Clinical characteristics.

Kabuki syndrome (KS) is characterized by typical facial features (long palpebral fissures with eversion of the lateral third of the lower eyelid; arched and broad eyebrows; short columella with depressed nasal tip; large, prominent, or cupped ears), minor skeletal anomalies, persistence of fetal fingertip pads, mild-to-moderate intellectual disability, and postnatal growth deficiency. Other findings may include: congenital heart defects, genitourinary anomalies, cleft lip and/or palate, gastrointestinal anomalies including anal atresia, ptosis and strabismus, and widely spaced teeth and hypodontia. Functional differences can include: increased susceptibility to infections and autoimmune disorders, seizures, endocrinologic abnormalities (including isolated premature thelarche in females), feeding problems, and hearing loss.

Diagnosis/testing.

The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following:

• Typical dysmorphic features (long palpebral fissures with eversion of the lateral third of the lower eyelid, and ≥2 of the following: arched and broad eyebrows with the lateral third displaying notching or sparseness; short columella with depressed nasal tip; large, prominent, or cupped ears; persistent fingertip pads)
• A heterozygous pathogenic variant in KMT2D or a heterozygous or hemizygous pathogenic variant in KDM6A

Management.

Treatment of manifestations: Thickened feedings and positioning after meals to treat gastroesophageal reflux; gastrostomy tube placement if feeding difficulties are severe. If cognitive difficulties are evident, psychoeducational testing and special education services to address the individual child's needs. Evaluation by a developmental pediatrician or psychiatrist if behavior suggests autism spectrum disorders. Standard anti-seizure treatment.

Prevention of secondary complications: Prophylactic antibiotic treatment prior to and during any procedure (e.g., dental work) may be indicated for those with specific heart defects.

Surveillance: Monitor height, weight, and head circumference at each well-child visit and, at a minimum, yearly. Developmental milestones should be followed with each well-child visit. Monitor vision and hearing on a yearly basis.

Genetic counseling.

KMT2D-related KS is inherited in an autosomal dominant manner; KDM6A-related KS is inherited in an X-linked manner.

Autosomal dominant inheritance: The proportion of KS caused by a de novo KMT2D pathogenic variant is unknown but is likely high based on clinical experience. In the rare case that a parent of the proband is affected, the risk to the sibs is 50%.

X-linked inheritance: If the mother of the proband has a KDM6A pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygous and may have features of KS.

Once the causative pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for KS are possible.

Suggestive Findings

KS should be suspected in individuals with any combination of the five cardinal manifestations as defined by Niikawa et al [1988], specific structural anomalies, and/or functional differences.

Cardinal manifestations

1.

Typical facial features:

• Long palpebral fissures with eversion of the lateral third of the lower eyelid
• Highly arched and broad eyebrows with the lateral third displaying sparseness or notching
• Short columella with depressed nasal tip
• Large, prominent, and/or cupped ears

2.

Skeletal anomalies:

• Spine abnormalities including sagittal clefts, hemivertebrae, butterfly vertebrae, narrow intervertebral disc space, and/or scoliosis
• Brachydactyly V
• Brachymesophalangy
• Clinodactyly of fifth digits

3.

Dermatoglyphic abnormalities: persistence of fetal fingertip pads

Note: While absence of digital triradius c and/or d and increased digital loop and hypothenar loop patterns can be observed, this type of analysis is not routinely done in clinical practice in most centers.

4.

Mild-to-moderate intellectual disability

5.

Postnatal growth deficiency

Structural anomalies in KS can include the following:

• Ophthalmologic anomalies including ptosis and strabismus
• Ear pits (a potentially helpful diagnostic clue when seen with other typical findings)
• Cleft lip and/or palate
• Dental anomalies including widely spaced teeth and hypodontia
• Congenital heart defects
• Gastrointestinal anomalies including anal atresia
• Genitourinary anomalies including cryptorchidism in males

Functional differences can include the following:

• Hearing loss
• Feeding problems
• Endocrinologic abnormalities including isolated premature thelarche in females
• Increased susceptibility to infections and autoimmune disorders
• Seizures

Establishing the Diagnosis

The diagnosis of KS is established in a proband of any age with a history of infantile hypotonia, developmental delay, and/or intellectual disability AND one or both of the following [Adam et al 2019]:

