Instability of the CGG repeat at the FRAXA locus and variable phenotypic expression in a large fragile X pedigree

Abstract

Fragile X syndrome is the major cause of inherited mental retardation. The molecular basis for the expression of the fragile X phenotype is the expansion of an unstable CGG repeat element which inhibits transcription of the FMR1 gene. The fragile X syndrome shows great diversity in its phenotype as well as in its cytogenetic and molecular status. We have studied, in a large fragile X family, the correlation between the molecular data and the phenotypic expression of the syndrome. We report two brothers who carry identical unmethylated premutated alleles but present different clinical phenotypes. We also suggest that reductions in allele size from one generation to another may be, as in other diseases, because of triplet amplifications, more common at the FRAXA locus than previously thought.