SEGREGATION OF THE FRAGILE-X MUTATION FROM A MALE WITH A FULL MUTATION - UNUSUAL SOMATIC INSTABILITY IN THE FMR-1 LOCUS

Fragile X syndrome is associated with an unstable CGG-repeat in the FM R-1 gene. There are few reports of affected males transmitting the FMR -1 gene to offspring, We report on a family in which the propositus an d his twin sister each had a full mutation with abnormal methylation, Their mother had an FRSR-1 allele in the normal range and a large prem utation, with normal methylation, The maternal grandmother had two nor mal FMR-1 alleles. The maternal grandfather had an unusual somatic FMR -1 pattern, with allele size ranging from premutation to full mutation . No allele was detectable by PCR analysis, Multiple Southern blot ana lyses identified a hybridization pattern that originated at a distinct premutation band and extended into the full mutation range, Methylati on studies revealed a mosaic pattern with both unmethylated premutatio ns and methylated full mutations. This individual declined formal eval uation but did not finish high school and has difficulty in reading an d writing The size of the premutation FMR-1 allele passed to his daugh ter is larger than his most prominent premutation allele. This is most likely due to gonadal mosaicism similar to that in his peripheral lym phocytes. Alternatively, this expansion event may have occurred during his daughter's early embryonic development and this large premutation allele is mitotically unstable, This pattern of FMR-1 alleles in a pr esumably mildly affected male is highly unusual, These findings are co nsistent with the absence of transmission of a full fragile X mutation through an expressing male, Studies of tissue specific FMR-1 allele e xpansion and FMR-1 protein expression on this individual should help t o determine the correlation of the molecular findings with the phenoty pic effects. (C) 1996 Wiley-Liss, Inc.