Epigenetic factors in intellectual disability: the Rubinstein-Taybi syndrome as a paradigm of neurodevelopmental disorder with epigenetic origin

The number of genetic syndromes associated with intellectual disability that are caused by mutations in genes encoding chromatin-modifying enzymes has sharply risen in the last decade. We discuss here a neurodevelopmental disorder, the Rubinstein-Taybi syndrome (RSTS), originated by mutations in the genes encoding the lysine acetyltransferases CBP and p300. We first describe clinical and genetic aspects of the syndrome to later focus on the insight provided by the research in animal models of this disease. These studies have not only clarified the molecular etiology of RSTS and helped to dissect the developmental and adult components of the syndrome but also contributed to outline some important connections between epigenetics and cognition. We finally discuss how this body of research has opened new venues for the therapeutic intervention of this currently untreatable disease and present some of the outstanding questions in the field. We believe that the progress in the understanding of this rare disorder also has important implications for other intellectual disability disorders that share an epigenetic origin.