Method. We studied 511 persons from 63 families with the fragile X syndrome. Mutations and abnormal methylation were detected by Southern blotting with a probe adjacent to the mutation target. Analysis of EcoRI and Eagl digests of DNA distinguished clearly in a single test between the normal genotype, the premutation, and the full mutation.

Results. DNA analysis unambiguously established the genetic status at the fragile X locus for all samples tested. This method was much more powerful and reliable than cytogenetic testing or segregation studies with closely linked polymorphic markers. The frequency of mental retardation in persons with premutations was similar to that in the general population, whereas all 103 males and 31 of 59 females with full mutations had mental retardation. About 15 percent of those with full mutations had some cells carrying only the premutation. All the mothers of affected children were carriers of either a premutation or a full mutation.

Conclusions. Direct diagnosis by DNA analysis is now an efficient and reliable primary test for the diagnosis of the fragile X syndrome after birth, as well as for prenatal diagnosis and genetic counseling.