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.