• Typical dysmorphic features * at some point of life
• A heterozygous pathogenic (or likely pathogenic) variant in KMT2D or a heterozygous or hemizygous pathogenic (or likely pathogenic) variant in KDM6A (Table 1)

* Typical dysmorphic features include long palpebral fissures (a palpebral fissure measurement ≥2 SD above the mean for age) with eversion of the lateral third of the lower eyelid AND two or more of the following:

• Arched and broad eyebrows with the lateral third displaying notching or sparseness
• Short columella with depressed nasal tip
• Large, prominent, or cupped ears
• Persistent fingertip pads

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include likely pathogenic variants. (2) The identification of variant(s) of uncertain significance cannot be used to confirm or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single-gene testing, concurrent or serial single-gene testing, multigene panel) and comprehensive genomic testing (chromosomal microarray analysis, exome sequencing, exome array, genome sequencing) depending on the phenotype.

Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Kabuki syndrome is broad, individuals with the distinctive findings described in Suggestive Findings are likely to be diagnosed using gene-targeted testing (see Option 1), whereas those in whom the diagnosis of Kabuki syndrome has not been considered are more likely to be diagnosed using genomic testing (see Option 2).

Clinical Description

This section summarizes findings in more than 400 individuals with a molecularly confirmed diagnosis of Kabuki syndrome (KS).

Phenotype Correlations by Gene

KMT2D

• Those with a KMT2D pathogenic variant are more likely to have the distinctive Kabuki facial phenotype, which may reflect the fact that a portion of those without a KMT2D pathogenic variant may indeed have been misdiagnosed.
• In general, those with a KMT2D pathogenic variant are also more likely to have renal anomalies, feeding problems, premature thelarche in females, joint dislocations, and palatal anomalies than are those without a KMT2D pathogenic variant [Bögershausen & Wollnik 2013, Courcet et al 2013].

KDM6A. The following are more common in individuals with a pathogenic variant in KDM6A [Banka et al 2015, Yap et al 2019]:

• Hypoglycemia as a result of hyperinsulinism
• Hypertrichosis
• Long halluces
• Large central incisors

Affected males are more likely to have moderate-to-severe developmental delay / cognitive impairment than are females, who may have mild-to-moderate intellectual disability. In general, females with a pathogenic variant in KDM6A tend to have milder features than affected males, despite the fact that KDM6A escapes X-chromosome inactivation [Banka et al 2015].

Genotype-Phenotype Correlations

KMT2D

• Individuals with KS caused by a heterozygous pathogenic missense variants in the terminal regions of KMT2D may have an increased risk for autoimmune disease [Lindsley et al 2016].
• Individuals with KS caused by a whole-gene deletion of KMT2D or pathogenic truncating variants that occur in the first half of the gene may have more severe intellectual disability [Lehman et al 2017].

Note: Individuals with a heterozygous pathogenic variant involving exons 38 or 39 potentially resulting in a gain of function may have some features similar to KS but otherwise have a phenotype that is noticeably different from KS (see Genetically Related Disorders).

KDM6A

• Based on small numbers of individuals with KDM6A-related KS, pathogenic variants at the 3' end of the gene are more common than those at the 5' end [Bögershausen et al 2016].
• Splice site variants, as compared to nonsense, missense, and small in/dels, are the most common type of single-nucleotide variant in individuals with KDM6A-related KS [Bögershausen et al 2016].

Penetrance

Penetrance for pathogenic variants in KMT2D appears to be complete; not enough information is available to make any conclusions regarding penetrance for those with pathogenic variants in KDM6A. Variable expressivity may lead to underascertainment of mildly affected individuals.

Prevalence

The prevalence of KS in Japan is estimated at 1:32,000 live births [Niikawa et al 1988]. The live birth prevalence outside Japan presumably approximates that seen in the Japanese population.

White et al [2004] calculated a minimum birth incidence of 1:86,000 in Australia and New Zealand.

Evaluations Following Initial Diagnosis

To establish the extent of disease and the needs of an individual diagnosed with KS, the following evaluations are recommended if they have not already been completed:

Treatment of Manifestations

See Therapies Under Investigation for discussion of histone deacetylase inhibitors and ketogenic diet as hypothesized treatments for individuals with KS. Currently neither of these therapies is recommended as a primary treatment for individuals with KS, outside of a clinical trial.

