THE FRAGILE-X PREMUTATION IN CARRIERS AND ITS EFFECT ON MUTATION SIZEIN OFFSPRING

The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolve s into the full mutation and the characteristic phenotype of the fra(X ) syndrome after passing through oogenesis or a postzygotic event. Fin dings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a ful l mutation in offspring with the mutation. Remarkably, the best-fittin g equations are nonlinear asymptotic functions. The close approximatio n to both the logistic model and Gompertz suggests a process of accumu lation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than-expected number of daughters of transmit ting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daught ers whose premutations are smaller than their mothers'. Intergeneratio nal decreases in premutation size have been reported in other trinucle otide-repeat disorders and also appear to be parent-of-origin specific . Thus, while intergenerational expansion to the full mutation in fra( X) may manifest a postzygotic event, decreases in mutation size may oc cur during or prior to meiosis.