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.