Surveillance

Agents/Circumstances to Avoid

In those with joint laxity, activities that increase the risk of joint damage (e.g., bouncing on a trampoline) should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Based on the function of KMT2D and KDM6A as regulators of chromatin expression (see Molecular Genetics), it has been hypothesized that histone deacetylase inhibitors (HDACi) could have a beneficial effect on individuals with Kabuki syndrome. Bjornsson et al [2014] created a mouse model of KS and found that treatment with HDACi normalized the structural and functional differences seen in certain brain areas in these affected mice, leading to improved neurogenesis and memory. This has yet to be tested in humans with KS, but clinical trials based on these mouse studies are in the planning phase.

Since ketosis acts as an endogenous HDACi, others have hypothesized that placing individuals with KS on a ketogenic diet could improve their cognitive issues [Benjamin et al 2017]. This is NOT currently a recommended treatment for KS, although some families and physicians have trialed this diet independently. Since the ketogenic diet as a treatment for KS has not been studied as part of a clinical trial, no results of these types of experimental treatments are available in the peer-reviewed literature.

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

KMT2D-related Kabuki syndrome is inherited in an autosomal dominant manner.

KDM6A-related Kabuki syndrome is inherited in an X-linked manner.

Autosomal Dominant Inheritance – Risk to Family Members

Parents of a proband

• A minority of individuals diagnosed with KMT2D-related KS have an affected parent.
• A proband with KMT2D-related KS may have the disorder as the result of a de novo pathogenic variant. Because simplex cases (i.e., a single occurrence in a family) have not been evaluated sufficiently to determine if the pathogenic variant was de novo, the proportion of KMT2D-related KS caused by a de novo pathogenic variant is unknown. However, based on clinical experience, the proportion of KMT2D-related KS caused by a de novo variant is likely high.
• Recommended evaluations for the parents of a proband include:
  • Molecular genetic testing if the pathogenic variant in the proband has been identified. If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband or germline mosaicism in a parent. Although no instances of germline mosaicism have been reported, it remains a possibility.
  • If the pathogenic variant in the proband is not known, clinical evaluation of the proband's parents, including a thorough physical examination by a clinical geneticist, is indicated to evaluate for any phenotypic features consistent with KS.
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.
• Note: If the parent is the individual in whom the pathogenic variant first occurred, the parent may have somatic mosaicism for the variant and may be mildly/minimally affected [Banka et al 2013, Lepri et al 2017].

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
  • If a parent of the proband is affected, the risk to the sibs is 50%.
  • If the KMT2D pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be slightly greater than that of the general population (though still <1%) because of the theoretic possibility of parental germline mosaicism.
• If both parents are clinically unaffected but have not been tested for the KMT2D pathogenic variant (or molecular genetic testing is not appropriate because a pathogenic variant has not been identified in the proband), the risk to the sibs of a proband appears to be low.

Offspring of a proband. Each child of an individual with KMT2D-related Kabuki syndrome has a 50% chance of inheriting the pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent is affected, the parent's family members may be at risk.

X-Linked Inheritance – Risk to Family Members

Parents of a male proband

• The father of an affected male will not have the disorder nor will he be hemizygous for the KDM6A pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If a woman has more than one affected child and no other affected relatives and if the KDM6A pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a de novo KDM6A pathogenic variant, in which case the mother is not a heterozygote. About 80% of affected males represent simplex cases [Bögershausen et al 2016].

Sibs of a male proband. The risk to sibs depends on the genetic status of the mother:

• If the mother of the proband has a KDM6A pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may have features of KS, although features in females tend to be milder than those in males (see Phenotype Correlations by Gene).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the KDM6A pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.

Offspring of a male proband. Because of the small number of affected males and the relatively recent identification of KDM6A as a gene implicated in KS, no reports in the literature have described an affected male who has reproduced.

Other family members. The proband's maternal aunts may be at risk of being heterozygotes for the pathogenic variant and the aunts' offspring, depending on their sex, may be at risk of being heterozygotes (carriers) for the pathogenic variant and/or being affected.

Heterozygote detection. Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the pathogenic variant has been identified in the proband. Note: Females who are heterozygous for this X-linked disorder can have a range of clinical manifestations (see Phenotype Correlations by Gene).

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the pathogenic variant is likely de novo. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or are carriers.

DNA banking. Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see Huang et al [2022].

