The diagnosis of mental retardation in fragile X syndrome is revolutionized by molecular genetics

: The fragile X syndrome is the most common cause of inherited mental retardation. Clinical signs, which are neither specific to the syndrome nor constant, become apparent late in childhood or after puberty, making early diagnosis difficult on a clinical basis alone. The inheritance of the syndrome is peculiar for an X linked disease, since a high proportion of female carriers show a certain degree of mental retardation and "normal transmitting males" do exist. Affected males can be diagnosed by cytogenetic demonstration of the typical fragile X site but only a minority of female carriers can be identified. This makes genetic counseling difficult. In 1991, the cloning and sequencing of the target site of the mutation marked an important step towards full understanding of the peculiarities of inheritance of the fragile X syndrome. A new type of mutation has been revealed: a multistep "expansion" of a small part of a gene that takes place over several generations. A new diagnostic technique by direct genotypic analysis has been developed. With a very high sensitivity and specificity, this analysis detects affected individuals with a "full mutation" (a large "expansion" associated with abnormal methylation of the surrounding region) and individuals with a "premutation" (smaller "expansion") who do not show mental retardation but are at risk of having affected children or grand children. With the direct DNA analysis at the fragile X locus, it is now possible to diagnose easily those children affected with the syndrome and to offer adequate genetic counseling and prenatal diagnosis to female carriers in affected families.(ABSTRACT TRUNCATED AT 250 WORDS)