Herein, we will discuss how defects in a developmentally important, promoter-activating and enhancer-commissioning pathways can link mutations in five different genes associated with three distinct congenital epigenetic diseases: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C) (Fig. 1a). This evidence concerns the gene CREBBP and Rubinstein-Taybi syndrome.