Both fragile X (FRAXA) syndrome and fragile XE (FRAXE) disorder are caused by an expansion of a polymorphic trinucleotide repeat and are associated with mental impairment. Based on the size and methylation status of the expansion, individuals are classified as having normal, intermediate, premutation or full mutation alleles. Unlike individuals with full mutations, carriers of intermediate and premutated alleles should not exhibit obvious clinical symptoms, since the FMR1 (FRAXA) or FMR2 (FRAXE) genes are not transcriptionally silenced. However, there are data suggesting a phenotype consequence of the FRAXA premutation alleles. We have investigated a population consisted of 276 males with idiopathic mental retardation or learning disability and a control sample of 207 non-affected boys in order to determine if there was a possible phenotype consequence of the expanded unmethylated alleles for FRAXA/FRAXE loci. Direct molecular diagnosis for the FRAXA/FRAXE loci were performed in both populations by using PCR technique and sizing of the amplification products by electrophoresis in denaturing polyacrilamide gels. No FRAXA/FRAXE premutations or FRAXE mutated alleles were observed. The 25 FRAXA full mutations alleles detected were confirmed by Southern blot analysis. We found an excess of intermediate alleles for both FRAXA and FRAXE in the target population, but it did not reach statistically significant difference. This suggests that relatively large unmethylated repeats may not be associated with an abnormal cognitive and/or behavioral phenotype. However, recent evidence that FRAXA premutation alleles in males have increased FMR1 message levels emphasizes the need of more studies using large sample sizes and proper control population to resolve this contradictory observation.

Related Articles