FRAGILE-X SYNDROME - DISCORDANT LEVELS OF CGG REPEAT MOSAICISM IN 2 BROTHERS

Fragile X syndrome is associated with an unstable repeated CGG trinucl eotide sequence in the 5' untranslated region of the FMR-1 gene. A sig nificant number of individuals with a mild or atypical presentation ar e mosaics for the CGG expansion. We report a family with two brothers, The proband had severe mental retardation as well as most of the Frag ile 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 inherite d the same FMR-1 allele and Xq27-q28 flanking sequences from the mothe r. The methylation status of the brothers indicated active FMR-1 trans cription as determined by using StB12.3/EcoRI + Eagl blots. CGG size o r methylation mosaicism was not apparent from Southern blots, Polymera se chain reaction and chemiluminescent detection identified that both brothers had different degrees of mosaicism for the CGG expansion, Lar ge expansions amounting to 70% of the total were visible in the proban d, 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 dis order. (C) 1995 Wiley-Liss, Inc.