Genetic counseling for autosomal dominant diseases with a negative family history

Abstract

The first appearance of an autosomal dominant disease in a family is often attributed to new mutation, and the parents may be given a very low risk of recurrence for future offspring. This counseling is not appropriate if penetrance of the disease is incomplete and the reproductive fitness of affected individuals is close to normal. The risk of recurrence (P_R) for an autosomal dominant disease in the sibling of an affected child, neither of whose parents is affected, may be estimated as: P_R= y(1‐y)/2(2‐y‐f) where f is fitness of the carrier genotype regardless of phenotype, y is penetrance, and mutation‐selection equilibrium is assumed to exist. Recurrence risks have been calculated with this formula for various values of f and y. In cases in which penetrance is moderate and fitness is moderate or high, the risk of recurrence in siblings of the proband is often greater than 10%. When fitness is very high (f±0.9), the risk to siblings may be greater than 25%. These observations have important implications for genetic counseling and may also affect mutation rate calculations, demonstration of paternal age effects, and determination of inheritance patterns in genetically heterogeneous conditions.