Advances in Molecular Analysis of Fragile X Syndrome

Fragile X syndrome is a common cause of mental retardation that is inherited as an X-linked dominant disorder with reduced penetrance. Fragile X syndrome has been shown to be caused by an unstable CGG repeat within the fragile X mental retardation—1 (FMR1) gene. The repeat is normally polymorphic with six to 52 repeats, while affected males and females exhibit a massive expansion resulting in 230 to more than 1000 repeats. Such expansions, called "full mutations," are associated with abnormal methylation of the FMR1 gene leading to transcriptional suppression. The resulting absence of the encoded protein, FMRP, a cytosolic RNA-binding protein, is believed to result in the phenotype. Nonpenetrant male carriers and many female carriers exhibit premutation alleles of intermediate length (50 to 230 repeats), which are normally expressed. Male carriers transmit only unstable premutations while female premutation carriers can have carrier offspring with premutations or affected children with full mutations. The risk of having an affected child is directly related to the number of maternal repeats, with sequentially increasing probabilities of these alleles converting to full mutations as they are transmitted to subsequent generations. Advances have led to highly accurate laboratory diagnoses of both carrier and affected individuals as well as markedly improved prenatal diagnosis. In addition, a previously unrecognized class of mutation, later found responsible for several other important genetic diseases, has emerged.

(JAMA. 1994;271:536-542)