FREQUENCY AND STABILITY OF THE FRAGILE-X PREMUTATION

Although considered the most common heritable cause of neurodevelopmen tal disability, precise prevalence figures for the FMR1 mutation in th e general population are lacking. Since no fragile X premutation allel es have yet been observed to originate from FMR1 alleles within the no rmal size range, there is also little information available about the origin of the fragile X premutation and mechanisms leading to instabil ity of the FMR1 trinucleotide repeat region. In this study, 977 geneti cally unrelated individuals from families unselected for mental retard ation or fragile X were analyzed with Southern blot analysis for the p resence of FMR1 mutations. A subgroup of subjects with evidence of a l arge CGG repeat number, and any available relatives, were further stud ied with PCR to investigate the stability of the trinucleotide repeat segment of FMR1. One subject had a 75 repeat length which was unstable (increased in size) when passed to subsequent generations. This inclu des one male descendent who had a premutation/full mutation mosaic pat tern. Two other alleles with greater than or equal to 46 repeats from different subjects were also found to be unstable and increased in siz e in subsequent generations. Considering all three unstable alleles to be indicative of an evolving or actual premutation, the estimated fre quency of the fragile X premutation is one in 510 X chromosomes. Howev er, since 11 other alleles with greater than or equal to 46 repeats we re found to be stable through at least one meiotic transmission, repea t length appears to be an important but not sufficient condition leadi ng to instability of the FMR1 gene.