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Genetic Basis of KS

Molecular Genetics 101

Originally described simultaneously by two Japanese groups in 1981, the cause and mechanisms underlying Kabuki syndrome have been largely unknown. Recent research, however, suggests that KS is a genetic syndrome, caused by a spectrum of mutations, including mutations in mixed lineage leukemia 2 (MLL2). To understand the etiology (cause) of KS, it is important to learn a few key terms used in scientific research.

To begin, the term phenotype (derived from Greek) is used to describe the “form that is shown” or variants in character form [1]. For instance, the symptoms, or clinical manifestations as a result of a non-functional MLL2 protein that we often see in KS, would be a phenotype.

Genotype, on the other hand, is the genetic makeup of a cell.  In most cases, when changes in the genotype of an individual occur, we see a phenotype resulting from alterations in a corresponding gene [1]. For example, mutations in the MLL2 gene would be a genotype [2] that may contribute to the symptoms seen in KS.

Types of Genetic Mutations Involved in KS

To date, researchers believe that genetic mutations seen in KS appear to be sporadic or “de novo“–meaning they are not inherited from either parent, but have occurred for the first time by chance.   However, instances where parent-to-child transmittance has occurred, may indicate an autosomal dominant pattern of inheritance [4].

Introductory Video | Discovery of a Gene for KS by Exome Sequencing by Dr. M Hannibal

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Regulating the Process of Transcription via Histone Modification (Image)

Before genetic material can be translated into a specific protein, it needs to go through the process of transcription during which genetic information, in the form of DNA, is copied into an RNA molecule [14]. The transcription process is the intermediate step going from gene to protein. This process is meticulously regulated by numerous factors and signals.  Changes in the transcription process may disrupt the process of translation.

In KS, mutations in the MLL2 and/or KDM6A genes (further discussed below), result in changes in the production of their respective proteins, the MLL2 and/or KDM6A enzymes. These enzymes, necessary for normal function of the body system, may become defective, or may not be synthesized at all.

Video of Regulation of the Transcription Process

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Histone Modifications

In Kabuki syndrome, genetic mutations of the MLL2 involve nonsense mutations, frameshift mutations, and missense mutations with a frequency of 37%, 35% and 16% respectively [12,15]. A second gene recently discovered by Lederer et al. involves primarily deletions of the KDM6A gene [9,15].

Mutations in the MLL2 and KDM6A genes may affect the initiation of transcription. Specifically, MLL2 is a histone methylase protein; whilst, KDM6A is a histone demethylase enzyme.  Histones are a type of basic protein that forms the unit around which DNA is coiled in the nucleosomes [1].  Each of the MLL2 protein and KDM6A protein catalyzes the methylation or demethylation of DNA molecule respectively [1, 12].

Epigenetics Video

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Video of Histone Modifications

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MLL2 histone methylase and KDM6A histone demethylase function in the modification of core histones in order to regulate gene activity, chromatin structure, dosage compensation and epigenetic memory [1, 12]. MLL2 is responsible for the regulation of cellular H3K4 methylation gene activities, whilst KDM6A reverses H3K27 di- trimethylation processes [12].

In KS patients, the processes of methylation and/or demethylation may go awry, and transcription activities can no longer be properly regulated, leading to the clinical features seen in the syndrome.

The MLL2 Gene

The clinical features of KS appear to be the result of loss-of-function mutations in the Mixed Lineage Leukemia-2 (MLL2/ALR) gene. The male-to-female ratio of occurrence is nearly equal [5].

The MLL2 gene is located on the long (q) arm of chromosome 12 at position 13.12 [3]. It functions to encode a histone methyl transferase enzyme important in controlling whether certain genes are actively expressed [6] during stages of embryogenesis and development [8]. This protein enzyme is involved in adding gene-activating modifications to histone proteins that function to regulate the activity of certain genes important for normal growth and development [4,10]. Specifically, mutations in the MLL2 gene is believed to cause the misregulation of gene expression [4].

The KDM6A Gene

Most recently a Belgian research group discovered the involvement of an X chromosome gene, lysine (K)-specific demethylase 6A, KDM6A, in the development of Kabuki Syndrome in a small group of MLL2-mutation-negative patients [9]. The KDM6A gene is located at Xp11.2, from base pair 44,732,423 to base pair 44,971,847, on the X chromosome [11].