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for Kabuki syndrome are possible.

Molecular Pathogenesis

Both KDM6A and KMT2D work as part of a complex of proteins termed the ASCOM complex. The function of this complex is to remove repressive epigenetic marks and deposit activating methylation marks on chromatin. This then recruits RNA polymerase II complex, resulting in an activated chromatin state [Bögershausen & Wollnik 2013]. KDM6A is an H3K27 demethylase that removes repressive polycomb-derived methylation marks [Agger et al 2007, Hong et al 2007]. KMT2D is a histone 3 lysine 4 (H3K4) N-methyltransferase that specifically modifies the lysine residue at the fourth amino acid position of the histone H3 protein, catalyzing the conversion from nonmethylated to mono-, di-, and trimethylated H3K4. The SET domain of KMT2D is responsible for the methyltransferase activity [Kouzarides 2007]. However, most target genes (and their respective functions) of the regulatory pathways in which KMT2D and KDM6A play a role are not yet known.

Mechanism of disease causation. Loss of function of KDM6A or KMT2D causes Kabuki syndrome.

KDM6A- or KMT2D-specific laboratory considerations. Of note, KDM6A escapes X-chromosome inactivation.

Cancer and Benign Tumors

KDM6A. Somatic variants in this gene have been described most commonly in urothelial carcinoma, T-cell acute lymphoblastic leukemia, and breast cancer, although a variety of cancers may contain somatic variants in this gene [Schulz et al 2019].

KMT2D. Deleterious somatic variants in this gene have been described in a variety of different cancers including central nervous system, gastrointestinal, and hematopoietic malignancies [Ford & Dingwall 2015, Rao & Dou 2015].

Revision History

• 15 September 2022 (sw) Revision: epigenetic signature analysis (Establishing the Diagnosis, Option 2)
• 15 July 2021 (ma) Revision: added KMT2D-related disorder (Genetically Related Disorders; Genotype-Phenotype Correlations) and associated references (Cuvertino and Baldridge)
• 21 October 2019 (aa) Revision: X-linked inheritance added to Summary
• 28 January 2019 (sw) Comprehensive update posted live
• 16 May 2013 (aa) Revision: mutations in KDM6A associated with Kabuki syndrome; large KMT2D (formerly MLL2) deletions/duplications reported as causative of Kabuki syndrome; addition of proposed phenotypic scoring system
• 1 September 2011 (me) Review posted live
• 8 July 2011 (ma) Original submission

Published Guidelines / Consensus Statements

• Kabuki Syndrome Guideline Development Group. Management of Kabuki Syndrome – A Clinical Guideline (pdf). Available online. 2010. Accessed 9-27-23.

