Epigenetics of fragile X syndrome and fragile X‐related disorders

The fragile X mental retardation 1 gene ( FMR 1 )‐related disorder fragile X syndrome ( FXS ) is the most common heritable form of cognitive impairment and the second most common cause of comorbid autism. FXS usually results when a premutation trinucleotide CGG repeat in the 5′ untranslated region of the FMR 1 gene ( CGG 55–200) expands over generations to a full mutation allele ( CGG >200). This expansion is associated with silencing of the FMR 1 promoter via an epigenetic mechanism that involves DNA methylation of the CGG repeat and the surrounding regulatory regions. Decrease in FMR 1 transcription is associated with loss of the FMR 1 protein that is needed for typical brain development. The past decade has seen major advances in our understanding of the genetic and epigenetic processes that underlie FXS . Here we review these advances and their implications for diagnosis and treatment for individuals who have FMR 1 ‐related disorders. What This Paper Adds Improved analysis of DNA methylation allows better epigenetic evaluation of the fragile X gene. New testing techniques have unmasked interindividual variation among children with fragile X syndrome. New testing methods have also detected additional cases of fragile X.