No mental retardation in a man with 40% abnormal methylation at the FMR-1 locus and transmission of sperm cell mutations as premutations

We report the case of a mentally normal male carrier of a fragile X full mutation with a ‘methylation mosaic’ hybridization pattern, who carried premutation-size mutations in his sperm cells and transmitted one of them to a daughter. Clinical evaluation of the father revealed a phenotype resembling that of the fragile X syndrome but without mental impairment and 4% fragile sites on cytogenetic analysis. Direct FRAXA genotyping revealed 40% abnormal methylation at the classical Eagl FMR-1 restriction site, a Δ of 400 bp to 1400 bp associated, in the non-methylated region, to a widely spread smear. This is thus a rare occurrence of a male carrier of a fragile X full mutation with significant methylation of the Eagl site and no mental impairment. A permutation of 400 bp was detected in his daughter's leukocytes and analysis of sperm cells from the father revealed a normal spermogram and only 400 bp permutations. This is the first documented case of transmission (with analysis of sperm DNA) of a fragile X mutation from a male carrier of a full fragile X mutation to a girl. This may be due to the early setting apart of progenitor germ cells in males having inherited a permutation from their mother. It is more likely that there could be a strong selection process favouring those cells with a reverted full mutation which produced a small and unmethylated FMR-1 CpG island allowing for re-expression of the FMR-1 gene, especially in male germ cells.