A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: The first 2,253 cases

F. Rousseau, D. Heitz, J. Tarleton, J. MacPherson, H. Malmgren, N. Dahl, A. Barnicoat, C. Mathew, E. Mornet, I. Tejada, A. Maddalena, R. Spiegel, A. Schinzel, J. A G Marcos, D. F. Schorderet, T. Schaap, L. Maccioni, S. Russo, P. A. Jacobs, C. SchwartzJ. L. Mandel

Research output: Contribution to journalArticlepeer-review

Abstract

We report the results of a 14-center collaborative study of genotype- phenotype correlations in 318 fragile X families; these families comprised 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 demonstrates that direct DNA diagnosis establishes the genotype at the FRAXA-FMR-1 locus. There was a significantly higher prevalence of 'mosaic' cases among males who carry a full mutation (12%) than among females who 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 abnormal methylation of the FMR-1-EagI site and the size of the expansion were highly correlated with cytogenetics, facial dysmorphism, macroorchidism, and mental retardation (MR). Among female carriers of a full mutation, those with MR had significantly larger expansion than did those without MR. Among 164 independent couples, 3 unrelated husbands carried a premutation that suggests that the prevalence of fragile X premutations in the general population is ~0.9% of the X chromosomes. Our data validate the use of direct DNA testing for fragile X diagnosis as well as for carrier identification and support and complete the established relationships among the DNA results and the cytogenetic, physical, and psychological aspects of the disease.

Original languageEnglish
Pages (from-to)225-237
Number of pages13
JournalAmerican Journal of Human Genetics
Volume55
Issue number2
Publication statusPublished - 1994

ASJC Scopus subject areas

  • Genetics

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