Epigenetic causes of overgrowth syndromes.

Human overgrowth disorders are characterized by excessive prenatal and/or postnatal growth of various tissues. These disorders often present with tall stature, macrocephaly, and/or abdominal organomegaly and are sometimes associated with additional phenotypic abnormalities such as intellectual disability and increased cancer risk. As the genetic etiology of these disorders have been elucidated, a surprising pattern has emerged; multiple monogenic overgrowth syndromes result from variants in epigenetic regulators: variants in histone methyltransferases NSD1 and EZH2 cause Sotos syndrome and Weaver syndrome respectively; variants in DNA methyltransferase DNMT3A cause Tatton-Brown-Rahman syndrome; variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth; while very recently, a variant in histone reader protein SPIN4 was identified in a new X-linked overgrowth disorder. In this review, we discuss the genetics of these overgrowth disorders and explore possible common underlying mechanisms by which epigenetic pathways regulate human body size.