Although fragile X syndrome (FXS; OMIM 300624) is generally regarded as the most common inherited form of cognitive impairment,1^–3 there is little consensus as to its prevalence in the general population or to sex-specific differences in prevalence. Estimates of FXS prevalence (∼1/4000–1/8000) that are based on population projections from cohorts of children with special education needs (SEN) generally underestimate the extent of clinical involvement (for a comprehensive summary, see Song et al 4), as many individuals affected by the behavioural, emotional and/or learning disabilities of FXS have IQs in the normal or borderline range.5 6 The latter may not be included in cohorts that use cognitive impairment as an inclusion criterion, a problem that is particularly marked for girls, with the majority having IQs within the normal range.7

A second difficulty with population studies is the tendency to conflate disease prevalence (projections from SEN cohorts) with allele/carrier frequencies within the general population, as prevalence estimates will only approach carrier frequencies for complete penetrance. Thus, seemingly paradoxical results among studies of prevalence may reflect the effects of selection bias, conflation and differing defining criteria for FXS across studies. Aspects of this “paradox” are exemplified by two important screening studies of Israeli women. Using the same cut-off point (55 CGG repeats) for premutation (PM) carriers, Toledano-Alhadef et al8 found a higher frequency of carriers (127/14 334 = 1/113) than did Pesso et al9 (62/9459 = 1/152), despite the fact that Pesso et al reported a higher frequency for full mutation (FM) alleles (4 FM carriers; 1/2365) than did Toledano-Alhadef et al (3 FM carriers; 1/4778). Although the numbers of FM alleles in the two studies are too small to attach significance to the difference in frequencies, the trend is consistent with the exclusion of individuals with a family history of …