What is Kabuki Syndrome?

Kabuki syndrome is a rare, multi-system genetic disorder characterized by multiple life-altering symptoms including varying degrees of intellectual disability, distinctive facial features, and other cardiac, immune, neurological, growth and skeletal symptoms. Severity and occurance of symptoms may vary from one person to another. There is much more to learn about Kabuki syndrome. And there is hope!

As we accelerate research towards treatments and a cure, 

we look forward to sharing all we

learn with you. Join us!

 

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Overview & Common Symptoms

Kabuki syndrome is a rare genetic disorder first described in 1981 by Japanese researchers, Dr. Norio Niikawa and Dr. Yoshikazu Kuroki.1,2 Dr. Niikawa noted similarities between the facial features of those with Kabuki syndrome and the make-up used in traditional Japanese Kabuki Theater and called the condition Kabuki make-up syndrome (KMS). Kabuki syndrome has been referred to as KMS, Niikawa-Kuroki syndrome, and Kabuki syndrome.

In 2010, researchers at the University of Washington discovered the first gene responsible for Kabuki syndrome: KMT2D, formerly known as MLL2.3  In 2012, KDM6A was confirmed as the second gene to cause Kabuki syndrome.4 Variants (or spelling changes) causing Kabuki syndrome on these genes usually occur randomly, but Kabuki syndrome can be inherited (passed from parents to children). 


Kabuki syndrome occurs in approximately 1:32,000 births and is believed to occur equally across all ethnicities and both sexes. Each person with Kabuki syndrome is unique. Symptoms and their severity can vary widely between individuals. Some of the most common symptoms include5, 6, 7:   

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The Epigenetic Mechanisms of Kabuki Syndrome

To understand new treatment pathways, we must first understand

Kabuki syndrome as an epigenetic disorder.

To date, researchers have identified two genes that can cause Kabuki syndrome when variants in the gene cause a dysfunction - known as pathogenic variants. Pathogenic variants in the KMT2D gene (formerly known as MLL2) account for 75% of cases.8 Pathogenic variants in the KDM6A gene account for ~10% of cases.1 Pathogenic changes in these genes can cause epigenetic changes. Understanding these changes may be key to identifying therapeutic targets and developing treatments.

 

DNA is the language of life, and how the cells in our bodies know what to do. The entirety of our DNA is the human genome, or “book of life.” If the genome is a book, the genes are the words. Even though researchers have had the entire human genome “book” for over 20 years, they are still learning how to read it. Each gene (“word”) can have hundreds of different meanings. One way to read a book in different ways is to highlight the words that you need, and maybe you even have a different color highlighter for different types of words. Your genome’s highlighting system, or how your DNA is read, is your epigenetics. 

 

Epigenetics are reversible and affected by your environment, including diet and drugs. Epigenetic marks (like highlights) change how the DNA is read, but not the DNA itself. Note that your DNA is not floating around in long lines, but it is often tightly packed into chromatin - a mixture of DNA wrapped around histone proteins that provide structural support. Epigenetic “highlights” in the form of histone marks can be added (highlighted) or removed (erased), changing which information in the DNA is read. Your genes and epigenetics normally complete these jobs of highlighting and erasing in a balanced way.

KMT2D is one such highlighter or writer. KMT2D marks histones to open chromatin, enables the DNA to be read, and ultimately influences gene expression (how your body looks and functions). Variants in KMT2D that cause Kabuki syndrome result in too much closed chromatin, and the instructions in DNA cannot be read. Without these instructions, gene expression is changed during development and throughout life, and this leads to the symptoms of Kabuki syndrome. Researchers are exploring different ways to restore the balance between open and closed chromatin to treat symptoms of Kabuki syndrome.9

 

Pathogenic variants in KDM6A also result in too much closed chromatin but in a different way. KDM6A “erases” or removes a close chromatin mark. If the marks to close the chromatin are not appropriately erased, too much chromatin is closed and an imbalance occurs. Researchers are also exploring ways to restore the balance between open and closed chromatin to treat symptoms in people with a KDM6A mutation.

 

Some individuals are clinically diagnosed with Kabuki syndrome.10 This means that no pathogenic variant was found on either gene, or that genetic testing was not completed or did not include these genes. In the future, additional genes and gene mutations that cause Kabuki syndrome may also be discovered.

