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.

Epigenetic Control of Skeletal Development by the Histone Methyltransferase Ezh2

“…We find that beyond a dysmorphic skull, loss of Ezh2 in mesenchymal cells also causes clinodactyly. Similar skull and hand abnormalities are seen in patients with Weaver syndrome that have hypomorphic germline mutations in EZH2 (65)(66)(67). Furthermore, limb and spine abnormalities we observe in mice with a mesenchymal deletion of Ezh2 reflect growth plate abnormalities that are reminiscent of human osteochondrodysplasias.…”

EZH2 and ALDH1 expression in ductal carcinoma in situ: Complex association with recurrence and progression to invasive breast cancer

“…7,11 EZH2 is deregulated by complex mechanisms in cancer and has diverse functional impacts related to development and cancer. [14][15][16][17] Consistent with such a concept, EZH2 expression was shown to progressively increase from normal breast tissue to atypical ductal hyperplasia, DCIS and IBC, suggesting that EZH2 protein levels increase as breast cancer develops. [18][19][20] Additionally, elevated EZH2 expression was detected in benign appearing breast epithelium from prophylactic mastectomies in women with BRCA1 mutation, indicating that EZH2 might predict increased risk for breast cancer.…”

Roles of enhancer of zeste homolog 2: From skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis

“…[117][118][119][120][121] These mutations show considerable overlap with mutations observed in other pathologies such as Weaver syndrome. 122 Likewise, in T-acute lymphoblastic leukemia, EZH2 and other PcG proteins are frequently mutated 123 with higher frequency of mutations in pediatric subtype of leukemia.…”