Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height

Abstract

The biological processes controlling human growth are diverse, complex and poorly understood. Genetic factors are important and human height has been shown to be a highly polygenic trait to which common and rare genetic variation contributes. Weaver syndrome is a human overgrowth condition characterised by tall stature, dysmorphic facial features, learning disability and variable additional features. We performed exome sequencing in four individuals with Weaver syndrome, identifying a mutation in the histone methyltransferase, EZH2, in each case. Sequencing of EZH2 in additional individuals with overgrowth identified a further 15 mutations. The EZH2 mutation spectrum in Weaver syndrome shows considerable overlap with the inactivating somatic EZH2 mutations recently reported in myeloid malignancies. Our data establish EZH2 mutations as the cause of Weaver syndrome and provide further links between histone modifications and regulation of human growth.

Figure 1. Facial features and height of EZH2 mutation-positive individuals

(a) Typical facial appearance of children with an EZH2 mutation and Weaver syndrome. (b) Height distribution of EZH2 mutation-positive individuals relative to the mean UK1990 height [22].

Figure 2. EZH2 structure, mutations and homology

(a) Schematic representation of the protein structure of EZH2 with domains and mutations. Missense mutations are represented above the protein and truncating mutations below the protein. (b) Across species homology of the EZH2 SET domain demonstrating missense mutations targeting conserved residues.