It appears that KDM6A encodes a histone demethylase enzyme that specifically catalyzes demethylation that mediates tissue-specific expression of some of the genes involved in developmental processes and the cell cycle [9].  Furthermore, the KDM6A gene regulates the genetic activity of MLL2 in epigenetic control processes [9], and that partial or complete deletions of KDM6A may contribute to the development of KS, even when no detectable MLL2 mutations have been found [11].


  1. Griffiths AJF, Wessler SW, Lewontin RC, Carroll SB. Introduction to Genetic Analysis. 8th ed. (2007) W.H. Freeman & Company.
  2. Kabuki Syndrome Gene Identified. Available from: Accessed Mar 10 2012.
  3. MLL2 myeloid/lymphoid or mixed lineage leukemia 2;  Available from: Accessed 18 June 2012.
  4. Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Clin Genet. 2011 Feb;79(2):133-4.
  5. Matsumoto N, Niikawa N. Kabuki Make-up Syndrome: A Review. American Journal of Medical Genetics Part C (Semin. Med. Genet.) 117C:57-65 (2003)
  6. Hannibal MC, Buckingham KJ, Ng SB, Ming JE, Beck AE, McMillin MJ, Gildersleeve HI, Bigham AW, Tabor HK, Mefford HC, Cook J, Yoshiura K, Matsumoto T, Matsumoto N, Miyake N, Tonoki H, Naritomi K, Kaname T, Nagai T, Ohashi H, Kurosawa K, Hou JW, Ohta T, Liang D, Sudo A, Morris CA, Banka S, Black GC, Clayton-Smith J, Nickerson DA, Zackai EH, Shaikh TH, Donnai D, Niikawa N, Shendure J, Bamshad MJ. Spectrum of MLL2 (ALR) mutations in 110 cases of Kabukisyndrome. Am J Med Genet A 2011 Jul; Vol. 155A (7), 1511-1516
  7. Daniel JA, Nussenzweig A. Roles for histone H3K4 methyltransferase activities during immunoglobulin class-switch recombination. Biochimica Et Biophysica Acta (BBA) – Gene Regulatory Mechanisms 2012, Feb.
  8. Paulussen ADC, Stegmann APA, et al. MLL2 Mutation Spectrum in 45 Patients with Kabuki Syndrome. Human Mutation: Mutation in Brief 32: E2018-E2025 (2010).
  9. Lederer D, Grisart B, Digilio M, Benoit V, Crespin M, Ghariani S, & … Verellen-Dumoulin C. (2012). Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Of Hum Genet, 90(1), 119-124.
  10. MLL2 myeloid/lymphoid or mixed lineage leukemia 2;  Available from: Accessed 18 June 2012.
  11. lysine (K)-specific demethylase 6A – Gene Cards | Protein | Antibody. Available from: Accessed May 15 2012.
  12. Micale L, and Merla G. (May 2012) Molecular Genetics of Kabuki Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023848] Accessed July 10 2012.
  13. Bokinni Y. Kabuki syndrome revisited. J Hum Genet 2012, Apr;57(4):223-7.
  14. Hartl DL, Jones EW. Genetics: Analysis of Genes and Genomess. 7th ed. (2009) Jones and Barlett Publishers, Inc.
  15. Bögershausen N, Wollnik B. Unmasking kabuki syndrome. Clin Genet 2012, Nov 6.

From Genotype to Phenotype

Kabuki syndrome is considered to be both phenotypically variable and genetically heterogeneous [1]. Because the MLL2 protein is found in many organs and tissues of the body, KS often results in a wide spectrum of clinical characteristics, involving multiple body systems [2].

To read more about phenotypic characteristics or symptoms often seen in KS, please visit our Symptoms section. 


  1. Micale L, and Merla G. (May 2012) Molecular Genetics of Kabuki Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0023848] Accessed July 10 2012.
  2. Kawame H, Hannibal M, Hudgins L, Pagon R. Phenotypic spectrum and management issues in Kabuki syndrome. Am J Med Genet (Semin Med Genet) 1999.