Molecular screening of fragile X (FRAXA) and FRAXE mental retardation syndromes in the Hellenic population of Greece and Cyprus: Incidence, genetic variation, and stability

This study presents the first large, population-based molecular investigati on of the fragile X (FRAXA) and FRAXE mental retardation syndromes in the H ellenic populations of Greece and Cyprus. The aims of this population scree ning were to determine the prevalence of FRAXA and FRAXE syndromes among id iopathic mentally retarded (LMR) individuals, to estimate the incidence in the general population, and to investigate the molecular mechanism of insta bility and expansion of the FMR1-repeat. Ten FRAXA patients were identified to have either the full mutation (eight) or premutation (two) from a Helle nic population of 866 unrelated IMR individuals (611 males and 255 females, age range 3-25 years), No FRAXE patients were identified among the 611 IMR males, The incidence of FRAXA in the Hellenic population of Cyprus is esti mated at 1 in 4,246 males, The repeat sites from the FMR1 and FMR2 alleles were accurately determined and showed similar distribution and frequencies with other population studies. The analysis of AGG interspersion within the FMR1-repeat in normal males revealed long, pure CGG repeats within the "gr ay zone" as well as variation within the 3' end showing polarity of instabi lity, This finding supports the hypothesis that the AGG interspersion and t he length of the pure repeat are major factors in determining allele stabil ity. Analysis of FRAXAC1, DXS548, and FRAXAC2 identified particular alleles and haplotypes to have a significant association with either gray zone all eles or alleles >15 pure CGG repeats. We hypothesize that this subgroup of alleles and haplotypes are associated with long pure CGGs (>15 CGG) or 35 r epeats and, having shared an evolutionary past, would have the tendency to expand. (C) 1999 Wiley-Liss, Inc.