Genetic and epigenetic influences on the phenotype of Rett syndrome

Rett syndrome is a rare neurodevelopmental disorder caused by a mutation in the MECP2 gene and associated with severe functional impairments and medical comorbidities. Since first described in 1966, there has been striking progress in understanding biological and clinical aspects. With the phenotype of the affected child in mind, this chapter describes the genetic cause and adverse biological effects of reduced MeCP2 production. We illustrate the clinical presentation of functional abilities and the health challenges of comorbidities, each of which can be associated with adverse effects on quality of life. We discuss the more recent field of epigenetics in relation to Rett syndrome and highlight possible therapeutic avenues that would aim to reduce adverse neighborhood effects on biological functioning and thereafter phenotype. Finally, we consider how these three fields of investigation can each contribute to insightful epidemiological datasets to accelerate the pipeline of discovery.