Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles
Faculty of Medicine and Health Sciences
New York, N.Y.
The American journal of human genetics. - New York, N.Y.
, p. 454-464
University of Antwerp
The CGG repeat in the 5′ untranslated region of the fragile X mental retardation 1 gene (FMR1) exhibits remarkable instability upon transmission from mothers with premutation alleles. A collaboration of 13 laboratories in eight countries was established to examine four issues concerning FMR1 CGG-repeat instability among females with premutation (∼55200 repeats) and intermediate (∼4660 repeats) alleles. Our central findings were as follows: (1) The smallest premutation alleles that expanded to a full mutation (>200 repeats) in one generation contained 59 repeats; sequence analysis of the 59-repeat alleles from these two females revealed no AGG interruptions within the FMR1 CGG repeat. (2) When we corrected for ascertainment and recalculated the risks of expansion to a full mutation, we found that the risks for premutation alleles with <100 repeats were lower than those previously published. (3) When we examined the possible influence of sex of offspring on transmission of a full mutationby analysis of 567 prenatal fragile X studies of 448 mothers with premutation and full-mutation alleleswe found no significant differences in the proportion of full-mutation alleles in male or female fetuses. (4) When we examined 136 transmissions of intermediate alleles from 92 mothers with no family history of fragile X, we found that, in contrast to the instability observed in families with fragile X, most (99/136 [72.8%]) transmissions of intermediate alleles were stable. The unstable transmissions (37/136 [27.2%]) in these families included both expansions and contractions in repeat size. The instability increased with the larger intermediate alleles (19% for 4954 repeats, 30.9% for 5559, and 80% for 6065 repeats). These studies should allow improved risk assessments for genetic counseling of women with premutation or intermediate-size alleles.