Segregation of the fragile X mutation from an affected male to his normal daughter

We report here a family in which the fragile X mutation segregates from an affected grandfather through his normal daughter to an affected grandson. The grandson shows clinical and cytogenetic expression of fragile X syndrome due to a full mutation (large methylated insertion) in the fragile X gene (FMR-1). The mother shows a premutation (small unmethylated insertion) in her FMR-1 gene as the sole manifestation of the fragile X syndrome. The grandfather expresses the fragile X syndrome at the clinical and cytogenetic level, whereas he is mosaic for a methylated full mutation and an unmethylated premutation. The absence of expression of the fragile X mutation when transmitted through an expressing male might present further evidence for genomic imprinting of the FMR-1 gene. Alternatively, it is possible that the grandfather transmitted his premutation to his daughter due to germline mosaicism with both the premutation and the full mutation present in his sperm.