PREVALENCE OF CARRIERS OF PREMUTATION-SIZE ALLELES OF THE FMRI GENE AND IMPLICATIONS FOR THE POPULATION-GENETICS OF THE FRAGILE-X SYNDROME

The fragile X syndrome is the second leading cause of mental retardati on after Down syndrome. Fragile X premutations are not associated with any clinical phenotype but are at high risk of expanding to full muta tions causing the disease when they are transmitted by a carrier woman . There is no reliable estimate of the prevalence of women who are car riers of fragile X premutations. We have screened 10,624 unselected wo men by Southern blot for the presence of FMR1 premutation alleles and have confirmed their size by PCR analysis. We found 41 carriers of all eles with 55-101 CGG repeats, a prevalence of 1/259 women (95% confide nce interval 1/373-1/198). Thirty percent of these alleles carry an in ferred haplotype that corresponds to the most frequent haplotype found in fragile X males and may indeed constitute premutations associated with a significant risk of expansion on transmission by carrier women. We identified another inferred haplotype that is rare in both normal and fragile X chromosomes but that is present on 13 (57%) of 23 chromo somes carrying FMR1! alleles with 53-64 CGG repeats. This suggests eit her (1) that this haplotype may be stable or (2) that the associated p remutation-size alleles have not yet reached equilibrium in this popul ation and that the incidence of fragile X syndrome may increase in the future.