KMT2C/D COMPASS complex-associated diseases [KCDCOM-ADs]: an emerging class of congenital regulopathies

Clin Epigenetics. 2020 Jan 10;12(1):10. doi: 10.1186/s13148-019-0802-2.


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.

Keywords: CBP; COMPASS complex; Demethylase; EHMT1; EP300; Epigenetics; Histone deacetylase; KDM6A; KMT2C; KMT2D; Kabuki syndrome; Kleefstra syndrome; Lysine methyltransferase; Rubinstein-Taybi syndrome.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Chromosome Deletion
  • Chromosomes, Human, Pair 9 / genetics
  • Craniofacial Abnormalities / diagnosis
  • Craniofacial Abnormalities / genetics*
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Face / abnormalities*
  • Female
  • Heart Defects, Congenital / diagnosis
  • Heart Defects, Congenital / genetics*
  • Hematologic Diseases / diagnosis
  • Hematologic Diseases / genetics*
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Neoplasm Proteins / genetics*
  • Neoplasm Proteins / metabolism
  • Phenotype
  • Rubinstein-Taybi Syndrome / diagnosis
  • Rubinstein-Taybi Syndrome / genetics*
  • Vestibular Diseases / diagnosis
  • Vestibular Diseases / genetics*


  • DNA-Binding Proteins
  • KMT2C protein, human
  • KMT2D protein, human
  • Neoplasm Proteins

Supplementary concepts

  • Kabuki syndrome
  • Kleefstra Syndrome