FAMILIAL TRANSMISSION OF THE FMR1 CGG REPEAT

To better define the nature of FMR1 CGG-repeat expansions, changes in allele sizes fur 191 families with fragile X and for 33 families with gray-zone repeats (40-60) were analyzed. Expansion of the fragile X ch romosome to the full mutation was seen in 13.4% of offspring from prem utation mothers with 56-59 repeats, 20.6% of those with 60-69 repeats, 57.8% of those with 70-79 repeats, 72.9% of those with 80-89 repeats, and 97.3% of those with 90-199 repeats. Fur premutation fathers, the majority (62%) of their daughters had a larger repeat number, while a few had either a smaller (22%) or the same (16%) repeat number, compar ed with their fathers' sizes. However, daughters with a smaller repeat number were observed only if their fathers had greater than or equal to 80 repeats. Fifteen (39.5%) of 38 such daughters carried a smaller repeat than did their fathers. We observed that a similar repeat numbe r was inherited more often than expected by chance, among the members of a sibship segregating fragile X. This familial clustering, observed in the offspring of both malts and females with a premutation, implie s there may be an additional factor, independent of parental repeat si ze, that influences CGG-repeat instability. Instability in gray-zone a llele transmissions was observed in 25% of alleles with 50-60 CGGs but in <8% of those with 40-49 CGGs. Examination of gray-zone allele orga nization revealed that long tracts of pul-e CGGs (>34) are not always unstably transmitted. These results raise new questions regarding the familial factors that nay determine transmission expansions.