A deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene causes the clinical phenotype of the fragile X syndrome.

The vast majority of individuals with the fragile X syndrome show expanded stretches of CGG repeats in the 5' non-coding region of FMR1. This expansion coincides with abnormal methylation patterns in that area resulting in the silencing of the FMR1 gene. Evidence is accumulating that this directly causes the fragile X phenotype. Very few other mutations in FMR1, causing the fragile X phenotype have been reported thus far and all concerned isolated cases. We, however, report a family, in which 11 individuals have a deletion of 1.6 kb proximal to the CGG repeat of the FMR1 gene. Although fragile X chromosomes were not detected, all 4 affected males and 2 of the carrier females show characteristics of the fragile X phenotype. Using RT-PCR we could demonstrate that FMR1 is not expressed in the affected males, strongly suggesting that the FMR1 promoter sequences 5' to the CGG repeat are missing. The deletion patients have approximately 45 CGG repeats in their FMR1 gene, though not interspersed by AGG triplets that are usually present in both normal and expanded repeats. It is hypothesized that prior to the occurrence of the deletion, an expansion of the repeat occurred, and that the deletion removed the 5' part of the CGG repeat containing the AGG triplets. Transmission of the deletion through the family could be traced back to the deceased grandfather of the affected males, which supports the hypothesis that the FMR1 gene product is not required for spermatogenesis. Finally, the data provide additional evidence that the fragile X syndrome is a single gene disorder.