Literature Cited

• 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, et al. Kabuki syndrome: international consensus diagnostic criteria. J Med Genet. 2019;56:89-95. [PubMed: 30514738]
• Agger K, Cloos PA, Christensen J, Pasini D, Rose S, Rappsilber J, Issaeva I, Canaani E, Salcini AE, Helin K (2007) UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature 449:731-4. [PubMed: 17713478]
• Aref-Eshghi E, Kerkhof J, Pedro VP, Groupe DI. France, Barat-Houari M, Ruiz-Pallares N, Andrau JC, Lacombe D, Van-Gils J, Fergelot P, Dubourg C, Cormier-Daire V, Rondeau S, Lecoquierre F, Saugier-Veber P, Nicolas G, Lesca G, Chatron N, Sanlaville D, Vitobello A, Faivre L, Thauvin-Robinet C, Laumonnier F, Raynaud M, Alders M, Mannens M, Henneman P, Hennekam RC, Velasco G, Francastel C, Ulveling D, Ciolfi A, Pizzi S, Tartaglia M, Heide S, Héron D, Mignot C, Keren B, Whalen S, Afenjar A, Bienvenu T, Campeau PM, Rousseau J, Levy MA, Brick L, Kozenko M, Balci TB, Siu VM, Stuart A, Kadour M, Masters J, Takano K, Kleefstra T, de Leeuw N, Field M, Shaw M, Gecz J, Ainsworth PJ, Lin H, Rodenhiser DI, Friez MJ, Tedder M, Lee JA, DuPont BR, Stevenson RE, Skinner SA, Schwartz CE, Genevieve D, Sadikovic B. Evaluation of DNA methylation episignatures for diagnosis and phenotype correlations in 42 mendelian neurodevelopmental disorders. Am J Hum Genet. 2020;106:356-70.
• Baldridge D, Spillmann RC, Wegner DJ, Wambach JA, White FV, Sisco K, Toler TL, Dickson PI, Cole FS, Shashi V, Grange DK. Phenotypic expansion of KMT2D-related disorder: Beyond Kabuki syndrome. Am J Med Genet A. 2020;182:1053-65. [PMC free article: PMC7295006] [PubMed: 32083401]
• Banka S, Howard E, Bunstone S, Chandler KE, Kerr B, Lachlan K, McKee S, Mehta SG, Tavares AL, Tolmie J, Donnai D. MLL2 mosaic mutations and intragenic deletion-duplications in patients with Kabuki syndrome. Clin Genet. 2013;83:467-71. [PubMed: 22901312]
• Banka S, Lederer D, Benoit V, Jenkins E, Howard E, Bunstone S, Kerr B, McKee S, Lloyd IC, Shears D, Stewart H, White SM, Savarirayan R, Mancini GM, Beysen D, Cohn RD, Grisart B, Maystadt I, Donnai D (2015) Novel KDM6A (UTX) mutations and a clinical and molecular review of the X-linked Kabuki syndrome (KS2). Clin Genet 87:252-8. [PubMed: 24527667]
• Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, Parker MJ, Crow YJ, Kerr B, Kingston H, Metcalfe K, Chandler K, Magee A, Stewart F, McConnell VP, Donnelly DE, Berland S, Houge G, Morton JE, Oley C, Revencu N, Park SM, Davies SJ, Fry AE, Lynch SA, Gill H, Schweiger S, Lam WW, Tolmie J, Mohammed SN, Hobson E, Smith A, Blyth M, Bennett C, Vasudevan PC, García-Miñaúr S, Henderson A, Goodship J, Wright MJ, Fisher R, Gibbons R, Price SM, de Silva DC, Temple IK, Collins AL, Lachlan K, Elmslie F, McEntagart M, Castle B, Clayton-Smith J, Black GC, Donnai D (2012) How genetically heterogeneous is Kabuki syndrome? MLL2 testing in 116 patients, review, and analyses of mutation and phenotypic spectrum. Eur J Hum Genet. 20:381-8. [PMC free article: PMC3306863] [PubMed: 22126750]
• Benjamin JS, Pilarowski GO, Carosso GA, Zhang L, Huso DL, Goff LA, Vernon HJ, Hansen KD, Bjornsson HT (2017) A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome. Proc Natl Acad Sci USA 114:125-130. [PMC free article: PMC5224378] [PubMed: 27999180]
• Bernier FE, Schreiber A, Coulombe J, Hatami A, Marcoux D (2017) Pilomatricoma associated with Kabuki syndrome. Pediatr Dermatol 34:e26-7. [PubMed: 27778401]
