Molecular Characterisation and Assessment of Clinical Significance of Small Fragile X Alleles

BACKGROUND: Fragile X syndrome is a genetic mental retardation syndrome caused by an unstable mutation in thefragile X mental retardation 1 gene (FMR1) on the X chromosome. FMR1 CGG repeat alleles are categorized accordingto number as normal, intermediate, premutation, and full mutation alleles. Considerable information is available, fromreported studies, on the structure of the full mutation alleles. METHODS: This review focused on the characterization of FMR1 CGG repeat size alleles in the premutation andintermediate ranges. RESULTS: The premutation and intermediate carriers, previously thought to be clinically unaffected, are recentlyknown to be at increased risk of premature ovarian failure (POF), fragile X-associated tremor/ataxia syndrome(FXTAS), autism, emotional problems, late-onset neurodegenerative deficits, and neurocognitive deficits. A number ofstudies have suggested that the underlying cause might be RNA toxicity resulting from abnormally high levels of FMR1mRNA in these alleles. CONCLUSIONS: It can be concluded that abnormality of FMR1 gene has different clinical presentations, especially insmall alleles, and should be considered more by physicians in clinics. KEYWORDS: FMR1 Gene, FXS, Permutation alleles, POF, FXTAS