Inactivating mutations in the histone demethylase KDM6A and loss-of-function mutations in the Trithorax gene MLL3 (Northcott et al., 2012) as well as elevated expression of the Polycomb proteins EZH2 (Robinson et al., 2012) and BMI1 (Behesti et al., 2013) were identified particularly in G4 MBs, raising the possibility that increased Polycomb repression is an important step in the pathogenesis of MBs and in particular of G4 tumors. This evidence concerns the gene EZH2 and Mobius syndrome.