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

vast majority of individuals with the fragile X syndrome showexpanded stretches of CGG repeats In the 5' non-coding regionof FMR1. This expansion coincides with abnormal methylatlonpatterns in that area resulting in the silencing of the FMR1gene. Evidence is accumulating that this directly causes thefragile X phenotype. Very few other mutations in FMR1, causingthe fragile X phenotype have been reported thus far and allconcerned isolated cases. We, however, report a family, In which11 Individuals have a deletion of 1.6 kb proximal to the CGGrepeat of the FMR1 gene. Although fragile X chromosomes werenot detected, all 4 affected males and 2 of the carrier femalesshow characteristics of the fragile X phenotype. Using RT-PCRwe could demonstrate that FMR1 Is not expressed In the affectedmales, strongly suggesting that the FMR1 promoter sequences5' to the CGG repeat are missing. The deletion patients haveapproximately 45 CGG repeats in their FMR1 gene, though notinterspersed by AGG triplets that are usually present in bothnormal and expanded repeats. It Is hypothesized that prior tothe occurrence of the deletion, an expansion of the repeat occurred,and that the deletion removed the 5' part of the CGG repeatcontaining the AGG triplets. Transmission of the deletion throughthe family could be traced back to the deceased grandfatherof the affected males, which supports the hypothesis that theFMR1 gene product is not required for spermatogenesls. Finally,the data provide additional evidence that the fragile X syndromeis a single gene disorder.