Absence of fragile X syndrome in Nova Scotia

Editor—Fragile X syndrome is the leading cause of inherited mental retardation, with an incidence that is generally estimated to be about 1/1250 to 1/4000 in males and 1/2000 to 1/8000 in females.1-3 An extremely high estimate was reported by Rousseau et al ,4who indicated that as many as 1/259 females from Quebec, Canada, are premutation carriers. In contrast, Tranebjaerg et al 5 reported a prevalence of 0.04/1000 males in Funen, Denmark. The syndrome is characterised clinically by the triad of (1) long, narrow face with protruding chin and large ears, (2) macro-orchidism, and (3) mental retardation.6 The molecular basis for the disease is usually an expanded triplet (CGG) repeat located in the 5′ region of the fragile X mental retardation ( FMR1 ) gene.7 8 In normal subjects, there are fewer than 60 copies of this CGG repeat; carrier females and transmitting males have a premutation that usually ranges from 60-200 repeats and in affected subjects the number is expanded to >200 copies.7 The mutations are associated with absence or reduction in FMR1 gene expression. “Fully expanded” alleles are heavily methylated, in contrast to normal alleles, which are unmethylated.9 Contrary to what might be expected of a very common disorder that confers a selective disadvantage, normal alleles appear to have a low mutation rate. The conversion of a normal allele to a premutation, or to a full mutation, has not been reported.10 Indirect evidence of a low mutation rate is provided by the finding of founder chromosomes.11 Studies of populations from the United States,12 France and Spain,13 Belgium/The Netherlands,14 northern Europe and the United States,15 Italy16, United Kingdom,17 Sweden,18 and Finland19-21 have shown that FMR1 mutations are in apparent linkage disequilibrium with …