A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases.
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.
Rousseau
F
F
Unité de Recherche en Génétique Humaine et Moléculaire, Centre de Recherche de l'Hôpital St-François-d'Assise, Québec, Canada.
Heitz
D
D
Tarleton
J
J
MacPherson
J
J
Malmgren
H
H
Dahl
N
N
Barnicoat
A
A
Mathew
C
C
Mornet
E
E
Tejada
I
I
D000293:Adolescent; D016009:Chi-Square Distribution; D015342:DNA Probes; D015226:Dinucleoside Phosphates / Q000378:metabolism; D005260:Female; D005600:Fragile X Syndrome / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology; D005787:Gene Frequency; D006580:Genetic Carrier Screening; D005838:Genotype; D006801:Humans; D016013:Likelihood Functions; D016015:Logistic Models; D008297:Male; D008745:Methylation; D009030:Mosaicism; D010641:Phenotype; D012737:Sex Factors
D015342:DNA Probes; D015226:Dinucleoside Phosphates; C015772:CpG dinucleotide