The number of CGG repeats of the FMR1 locus in premutated and fully mutated heterozygotes and their offspring: implications for the origin of mosaicism.

The size of the CGG repeat of the FMR1 gene was investigated with probe StB12.3 in 154 transmissions to the offspring of heterozygotes for the premutation and the full mutation. Among the 135 offspring of premutated heterozygotes there were three decreases in size of the repeats: in two of these cases a full mutation was present along with the decreased premutation, and in a third mosaic (46,fra(X)(q27.3),Y), a normal allele was observed. In the 19 offspring of fully mutated females with no detected mosaicism, there were three mosaics and three individuals who had full mutations that included a number of repeats smaller than those present in their mothers. Among the 32 offspring who received a premutation from their premutated mothers, 27 alleles were increased in size and 5 remained unaltered. Among 11 mosaic offspring of premutated mothers, the premutation increased in 4, decreased in 3, and was unchanged in 4. In contrast to the trend of an increasing premutation size in the non-mosaic offspring, the premutation present in mosaics can be smaller, larger, or of unaltered size with approximately equal frequencies. These data suggest that the premutations present in mosaics result from mitotic instability of the inherited full mutations. This is further supported by the finding of a mosaic male with a normal sized allele.