Prediction of mental status in carriers of the fragile X mutation using CGG repeat length

Abstract

For genetic counseling in fragile X (fra(X)) families, it is important to know the diagnostic impact of the CGG repeat length in carriers of the fragile X mutation. We have analyzed the CGG repeat length in 106 males and 73 females who had inherited the maternal fra(X) mutation. The sensitivity, specificity, and predictive value of the CGG repeat analyses, as measured on Southern blots of PstI/EcoRI digests, were calculated. In males the sensitivity, specificity and negative predictive value were 99%, 100% and 94%; respectively. In females the specificity (60%) and, consequently, the positive predictive value (82%) was reduced. Therefore, it remains impossible to predict accurately whether a female fetus demonstrating a full mutation will be affected. On the other hand, the negative predictive value of the CGG test in females was 100%. We have no evidence, as yet, that for female carriers with the full mutation, cytogenetic analysis is of additional value to predict the mental status. However, we have observed one mentally retarded fra(X) case with extreme mosaicism in which a typical premutation fragment was the predominant DNA species. Therefore, until more data and better DNA tests are available, we would like to advocate additional cytogenetic investigation if in a fetus a CGG repeat length in the premutation range is found.

FRAXA and FRAXE prevalence in patients with nonspecific mental retardation in the Hellenic population

“…In recent studies, large premutation size expansions are associated with limited phenotypic effects of fragile X syndrome in males [Rousseau et al, 1994;Smits et al, 1994;Hagerman et al, 1996;Dorn et al, 1994;Loesch et al, 1994]. The unmethylated premutations detected in our two patients with borderline mental retardation have only 80 repeats and their phenotype could be due to other etiologies, the premutation being possibly a random finding.…”

Screening for Fragile X Syndrome: Information Needs for Health Planners

“…161 Males with an FM nearly always have a typical fragile X phenotype and there does not seem to be any correlation between the degree of mental retardation and the repeat size. 142 The existence of high functioning males with the fragile X phenotype has been suggested to relate to the level of FMRP produced.…”

Understanding fragile X syndrome: insights from animal models

“…Unlike most X-linked disorders, females can also be affected. 50-70 % of females carrying a disease-causing mutation also show mental impairment, although generally less severe compared to males with a disease-causing mutation (Rousseau et al, 1991a(Rousseau et al, , 1991bSmits et al, 1994;Taylor et al, 1994;De Vries et al, 1996b).…”