RECURRENT AND UNEXPECTED SEGREGATION OF THE FMR1 CGG REPEAT IN A FAMILY WITH FRAGILE-X SYNDROME

Fragile X syndrome, the most common cause of hereditary mental retarda tion, results from amplification of a CGG trinucleotide repeat in the FMR1 gene. The transmission of the CGG repeat from premutated individu als to their premutated descendants is usually unstable, showing an in crease in the size of the repeat. We report here a family which exhibi ts recurrent and unexpected transmission of the maternal premutation t o three daughters. The first daughter exhibited mosaicism with two pre mutated alleles, one contracted and the other expanded. The second da ughter showed a reversion from the maternal premutation to the normal range, and the third carried an expanded premutated allele associated with an expanded paternal allele within the normal range. These variat ions in the size of the CGG repeat may result from many different mech anisms such as DNA polymerase slippage on the leading or lagging stran d during replication, large contractions of repeats on the parental st rand during replication, or recombination through unequal crossover be tween sister chromatids. Our results suggest that the variation of the CGG premutated alleles in this family may be the result of intrinsic instability associated with a trans-acting factor such as a mismatch r epair gene product.