A Microdeletion ofLessthan250kb,Including theProximal Part oftheFMR-IGeneandtheFragile-X Site, ina Malewiththe Clinical Phenotype ofFragile-X Syndrome

Summary A genedesignated "FMR-1"hasbeenisolated atthefragile-X locus. Oneexon ofthis geneiscarried on a 5.1-kb EcoRIfragment that exhibits length variation infragile-X patients because ofamplification ofor insertion into a CGG-repeat sequence.This repeatprobably represents thefragile site. TheEcoRIfragment also includes an HTFisland that ishypermethylated infragile-X patients showing absence ofFMR-1mRNA. Inthis paper,we presentfurther evidence that theFMR-1geneisinvolved intheclinical manifestation ofthe fragile-X syndrome andalso intheexpression ofthecellular phenotype. Adeletion including theHTFisland andexonsoftheFMR-1gene was detected inafragile X-negative mentally retarded malewhopresented the clinical phenotype ofthefragile-X syndrome. Thedeletion involves less than250kbofgenomic DNA, including DXS548andatleast five exonsoftheFMR-1gene.These data supportthehypothesis that loss of function oftheFMR-1geneleads totheclinical phenotype ofthefragile-X syndrome. Inthefragile-X syndrome, there arepathogenetic mechanisms other thanamplification oftheCGG repeatthat dohavethe same phenotypic consequences.