The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically 
active scaffold proteins that form the core of nuclear regulatory structures 
known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). 
These evolutionarily conserved proteins regulate DNA promoter and enhancer 
elements, modulating the activity of diverse cell types critical for embryonic 
morphogenesis, central nervous system development, and post-natal survival. 
KMT2C/D COMPASS complexes and their binding partners enhance active gene 
expression of specific loci via the targeted modification of histone-3 tail 
residues, in general promoting active euchromatic conformations. Over the last 
20 years, mutations in five key COMPASS complex genes have been linked to three 
human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), 
Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome 
type 2 (KMT2C). Here, we review the composition and biochemical function of the 
KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS 
complex are highlight with a focus on clinically relevant mechanisms sensitive 
to haploinsufficiency. The phenotypic similarities and differences between the 
members of this new family of disorders are outlined and emerging therapeutic 
strategies are detailed.