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Fragile X syndrome (MIM No 3009550) is the most common inherited mental retardation disorder, affecting approximately 1 in 4000 males and 1 in 8000 females.1 Its name was derived from the observation of a fragile site on chromosome Xq27.3, designated FRAXA (fragile site, X chromosome, A site). This syndrome is caused by mutations in the fragile X mental retardation-1 gene (FMR1), more than 95% of which involve hyperexpansion and hypermethylation of a polymorphic CGG trinucleotide repeat in the 5′ untranslated region (5′UTR) of the gene.1–4
Among normal individuals, the number of CGG repeats ranges between 6 and 55. In most affected patients, the CGG repeats are massively expanded to over 200 repeats, and the gene becomes methylated at CpG islands and is silenced. Individuals with CGG repeats in the premutation range of 55 to 200 repeats are clinically unaffected, but these repeats are likely to be unstable during transmission to the next generation.1,2 This instability depends on the size of the premutation allele and is much more pronounced during maternal transmission. The larger the premutation alleles, the more likely they will be to expand to full mutations.1,5,6
Numerous diagnostic methods have been developed for fragile X syndrome, including cytogenetic, Southern blot, polymerase chain reaction (PCR), methylation specific PCR (ms-PCR), reverse transcription PCR (RT-PCR), and immunohistochemical analyses.7–10 The most commonly used molecular methods for the diagnosis of fragile X syndrome are Southern blot and PCR/ms-PCR analyses. The major disadvantage of the Southern blot method is its difficulty in distinguishing between large normal and small premutation alleles, while current PCR/ms-PCR techniques have poor sensitivity for detecting large premutation and full mutation alleles, especially in females.7–10 Although the combination of Southern and PCR methods enables reliable diagnosis of fragile X syndrome, …
Competing interests: none declared