AN ATYPICAL CASE OF FRAGILE-X SYNDROME CAUSED BY A DELETION THAT INCLUDES THE FMRI GENE

Fragile X syndrome is the most common form of inherited mental retarda tion and results from the transcriptional inactivation of the FMR1 gen e. In the vast majority of cases, this is caused by the expansion of a n unstable CGG repeat in the first exon of the FMR1 gene. We describe here a phenotypically atypical case of fragile X syndrome, caused by a deletion that includes the entire FMR1 gene and greater than or equal to 9.0 Mb of flanking DNA. The proband, RK, was a 6-year-old mentally retarded male with obesity and anal atresia. A diagnosis of fragile X syndrome was established by the failure of RK's DNA to hybridize to a 558-bp PstI-XhoI fragment (pfxa3) specific for the 5'-end of the FMR1 gene. The analysis of Banking markers in the interval from Xq26.3-q28 indicated a deletion extending from between 160-500 kb distal and 9.0 Mb proximal to the FMR1 gene. High-resolution chromosome banding conf irmed a deletion with breakpoints in Xq26.3 and Xq27.3. This deletion was maternally transmitted and arose as a new mutation on the grandpat ernal X chromosome. The maternal transmission of the deletion was conf irmed by FISH using a 34-kb cosmid (c31.4) containing most of the FMR1 gene. These results indicated that RK carried a deletion of the FMR1 region with the most proximal breakpoint described to date. This patie nt's unusual clinical presentation may indicate the presence of genes located in the deleted interval proximal to the FMR1 locus that are ab le to modify the fragile X syndrome phenotype.