Mechanisms of Repeat Instability in Fragile X Syndrome

Abstract Most cases of fragile X syndrome (FXS) result from the inheritance of an FMR1 allele that has >200 CGG/CCG-repeats in its 5’ untranslated region. This allele arises on maternal transmission of an allele that has 55–200 repeats, with the repeat tract undergoing an expansion, or an increase in repeat number, during oogenesis or early embryogenesis. The mechanism responsible for this unusual mutation is unknown, but it is likely shared with the 20+ other genetic disorders, known collectively as the repeat expansion diseases, that arise from a similar repeat expansion. This chapter will review what we know about the epidemiology and natural history of the expansion mutation from studies of fragile X families. It will also discuss what we have learnt about the mechanisms responsible for repeat instability from various model systems of FXS and other related disorders.