Weaver syndrome is caused by loss-of-function mutations in EZH2. A. S. A. Cohen1,2, D. B. Yap3,4, X. Han5, S. M. E. Lewis1,2,6, C. Chijiwa1,6, M. A. Ramos-Arroyo7, D. D. Weaver8, C. J. D. Ross1,2,5, S. Aparício3,4, W. T. Gibson1,2 1) Department of Medical Genetics, University of British Columbia, Vancouver, BC V6T 1Z3, Canada; 2) Child and Family Research Institute, Vancouver, BC V5Z 4H4, Canada; 3) Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, V6T 2B5, Canada; 4) Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, BC V5Z 1L3, Canada; 5) Centre for Molecular Medicine and Therapeutics, Vancouver, BC V5Z 4H4, Canada; 6) British Columbia Childrens and Womens Health Center, Vancouver, V6H 3N1, Canada; 7) Department of Medical Genetics, Complejo Hospitalario de Navarra, Pamplona 31008, Spain; 8) Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

   In late 2011, we and others found that constitutional mutations in the epigenetic regulator EZH2 (enhancer of zeste homolog 2) cause Weaver Syndrome (WS). WS is characterized by overgrowth, increased height, large head, accelerated bone growth and maturation, intellectual disability, neuronal migration defects and susceptibility to various cancers. Having established a diagnostic test, we are now investigating the link between EZH2 mutations and the clinical features of WS, including cancer development.
   In addition to the mutations we previously reported, we have identified EZH2 mutations in three other patients from our cohort of 29 individuals with Weaver-like phenotypes: two novel mutations and one reoccurring mutation. Our goal is to look at phenotype/genotype correlations, with particular emphasis on determining characteristics that would help us predict the likelihood of these patients developing cancer. This would allow for early screening to detect both solid tumours and haematological malignancies, which should increase the patients' chances of survival.
   Furthermore, by collaborating with the Aparício lab at the BC Cancer Agency, we have investigated the effects of WS-associated mutations on protein function using in vitro assays. Normally, EZH2 acts as a histone methyltransferase in the polycomb-repressive complex 2 (PRC2), and silences transcription through methylation of histone H3 lysine 27 (H3K27). In contrast to the enhanced trimethylation activity seen in some somatic mutations that cause leukemia, the WS-associated EZH2 mutants show reduced methylation activity. These results support the hypothesis that WS is caused by loss-of-function mutations in EZH2. Although strategies to reduce EZH2 activity are currently being explored in common cancers such as leukemias, prostate cancer and breast cancer, our data suggest that these strategies may not be effective in rare cancers associated with WS.

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