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 FMR- 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 and his twin sister each had a full mutation with abnormal methylation. Their mother had an FMR-1 allele in the normal range and a large premutation, with normal methylation. The maternal grandmother had two normal 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 analyses identified a hybridization pattern that originated at a distinct premutation band and extended into the full mutation range. Methylation studies revealed a mosaic pattern with both unmethylated premutations and methylated full mutations. This individual declined formal evaluation but did not finish high school and has difficulty in reading and writing. The size of the premutation FMR-1 allele passed to his daughter is larger than his most prominent premutation allele. This is most likely due to gonadal mosaicism similar to that in his peripheral lymphocytes. 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 presumably mildly affected male is highly unusual. These findings are consistent with the absence of transmission of a full fragile X mutation through an expressing male. Studies of tissue specific FMR-1 allele expansion and FMR-1 protein expression on this individual should help to determine the correlation of the molecular findings with the phenotypic effects.