Population studies of the fragile X: a molecular approach.

Abstract

The fragile X mutation can now be recognised by a variety of molecular techniques. We report a pilot screening survey of a population of children with mental impairment in which we used Southern blotting methods to detect the fragile X mutation, augmented by cytogenetic studies on children whose phenotype suggested a possible chromosome abnormality. There were 873 children with special educational needs in our survey and 310 fulfilled our criteria for testing. A sample was obtained from 254, of whom four were found to have a full fra(X) mutation (AL) and none to have a premutation.The number of CGG repeats in our population of X chromosomes was measured by PCR analysis and the genotype at the closely linked polymorphic locus FRAXAC1 established. The distribution of CGG repeat numbers was very similar to that of the control population reported by Fu et a) and the distribution of FRAXACI alleles almost identical to that of the control population reported by Richards et al. Among the non-fragile X chromosomes, we found a very significant correlation between the size of the CGG repeat and the FRAXACI genotype. There was a dearth of A and D genotypes in subjects with a small number of CGG repeats and an excess of the A genotype in those with a large number of CGG repeats. These observations are considered in the light of the reported disequilibrium between the A (and possibly also the D) genotype and the fra(X) mutation. (J Med Genet 1993;30:454-9)

Analysis of FMR1 and flanking microsatellite markers in normal and fragile X chromosomes in Portugal: evidence for a “protector” haplotype

“…In agreement with other studies, [21][22][23][24][25][26][27][28][29] A-2 and D-6 were also highly prevalent in our sample (38% of patients), supporting the contention that these two haplotypes are present on ancestral European fragile X founder chromosomes. 28,29 The presence of haplotypes C-2 and C-5 in 16 (38%) fragile X chromosomes, suggests the existence of specific founder mutations in Portuguese patients, since no similar findings have been observed in other populations.…”

Why do fragile X carrier frequencies differ between Asian and non-Asian populations?

“…Our inference of disparate rates of normal-topremutation events is consistent with early suggestions of chromosomal haplotype effects on FMR1 stability (Richards et al, 1992;Chakravarti, 1992;Jacobs et al, 1993), and with subsequent analyses of the substructure of CGG repeats, which revealed greater stability for alleles with AGG interruptions (Eichler et al, 1995;Kunst and Warren, 1994). Significant differences in the abundance and locations of stabilizing AGG interruptions have been reported for alleles sampled in Japan as compared to alleles sampled in non-Asian populations (Hirst et al, 1997).…”

“…2). This finding suggests that different rates of normal-to-premutation, as proposed under the founder-haplotype hypothesis (Richards et al, 1992;Chakravarti, 1992;Jacobs et al, 1993), could be sufficient to yield substantial variation in carrier frequencies. This founder-haplotype hypothesis is also consistent with earlier reports that Asian and non-Asian populations may differ in their distributions of FMR1 alleles with various numbers and positions of AGG repeats within the CGGrepeat region (see, for example Hirst et al, 1997).…”

A Rapid Polymerase Chain Reaction-Based Screening Method for Identification of All Expanded Alleles of the Fragile X (FMR1) Gene in Newborn and High-Risk Populations

“…As a consequence, essentially all estimates to date have targeted populations with special education needs or mental retardation, with subsequent extrapolation to the general population. Earlier estimates of one full-mutation allele in 5000 to 9000 individuals [13][14][15] are likely to be too low, because those estimates did not fully account for fragile X children without mental retardation. More recent estimates are generally higher, from one in 2500 to 5000 for the larger studies of special education needs children 6,16,17,18 -20 ; however, as for premutation alleles, there have been no large-scale unbiased (eg, newborn) screens for full-mutation FMR1 alleles in the general population, due in part to the absence of an effective screening tool.…”