Computer simulation of linkage and heterogeneity in tuberous sclerosis: a critical evaluation of the collaborative family data.

The existence of locus heterogeneity for a genetic disease may complicate linkage studies considerably, especially when very few large families with the disease are available. In this situation a modest collection of families is unlikely to be sufficient for successful localisation of one or more disease genes. Recently, eight research groups working on tuberous sclerosis (TSC) brought together linkage data pertaining to the candidate chromosomes 9, 11, and 12 for a large group of families. In a series of simulation studies we determined the probability of detecting linkage and linkage heterogeneity in this set of families. On average TSC families are very small; in most cases there are fewer than two informative meioses. The size distribution of chromosome 9 linked families was similar to that of non-linked families. This indicates that a dramatic difference in the clinical severity of major genetic forms of TSC is unlikely. The results of our simulation studies show that this set of families can generate highly significant evidence for linkage and heterogeneity. When two TSC genes are equally common, the strongest evidence for linkage and heterogeneity could be obtained using a method based on the incorporation of multiple candidate regions in a single analysis, with an average lod score of 24.27.