A MULTICENTER STUDY ON GENOTYPE-PHENOTYPE CORRELATIONS IN THE FRAGILE-X-SYNDROME, USING DIRECT DIAGNOSIS WITH PROBE STB-12.3 - THE FIRST 2,253 CASES

We report the results of a 14-center collaborative study of genotype-p henotype correlations in 318 fragile X families; these families compri sed 2,253 individuals, 1,344 of whom carried a fragile X mutation and 693 of whom had a typical full fragile X mutation. This study demonstr ates that direct DNA diagnosis establishes the genotype at the FRAXA-F MR-1 locus. There was a significantly higher prevalence of ''mosaic'' cases among males who carry a full mutation (12%) than among females w ho carry a full mutation (6%); the mosaic males had a larger expansion than did the mosaic females. Mental status of premutated individuals did not differ from that of those with a normal genotype. Both the abn ormal methylation of the FMR-1-EagI site and the size of the expansion were highly correlated with cytogenetics, facial dysmorphism, macroor chidism, and mental retardation (MR). Among female carriers of a full mutation, those with MR had significantly larger expansion than did th ose without MR. Among 164 independent couples, 3 unrelated husbands ca rried a premutation that suggests that the prevalence of fragile X pre mutations in the general population is similar to 0.9% of the X chromo somes. Our data validate the use of direct DNA testing for fragile X d iagnosis as well as for carrier identification and support and complet e the established relationships among the DNA results and the cytogene tic, physical, and psychological aspects of the disease.