Closely linkedcis‐acting modifier of expansion of the CGG repeat in high riskFMR1haplotypes

Abstract

Communicated by Pui-Yan KwokIn its expanded form, the fragile X triplet repeat at Xq27.3 gives rise to the most common form of inherited mental retardation, fragile X syndrome. This high population frequency persists despite strong selective pressure against mutation-bearing chromosomes. Males carrying the full mutation rarely reproduce and females heterozygous for the premutation allele are at risk of premature ovarian failure. Our diagnostic facility and previous research have provided a large databank of X chromosomes that have been tested for the FRAXA allele. Using this resource, we have conducted a detailed genetic association study of the FRAXA region to determine any cis-acting factors that predispose to expansion of the CGG triplet repeat. We have genotyped SNP variants across a 650-kb tract centered on FRAXA in a sample of 877 expanded and normal X chromosomes. These chromosomes were selected to be representative of the haplotypic diversity encountered in our population. We found expansion status to be strongly associated with a $50-kb region proximal to the fragile site. Subsequent detailed analyses of this region revealed no specific genetic determinants for the whole population. However, stratification of chromosomes by risk subgroups enabled us to identify a common SNP variant which cosegregates with the subset of D group haplotypes at highest risk of expansion (v 1 2 5 17.84, p 5 0.00002). We have verified that this SNP acts as a marker of repeat expansion in three independent samples. Hum Mutat 28(12), [1216][1217][1218][1219][1220][1221][1222][1223][1224] 2007.

Screening and instability of FMR1 alleles in a prospective sample of 24,449 mother–newborn pairs from the general population

“…This is in line with previous reports and has been discussed in Dombrowski et al (7). This reinforces the hypothesis of a cis ‐acting genomic element influencing FMR1 instability other than the triplet‐repeats themselves (36) since the vast majority of such alleles have two AGG interruptions in the FMR1 triplet array (7, 37). With respect to transmission instability, we detected a statistically significant effect of haplotypes on instability, even for these unselected samples from the general population.…”

Genetic Diversity of the Fragile X Syndrome Gene (FMR1) in a Large Sub‐Saharan West African Population

“…As Ghana represents an older and more diverse population, haplotype analyses may not provide additional hints with respect to susceptibility factors due to weak linkage disequilibrium (LD), as suggested previously for studies among African Americans (Crawford et al , 2000c, Eichler et al , 1994b). Further, recently identified cis-elements may be difficult to identify if LD is reduced (Beilina et al , 2004, Entezam & Usdin, 2008, Ennis et al , 2007). A complementary study of the frequency and haplotype backgrounds of chromosomes with the expanded fragile X mutation in the Ghanaian population would be useful to further characterize potential mutational pathways.…”

Repeat instability during DNA repair: Insights from model systems

“…A role for cis -acting factors in expansion is suggested by the fact that in many of the repeat expansion diseases some haplotypes are more likely to expand than others (Ennis et al ., 2007; Martins et al ., 2008; Murray et al ., 2000; Richards et al ., 1992; Takiyama et al ., 1995; Warby et al ., 2009). In addition, a comparison of different CAG/CTG triplet repeat loci indicated that the flanking CG content and proximity to CpG islands modifies the repeat expandability (Brock et al ., 1999; Nestor & Monckton, 2011).…”