Variable FMR1 gene methylation of large expansions leads to variable phenotype in three males from one fragile X family.

The fragile X syndrome is caused by an expanded CGG repeat (> 200 units, full mutation) at the 5' end of the FMR1 gene, which is associated with methylation of a CpG island upstream of the FMR1 gene and down regulation of the transcription. We describe three related males with full mutations in the FMR1 gene, as defined by size, but with different percentages of unmethylated alleles (+/-90%, 35%, and 15%, respectively) as studied in leucocytes. Normal mental status was observed in the male who showed 90% lack of methylation, whereas his two cousins were retarded. The mentally normal male did show some minor facial features of the fragile X syndrome; the FMR protein was detectable in 75% of his leucocytes. In all three cases, the proportion of unmethylated FMR1 genes corresponded to the percentage of leucocytes showing FMR1 protein production. Our results indicated a direct relationship between methylation and the ability to produce FMR protein. These cases will be discussed in relation to the phenotypic effects of incompletely methylated full mutations in the FMR1 gene as observed by others.