AN EXTENSION OF THE ADMIXTURE TEST FOR THE STUDY OF GENETIC-HETEROGENEITY IN HEREDITARY MULTIPLE EXOSTOSES

Hereditary multiple exostoses (EXT) is an autosomal dominant disorder characterized by the presence of multiple cartilage-capped exostoses i n the juxta-epiphyseal regions of the long bones. EXT is heterogeneous with at least three different locations currently having been identif ied on chromosomes 8, 11 and 19. We have tested a series of 29 EXT fam ilies for possible linkage to the three disease loci and estimated the probability of linkage of the disease to each locus in our series, by using an extension of the admixture test, which makes modelling of he terogeneous monogenic disease feasible. The maximum likelihood was obt ained for proportions of 44%, 28% and 28% of families being linked to chromosome 8, 11 and 19, respectively. The a posteriori probability of linkage of the disease to EXT1, EXT2 and EXT3 was greater than 80% fo r 8/29, 5/29 and 3/29 families, respectively, and did not give evidenc e of a fourth locus for the disease. The present approach can be gener alized to the investigation of genetic heterogeneity in other monogeni c diseases, as it simultaneously estimates the location of each diseas e gene and the proportion of families linked to each locus.