2 NEW CASES OF FMRI DELETION ASSOCIATED WITH MENTAL IMPAIRMENT

Screening of families clinically ascertained for the fragile X syndrom e phenotype revealed two mentally impaired males who were cytogenetica lly negative for the fragile X chromosome. In both cases, screening fo r the FMR1 trinucleotide expansion mutation revealed a rearrangement w ithin the FMR1 gene. In the first case, a 660-bp deletion is present i n 40% of peripheral lymphocytes. PCR and sequence analysis revealed it to include the CpG island and the CGG trinucleotide repeat, thus remo ving the FMR1 promoter region and putative mRNA start site. In the sec ond case, PCR analysis demonstrated that a deletion extended from a po int proximal to FMR1 to 25 kb into the gene, removing all the region 5 ' to exon II. The distal breakpoint was confirmed by Southern blot ana lysis and localized to a 600-bp region, and FMR1-mRNA analysis in a ce ll line established from this individual confirmed the lack of a trans cript. These deletion patients provide further confirmatory evidence t hat loss of FMR1 gene expression is indeed responsible for mental reta rdation. Additionally, these cases highlight the need for the careful examination of the FMR1 gene, even in the absence of cytogenetic expre ssion, particularly when several fragile X-like clinical features are present.