Grant: Travel Awards - Institute Community Support

In late 2011, our lab discovered that constitutional mutations in EZH2 are the main cause for Weaver syndrome (WS). Individuals with WS generally have overgrowth of the body and head, intellectual disability and cancer susceptibility. We found pathogenic mutations in EZH2 among 7 of 56 patients with Weaver-like features, of which two had developed malignancies prior to referral. The same gene has been associated to many cancers in the general population, suggesting its important role in cancer initiation and progression. We are collecting detailed phenotypic information on our patients hoping to identify predictors of cancer initiation. This strategy will also inform us further on the role of EZH2 in common cancers. Furthermore, given that EZH2 is a histone-modifying enzyme, we hypothesized that constitutional mutations in other epigenetic regulators associated to cancer could explain the overgrowth features seen in our undiagnosed patients. Using whole-exome-sequencing, we identified a novel de novo mutation in EED in one of our patients. EED is the main partner protein of EZH2 within the Polycomb Repressive Complex 2, which maintains gene silencing. Although somatic mutations in EED have been reported in various cancers, this is the first report of a constitutional mutation in the human gene, and its first association with overgrowth syndromes. Subsequently, we have identified a second patient with a different rare mutation in EED, and with significant phenotypic overlap to our first case. As such, we are confident that we have identified a novel overgrowth gene. These findings strengthen the hypothesis that cancer genes play a major role in regulating growth. Further investigations are needed to make a definitive link between mutations in these genes, Weaver-like syndromes, and cancer development.