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Additional Resources for Families & Providers

From Genotype to Phenotype - A Review of Kabuki Syndrome.

Includes "Recommended initial evaluation by organ system" starting on page 7.

Barry KK, Tsaparlis M, Hoffman D, Hartman D, Adam MP, Hung C, Bodamer OA. From Genotype to Phenotype—A Review of Kabuki Syndrome. Genes. 2022; 13(10):1761. https://doi.org/10.3390/genes13101761

Caregiver-reported Clinical Characteristics and the burden associated with Kabuki syndrome.

Theodore-Oklota C, Egan S, Paulich M, et al. Caregiver-reported clinical characteristics and the burden associated with Kabuki syndrome. Am J Med Genet Part A. 2020;1–9. https://doi.org/10.1002/ajmg.a.61584

International consensus of diagostic criteria.

Adam MP, Banka S, Bjornsson HT, Bodamer O, Chudley AE, Harris J, Kawame H, Lanpher BC, Lindsley AW, Merla G, Miyake N, Okamoto N, Stumpel CT, Niikawa N; Kabuki Syndrome Medical Advisory Board. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2019 Feb;56(2):89-95. doi: 10.1136/jmedgenet-2018-105625. Epub 2018 Dec 4. PMID: 30514738.

Growth charts in Kabuki syndrome 1.

Ruault V, Corsini C, Duflos C, et al. Growth charts in Kabuki syndrome 1. Am J Med Genet Part A. 2020;182A: 446 - 453.  https://doi.org/10.1002/ajmg.a.61462

Sources as Cited Above

 

  1. Niikawa N, Matsuura N, Fukushima Y, Ohsawa T, Kajii T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J Pediatr. 1981 Oct;99(4):565-9. doi: 10.1016/s0022-3476(81)80255-7. PMID: 7277096.

  2. Kuroki Y, Suzuki Y, Chyo H, Hata A, Matsui I. A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J Pediatr. 1981 Oct;99(4):570-3. doi: 10.1016/s0022-3476(81)80256-9. PMID: 7277097.

  3. 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. Nat Genet. 2010 Sep;42(9):790-3. doi: 10.1038/ng.646. Epub 2010 Aug 15. PMID: 20711175; PMCID: PMC2930028.

  4. Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, Maystadt I, Dallapiccola B, Verellen-Dumoulin C. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012 Jan 13;90(1):119-24. doi: 10.1016/j.ajhg.2011.11.021. Epub 2011 Dec 22. PMID: 22197486; PMCID: PMC3257878.

  5. Adam MP, Hudgins L, Hannibal M. Kabuki Syndrome. 2011 Sep 1 [Updated 2021 Jul 15]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62111/

  6. Caciolo C, Alfieri P, Piccini G, Digilio MC, Lepri FR, Tartaglia M, Menghini D, Vicari S. Neurobehavioral features in individuals with Kabuki syndrome. Mol Genet Genomic Med. 2018 May;6(3):322-331. doi: 10.1002/mgg3.348. Epub 2018 Mar 13. PMID: 29536651; PMCID: PMC6014453.

  7. Rapp T, Kalinousky AJ, Johnson J, Bjornsson H, Harris J. Sleep disturbance is a common feature of Kabuki syndrome. Am J Med Genet A. 2022 Oct;188(10):3041-3048. doi: 10.1002/ajmg.a.62921. Epub 2022 Aug 5. PMID: 35930004; PMCID: PMC9474613.

  8. Adam MP, Hudgins L, Hannibal M. Kabuki Syndrome. 2011 Sep 1 [Updated 2021 Jul 15]. In: Adam MP, Everman DB, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK62111/

  9. Björnsson H. Kabuki syndrome: A potentially treatable cause of intellectual disability. Lecture presented: Kabuki Syndrome Foundation Research Conference at Johns Hopkins University Hospital; June 27, 2015; Baltimore, MD.

  10. Adam MP, Banka S, Bjornsson HT, Bodamer O, Chudley AE, Harris J, Kawame H, Lanpher BC, Lindsley AW, Merla G, Miyake N, Okamoto N, Stumpel CT, Niikawa N; Kabuki Syndrome Medical Advisory Board. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2019 Feb;56(2):89-95. doi: 10.1136/jmedgenet-2018-105625. Epub 2018 Dec 4. PMID: 30514738.