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.
Highlights
The control of human growth is a complex process involving multiple different biological pathways
EZH2 (Enhancer of Zeste, Drosophila, homolog 2) encodes the catalytic component of the polycomb repressive complex 2 (PRC2), which epigenetically regulates chromatin structure and gene expression through trimethylation at H3K27 and recruitment of DNA methyltransferases, both of which act to repress transcription [11, 12]
EZH2 contains a number of functional domains and it is noteworthy that the majority of the mutations we identified are missense mutations that target highly conserved residues within these domains (Figure 2)
Summary
The control of human growth is a complex process involving multiple different biological pathways. Several conditions associated with human overgrowth are recognised and the underlying causes are extremely diverse [6]. GWAS studies have identified over 180 loci that contribute to human height, some of which overlap with Mendelian syndromes [1]. Weaver syndrome was first described in 1974 and is characterised by pre and postnatal overgrowth, variable learning disability and a distinctive facial appearance [2, 3]. The majority of cases are sporadic, though rare familial cases exhibiting an autosomal dominant pattern of inheritance have been reported [7,8,9]. We have undertaken exome sequencing and sanger sequencing to identify the cause of Weaver syndrome and to characterise the molecular and clinical associations of the causative gene
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