Fragile X syndrome: discordant levels of CGG repeat mosaicism in two brothers.

Fragile X syndrome is associated with an unstable repeated CGG trinucleotide sequence in the 5' untranslated region of the FMR-1 gene. A significant number of individuals with a mild or atypical presentation are mosaics for the CGG expansion. We report a family with two brothers. The proband had severe mental retardation as well as most of the Fragile X syndrome stigmata, whereas his brother shows only mild learning difficulties. Both inherited a 80 x CGG trinucleotide premutation from the mother. They were negative for the FRAXA fragile site in over 100 metaphases examined. Flanking markers verified that both had inherited the same FMR-1 allele and Xq27-q28 flanking sequences from the mother. The methylation status of the brothers indicated active FMR-1 transcription as determined by using StB12.3/EcoRI + Eagl blots. CGG size or methylation mosaicism was not apparent from Southern blots. Polymerase chain reaction and chemiluminescent detection identified that both brothers had different degrees of mosaicism for the CGG expansion. Large expansions amounting to 70% of the total were visible in the proband, whereas less than 5% of the signal was larger than the premutation in his mildly affected brother. These findings suggest that mosaicism may be responsible for some of the variation in penetrance in this disorder.