• Bjornsson HT, Benjamin JS, Zhang L, Weissman J, Gerber EE, Chen YC, Vaurio RG, Potter MC, Hansen KD, Dietz HC (2014) Histone deacetylase inhibition rescues structural and functional brain deficits in a mouse model of Kabuki syndrome. Sci Transl Med 6:256ra135. [PMC free article: PMC4406328] [PubMed: 25273096]
• Bögershausen N, Wollnik B (2013) Unmasking Kabuki syndrome. Clin Genet 83:201-11. [PubMed: 23131014]
• Bögershausen N, Gatinois V, Riehmer V, Kayserili H, Becker J, Thoenes M, Simsek-Kiper PÖ, Barat-Houari M, Elcioglu NH, Wieczorek D, Tinschert S, Sarrabay G, Strom TM, Fabre A, Baynam G, Sanchez E, Nürnberg G, Altunoglu U, Capri Y, Isidor B, Lacombe D, Corsini C, Cormier-Daire V, Sanlaville D, Giuliano F, Le Quan Sang KH, Kayirangwa H, Nürnberg P, Meitinger T, Boduroglu K, Zoll B, Lyonnet S, Tzschach A, Verloes A, Di Donato N, Touitou I, Netzer C, Li Y, Geneviève D, Yigit G, Wollnik B (2016) Mutation update for Kabuki syndrome genes KMT2D and KDM6A and further delineation of X-linked Kabuki syndrome subtype 2. Hum Mutat 37:847-64. [PubMed: 27302555]
• Brackmann F, Krumbholz M, Langer T, Rascher W, Holter W, Metzler M (2013) Novel MLL2 mutation in Kabuki syndrome with hypogammaglobulinemia and severe chronic thrombopenia. J Pediatr Hematol Oncol 35:e314-6. [PubMed: 23042018]
• Butcher DT, Cytrynbaum C, Turinsky AL, Siu MT, Inbar-Feigenberg M, Mendoza-Londono R, Chitayat D, Walker S, Machado J, Caluseriu O, Dupuis L, Grafodatskaya D, Reardon W, Gilbert-Dussardier B, Verloes A, Bilan F, Milunsky JM Basran R, Papsin B, Stockley TL, Scherer SW, Choufani S, Brudno M, Weksberg R (2017) CHARGE and Kabuki syndromes: gene-specific DNA methylation signatures identify epigenetic mechanisms linking these clinically overlapping conditions. Am J Hum Genet 100:773-88. [PMC free article: PMC5420353] [PubMed: 28475860]
• Caciolo C, Alfieri P, Piccini G, Digilio MC, Lepri FR, Tartaglia M, Menghini D, Vicari S. (2018) Neurobehavioral features in individuals with Kabuki syndrome. Mol Genet Genomic Med 6:322-31. [PMC free article: PMC6014453] [PubMed: 29536651]
• Chen YH, Sun MH, Hsia SH, Lai CC, Wu WC (2014) Rare ocular features in a case of Kabuki syndrome (Niikawa-Kuroki syndrome). BMC Ophthalmol. 14:143. [PMC free article: PMC4251844] [PubMed: 25421742]
• Cheon CK, Ko JM. (2015) Kabuki syndrome: clinical and molecular characteristics. Korean J Pediatr. 58:317-24. [PMC free article: PMC4623449] [PubMed: 26512256]
• Cheon CK, Sohn YB, Ko JM, Lee YJ, Song JS, Moon JW, Yang BK, Ha IS, Bae EJ, Jin HS, Jeong SY (2014) Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. J Hum Genet 59:321-5. [PubMed: 24739679]
• Ciprero KL, Clayton-Smith J, Donnai D, Zimmerman RA, Zackai EH, Ming JE (2005) Symptomatic Chiari I malformation in Kabuki syndrome. Am J Med Genet A 132A:273-5. [PubMed: 15523623]
• Cocciadiferro D, Augello B, De Nittis P, Zhang J, Mandriani B, Malerba N, Squeo GM, Romano A, Piccinni B, Verri T, Micale L, Pasqualucci L, Merla G. Dissecting KMT2D missense mutations in Kabuki syndrome patients. Hum Mol Genet. 2018;27:3651-68. [PMC free article: PMC6488975] [PubMed: 30107592]
• Courcet JB, Faivre L, Michot C, Burguet A, Perez-Martin S, Alix E, Amiel J, Baumann C, Cordier MP, Cormier-Daire V, Delrue MA, Gilbert-Dussardier B, Goldenberg A, Jacquemont ML, Jaquette A, Kayirangwa H, Lacombe D, Le Merrer M, Toutain A, Odent S, Moncla A, Pelet A, Philip N, Pinson L, Poisson S, Kim-Han-Ie QS, Roume J, Sanchez E, Willems M, Till M, Vincent-Delorme C, Mousson C, Vinault S, Binquet C, Huet F, Sarda P, Salomon R, Lyonnet S, Sanlaville D, Geneviève D (2013) Clinical and molecular spectrum of renal malformations in Kabuki syndrome. J Pediatr 163:742-6. [PubMed: 23535010]
