The effect of disease penetrance, family size, and age of onset on family history with application to setting eligibility criteria for genetic testing.

The concept of family history of disease has been used as a surrogate for genetic susceptibility in many epidemiological studies and has also been important as a criterion for selecting individuals for genetic testing. However, little is known about the precise interplay between the true genetic model (genotype-specific penetrances, age of onset distribution), life expectancy, and reproductive patterns in determining the level of family history. In order to address these questions, we performed a simulation study to address these relationships. Factors examined were the age-, sex-, and genotype-specific penetrance of the disease and the distribution of the number of offspring per family. When considering the average number of affected individuals among first-degree relatives of mutation positive probands, penetrance-related factors accounted for 64% of the variance in the average number of affected first-degree relatives, and 58% of the variance in the number of affected first- or second-degree relatives. In general, the average proportion of mutation-positive probands with at least one affected first-degree relative was low, especially for a sex-limited disease, ranging between 20% and 46%, depending on the lifetime penetrance in mutation carriers. Lack of family history among first-degree relatives of mutation positive probands is not necessarily unexpected even for loci conferring relatively high lifetime risk. In selecting probands for genetic testing, we found that under a wide variety of conditions, criteria based on the number of affected among first- and second-degree relatives were superior to those based on first-degree family history alone.