Molecular genetic analysis of mentally retarded males with features of the fragile-X syndrome.

The fragile-X[fra(X)] or Martin-Bell syndrome is the most common familial cause of mental retardation and is characterized by the presence of an Xq27.3 chromosome fragile site. Unstable DNA sequences representing large increases in the number of CGG trinucleotide DNA base repeats of the FMR-1 gene are located at the fragile site and responsible for the fra(X) syndrome. In order to identify whether cytogenetically normal yet mentally retarded males without a known cause of their retardation had expansion of the CGG repeat segment of the FMR-I gene, molecular genetic studies using Southern hybridization were performed with two DNA probes (fxa241 and Ox1.9) following digestion of genomic DNA from each patient with restriction enzymes Pstl and EcoRl/Eagl, respectively. DNA studies were performed on 20 (12.3%) out of 162 (122 white and 40 black people) cytogenetically normal mentally retarded males without a known cause of their retardation, but with high anthropometric discriminant values and/or clinical checklist scores identified previously and consistent with the fra(X) syndrome. None of the 20 males showed expansion of the CGG repeat of the FMR-1 gene detectable with the two probes used in this study. While heterogeneous single base pair substitutions, or small deletions or insertions in the FMR-I gene could exist in our patients, aberrations in other X-linked mental retardation genes, not identified to date but whose gene product can produce a phenotype similar to fra(X), either independently or in conjunction with the recently identified FMR-I protein, should be considered and are under investigation. Our study supports the idea that major FMR-I gene expansion detectable with Southern hybridization is rare in cytogenetically normal mentally retarded males, including those with physical and behavioural features seen in the fra(X) syndrome.