No abstract

International audienceThis study was an investigation of 79 patients referred to the Wessex Regional Genetics Laboratory with suspected Russell-Silver Syndrome or unexplained short stature/intra uterine growth restriction, warranting genetic investigation. Methylation status was analysed at target sequences within eleven imprinted loci (PLAGL1, IGF2R, PEG10, MEST1, GRB10, KCNQ1OT1, H19, IGF2P0, DLK1, PEG3, NESPAS). 37% (29/79) of samples were demonstrated to have a methylation abnormality. The commonest finding was a loss of methylation at H19 (23/29), as previously reported in Russell-Silver Syndrome. In addition, four of these patients had methylation anomalies at other loci, of whom two show hypomethylation of multiple imprinted loci, and two showed a complete gain of methylation at IGF2R. This latter finding was also present in five further patients who did not have demonstrable changes at H19. In total, 7/79 patients showed a gain of methylation at IGF2R and this was significantly different from a normal control population of 267 individuals (p=0.002). This study demonstrates the importance of widening the epigenetic investigation to include multiple imprinted loci and highlights potential involvement of the IGF2R locus in growth restriction

A number of recent studies have found non-random association between the fragile X mutation and genotypes for the closest-linked flanking markers, suggesting either a limited number of 'founder' mutations or, alternatively, a predisposing haplotype for the fragile X expansions. Using three microsatellite markers within 150 kb of FRAXA, we have compared haplotypes in a series of fragile X males and in a control population and find a markedly different distribution in the two samples, with apparently greater haplotype diversity in the fragile X sample. In the control sample, various non-random associations of CGG repeat numbers with flanking haplotypes were recorded which provide a clue to the likely origins of the fragile X mutation, suggesting more than one mechanism for the initial expansion event.

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)