TY - JOUR
T1 - The fragile X premutation in carriers and its effect on mutation size in offspring
AU - Fisch, Gene S.
AU - Snow, Karen
AU - Thibodeau, Stephen N.
AU - Chalifaux, Maryse
AU - Holden, Jeanette J.A.
AU - Nelson, David L.
AU - Howard-Peebles, Patricia N.
AU - Maddalena, Anne
PY - 1995/5
Y1 - 1995/5
N2 - The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolves into the full mutation and the characteristic phenotype of the fra(X) syndrome after passing through oogenesis or a postzygotic event. Findings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a full mutation in offspring with the mutation. Remarkably, the best-fitting equations are nonlinear asymptotic functions. The close approximation to both the logistic model and Gompertz suggests a process of accumulation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than- expected number of daughters of transmitting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daughters whose premutations are smaller than their mothers'. Intergenerational decreases in premutation size have been reported in other trinucleotide-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 occur during or prior to meiosis.
AB - The pattern of inheritance in the fragile X (fra(X)) mutation follows a multistage intergenerational process in which the premutation evolves into the full mutation and the characteristic phenotype of the fra(X) syndrome after passing through oogenesis or a postzygotic event. Findings from our multicenter study confirm a strong direct relationship between fra(X) premutation size in the mother and probability of a full mutation in offspring with the mutation. Remarkably, the best-fitting equations are nonlinear asymptotic functions. The close approximation to both the logistic model and Gompertz suggests a process of accumulation of errors in DNA synthesis, as has been proposed previously. We also note that a larger-than- expected number of daughters of transmitting males have premutations that are smaller than their fathers', and that proportion is significantly higher than the proportion of daughters whose premutations are smaller than their mothers'. Intergenerational decreases in premutation size have been reported in other trinucleotide-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 occur during or prior to meiosis.
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M3 - Article
C2 - 7726171
AN - SCOPUS:0028969636
SN - 0002-9297
VL - 56
SP - 1147
EP - 1155
JO - American journal of human genetics
JF - American journal of human genetics
IS - 5
ER -