• Cuvertino S, Hartill V, Colyer A, Garner T, Nair N, Al-Gazali L, Canham N, Faundes V, Flinter F, Hertecant J, Holder-Espinasse M, Jackson B, Lynch SA, Nadat F, Narasimhan VM, Peckham M, Sellers R, Seri M, Montanari F, Southgate L, Squeo GM, Trembath R, van Heel D, Venuto S, Weisberg D, Stals K, Ellard S; Genomics England Research Consortium, Barton A, Kimber SJ, Sheridan E, Merla G, Stevens A, Johnson CA, Banka S. A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome. Genet Med. 2020;22:867-77. [PMC free article: PMC7200597] [PubMed: 31949313]
• Digilio MC, Gnazzo M, Lepri F, Dentici ML, Pisaneschi E, Baban A, Passarelli C, Capolino R, Angioni A, Novelli A, Marino B, Dallapiccola B. (2017) Congenital heart defects in molecularly proven Kabuki syndrome patients. Am J Med Genet A 173:2912-22. [PubMed: 28884922]
• Ford DJ, Dingwall AK (2015) The cancer COMPASS: navigating the functions of MLL complexes in cancer. Cancer Genet 208:178-91. [PubMed: 25794446]
• Giordano P, Lassandro G, Sangerardi M, Faienza MF, Valente F, Martire B. Autoimmune haematological disorders in two Italian children with Kabuki syndrome. Ital J Pediatr. 2014;40:10. [PMC free article: PMC3917534] [PubMed: 24460868]
• 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 (2011) Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet A. 155A:1511-6. [PMC free article: PMC3121928] [PubMed: 21671394]
• Hong S, Cho YW, Yu LR, Yu H, Veenstra TD, Ge K (2007) Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc Natl Acad Sci U S A. 104:18439-44. [PMC free article: PMC2141795] [PubMed: 18003914]
• Huang SJ, Amendola LM, Sternen DL. Variation among DNA banking consent forms: points for clinicians to bank on. J Community Genet. 2022;13:389-97. [PMC free article: PMC9314484] [PubMed: 35834113]
• Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, Ma J, Edmonson MN, Hedlund EK, Rusch MC, Shurtleff SA, Mulder HL, Boggs K, Vadordaria B, Cheng J, Yergeau D, Song G, Becksfort J, Lemmon G, Weber C, Cai Z, Dang J, Walsh M, Gedman AL, Faber Z, Easton J, Gruber T, Kriwacki RW, Partridge JF, Ding L, Wilson RK, Mardis ER, Mullighan CG, Gilbertson RJ, Baker SJ, Zambetti G, Ellison DW, Zhang J, Downing JR (2014) The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun 5:3630. [PMC free article: PMC4119022] [PubMed: 24710217]
• Karagianni P, Lambropoulos V, Stergidou D, Fryssira H, Chatziioannidis I, Spyridakis I (2016) Recurrent giant cell fibroblastoma: Malignancy predisposition in Kabuki syndrome revisited. Am J Med Genet A 170A:1333-8. [PubMed: 26898171]
• Kouzarides T (2007) Chromatin modifications and their function. Cell 128:693-705. [PubMed: 17320507]
• Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, Maystadt I, Dallapiccola B, Verellen-Dumoulin C (2012) Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet 90:119-24. [PMC free article: PMC3257878] [PubMed: 22197486]
• Lederer D, Shears D, Benoit V, Verellen-Dumoulin C, Maystadt I (2014) A three generation X-linked family with Kabuki syndrome phenotype and a frameshift mutation in KDM6A. Am J Med Genet A 164A;1289-92. [PubMed: 24664873]
• Lehman N, Mazery AC, Visier A, Baumann C, Lachesnais D, Capri Y, Toutain A, Odent S, Mikaty M, Goizet C, Taupiac E, Jacquemont ML, Sanchez E, Schaefer E, Gatinois V, Faivre L, Minot D, Kayirangwa H, Sang KLQ, Boddaert N, Bayard S, Lacombe D, Moutton S, Touitou I, Rio M, Amiel J, Lyonnet S, Sanlaville D, Picot MC, Geneviève D (2017) Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations. Clin Genet 92:298-305. [PubMed: 28295206]
