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

Am J Hum Genet. 1994 Aug;55(2):225-37.


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 approximately 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.

Publication types

  • Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Chi-Square Distribution
  • DNA Probes*
  • Dinucleoside Phosphates / metabolism
  • Female
  • Fragile X Syndrome / diagnosis*
  • Fragile X Syndrome / genetics*
  • Fragile X Syndrome / pathology
  • Gene Frequency
  • Genetic Carrier Screening
  • Genotype
  • Humans
  • Likelihood Functions
  • Logistic Models
  • Male
  • Methylation
  • Mosaicism
  • Phenotype
  • Sex Factors


  • DNA Probes
  • Dinucleoside Phosphates
  • cytidylyl-3'-5'-guanosine