Epigenetic Causes of Overgrowth Syndromes

Abstract

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, and variants in chromatin remodeler CHD8 cause an autism spectrum disorder with overgrowth. In addition, 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.

Keywords: WNT signaling; epigenetic modifications; histone; methylation; tall stature.

Figure 1.

Schematic diagrams of NSD1, EZH2, DNMT3A, and CHD8 proteins. Rectangles indicate functional domains; circles, ovals and diamonds indicate other proteins that interact with these domains. The numbers above each diagram indicate the number of reported variants within or between functional domains. Citations are shown as PubMed ID numbers.

Figure 2.

Diagram depicting epigenetic mechanisms involved in overgrowth syndromes. In the cell nucleus, the double helix DNA is packaged around histones forming nucleosomes, the repeating structural unit of chromatin and chromosome. Variants in genes that regulate DNA or histone modifications, which in turn affect gene expression, could result in a variety of overgrowth syndromes.