Objective. - Fragile X syndrome is caused by a mutation involving expansion of a CGG trinucleotide repeat segment in the fragile X mental retardation-1 (FMR1) gene on the long arm of the X chromosome. This study was undertaken to determine the relative impact of three molecular characteristics of the FMR1 mutation-number of CGG repeats, methylation status, and X inactivation ratio-on the cognitive involvement of female carriers of fragile X syndrome. Design. - Retrospective study with new DNA analysis of known female carriers of fragile X syndrome. Setting. - Molecular studies were conducted in a university-based DNA diagnostic laboratory. Patients were originally ascertained through a regional fragile X clinic in a university-affiliated pediatric hospital. Patients. - Forty-eight female carriers of fragile X syndrome were studied, including 22 with a premutation (a small expansion to approximately 50 to 200 CGG repeats), 23 with a full mutation (a full expansion to >200 CGG repeats), and three with both types of mutations (mosaics). Results. - Median IQ score was significantly lower for females with a full mutation than for females with a premutation. No significant relationship was found between IQ score and number of CGG repeats or percentage methylation of the mutant allele within each mutation category. In addition, no significant relationship was found between IQ score and the proportion of normal FMR1 alleles on the active X chromosome in the carrier female group as a whole or in either mutation subgroup. Comparisons of leukocytes and saliva-borne epithelial cells in certain full-mutation carriers revealed striking differences in FMR1 mutation sizes. Conclusions. - Mutation category remains the most important predictor of affectedness in female carriers of fragile X syndrome. Our data do not support use of the proportion of normal FMR1 alleles on the active X chromosome as a predictor of cognitive involvement in female carriers with full mutations. Individual tissue-specific differences exist in the heterogeneous sizes of full mutations and in the presence of premutation/full-mutation mosaicism.
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