evaluate the counsellor's statement.
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The statement is incorrect. III-1 is unaffected, and testing shows they do not carry the variant, so for this individual the risk is essentially the population background, not the family variant. However, the counsellor's reasoning ('unaffected, so cannot pass it on') is flawed in general because the variant has 80% penetrance. An unaffected carrier can exist: 20% of carriers show no phenotype. If III-1 had not been tested, their probability of being a carrier would need calculation. Since III-1 tested negative, their children are not at elevated risk from this variant. The correct advice is based on the test result, not on the phenotype alone.
2. Calculate the probability that III-2's child IV-1 inherited the variant, given III-2 is affected and the partner is unaffected.
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III-2 is affected and carries the variant. Because the condition is autosomal dominant, III-2 has one variant allele and one normal allele (assuming heterozygosity, which is typical for rare dominant conditions). Each child has a 1/2 chance of inheriting the variant. The partner is unaffected and, for a rare variant, is assumed not to carry it. So IV-1's probability of inheriting the variant is 1/2, or 50%. IV-1 is affected, which is consistent with inheriting the variant, but because penetrance is 80%, an inherited variant does not guarantee the phenotype. The fact that IV-1 is affected slightly raises the probability that they carry the variant above 50%, but the simple Mendelian expectation is 50%.