Independent studies have confirmed MECP2 as the major causative gene for Rett syndrome by the identification of multiple pathogenic mutations in approximately 95% of classic cases. Approximately 85% of classic Rett patients have point mutations and small rearrangements within the coding region; more recently, large gene rearrangements involving MECP2 were identified in ~10% of classic cases.22 Mutations also were found in atypical mild variant cases and in severe early-onset variant cases of Rett syndrome. MECP2 mutations also have been identified in rare affected males with variable phenotypes ranging from neonatal-lethal encephalopathy and a Rett syndrome-like presentation in mosaic or Klinefelter males, to males with uncharacterized MR. In addition, MECP2 mutations were documented in patients with an AS-like presentation and in patients with autistic phenotypes. The variability in phenotypic severity observed in individuals carrying an MECP2 mutation can result from allelic heterogeneity, as well as the X-inactivation pattern in females.21 Given the spectrum of neurodevelopmental phenotypes associated with MECP2 mutations, the clinical utility of molecular testing is significant.
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