FOUNDER EFFECT IN A BELGIAN-DUTCH FRAGILE-X POPULATION

For many years, the high prevalence of the fragile X syndrome was thou ght to be caused by a high mutation frequency. The recent isolation of the FMR1 gene and identification of the most prevalent mutation enabl e a more precise study of the fragile X mutation. As the vast majority of fragile X patients show amplification of an unstable trinucleotide repeat, DNA studies can now trace back the origin of the fragile X mu tation. To date, de novo mutations leading to amplification of the CGG repeat have not yet been detected. Recently, linkage disequilibrium w as found in the Australian and US populations between the fragile X mu tation and adjacent polymorphic markers, suggesting a founder effect o f the fragile X mutation. We present here a molecular study of Belgian and Dutch fragile X families. No de novo mutations could be found in 54 of these families. Moreover, we found significant (P < 0.0001) link age disequilibrium in 68 unrelated fragile X patients between the frag ile X mutation and an adjacent polymorphic microsatellite at DXS548. T his suggests that a founder effect of the fragile X mutation also exis ts in the Belgian and Dutch populations. Both the absence of new mutat ions and the presence of linkage disequilibrium suggest that a few anc estral mutations are responsible for most of the patients with fragile X syndrome.