• Lepri FR, Cocciadiferro D, Augello B, Alfieri P, Pes V, Vancini A, Caciolo C, Squeo GM, Malerba N, Adipietro I, Novelli A, Sotgiu S, Gherardi R, Digilio MC, Dallapiccola B, Merla G (2017) Clinical and neurobehavioral features of three novel Kabuki syndrome patient with mosaic KMT2D mutations and a review of the literature. Int J Mol Sci 19 pii: E82. [PMC free article: PMC5796032] [PubMed: 29283410]
• Levy MA, McConkey H, Kerkhof J, Barat-Houari M, Bargiacchi S, Biamino E, Bralo MP, Cappuccio G, Ciolfi A, Clarke A, DuPont BR, Elting MW, Faivre L, Fee T, Fletcher RS, Cherik F, Foroutan A, Friez MJ, Gervasini C, Haghshenas S, Hilton BA, Jenkins Z, Kaur S, Lewis S, Louie RJ, Maitz S, Milani D, Morgan AT, Oegema R, Østergaard E, Pallares NR, Piccione M, Pizzi S, Plomp AS, Poulton C, Reilly J, Relator R, Rius R, Robertson S, Rooney K, Rousseau J, Santen GWE, Santos-Simarro F, Schijns J, Squeo GM, St John M, Thauvin-Robinet C, Traficante G, van der Sluijs PJ, Vergano SA, Vos N, Walden KK, Azmanov D, Balci T, Banka S, Gecz J, Henneman P, Lee JA, Mannens MMAM, Roscioli T, Siu V, Amor DJ, Baynam G, Bend EG, Boycott K, Brunetti-Pierri N, Campeau PM, Christodoulou J, Dyment D, Esber N, Fahrner JA, Fleming MD, Genevieve D, Kerrnohan KD, McNeill A, Menke LA, Merla G, Prontera P, Rockman-Greenberg C, Schwartz C, Skinner SA, Stevenson RE, Vitobello A, Tartaglia M, Alders M, Tedder ML, Sadikovic B. Novel diagnostic DNA methylation episignatures expand and refine the epigenetic landscapes of Mendelian disorders. HGG Adv. 2021;3:100075. [PMC free article: PMC8756545] [PubMed: 35047860]
• Li Y, Bögershausen N, Alanay Y, Simsek Kiper PO, Plume N, Keupp K, Pohl E, Pawlik B, Rachwalski M, Milz E, Thoenes M, Albrecht B, Prott EC, Lehmkühler M, Demuth S, Utine GE, Boduroglu K, Frankenbusch K, Borck G, Gillessen-Kaesbach G, Yigit G, Wieczorek D, Wollnik B (2011) A mutation screen in patients with Kabuki syndrome. Hum Genet. 130:715-24. [PubMed: 21607748]
• Lin JL, Lee WI, Huang JL, Chen PK, Chan KC, Lo LJ, You YJ, Shih YF, Tseng TY, Wu MC (2015) Immunologic assessment and KMT2D mutation detection in Kabuki syndrome. Clin Genet 88:255-60. [PubMed: 25142838]
• Lindgren AM, Hoyos T, Talkowski ME, Hanscom C, Blumenthal I, Chiang C, Ernst C, Pereira S, Ordulu Z, Clericuzio C, Drautz JM, Rosenfeld JA, Shaffer LG, Velsher L, Pynn T, Vermeesch J, Harris DJ, Gusella JF, Liao EC, Morton CC (2013) Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate. Hum Genet 132:537-52. [PMC free article: PMC3627823] [PubMed: 23354975]
• Lindsley AW, Saal HM, Burrow TA, Hopkin RJ, Shchelochkov O, Khandelwal P, Xie C, Bleesing J, Filipovich L, Risma K, Assa'ad AH, Roehrs PA, Bernstein JA (2016) Defects of B-cell terminal differentiation in patients with type-1 Kabuki syndrome. J Allergy Clin Immunol 137:179-87.e10. [PMC free article: PMC4715656] [PubMed: 26194542]
• Liu S, Hong X, Shen C, Shi Q, Wang J, Xiong F, Qiu Z. Kabuki syndrome: a Chinese case series and systematic review of the spectrum of mutations. BMC Med Genet. 2015;16:26. [PMC free article: PMC4630853] [PubMed: 25896430]
• Makrythanasis P, van Bon BW, Steehouwer M, Rodríguez-Santiago B, Simpson M, Dias P, Anderlid BM, Arts P, Bhat M, Augello B, Biamino E, Bongers EM, Del Campo M, Cordeiro I, Cueto-González AM, Cuscó I, Deshpande C, Frysira E, Izatt L, Flores R, Galán E, Gener B, Gilissen C, Granneman SM, Hoyer J, Yntema HG, Kets CM, Koolen DA, Marcelis CL, Medeira A, Micale L, Mohammed S, de Munnik SA, Nordgren A, Reardon SP, Revencu N, Roscioli T, Ruiterkamp-Versteeg M, Santos HG, Schoumans J, Schuurs-Hoeijmakers JH, Silengo MC, Toledo L, Vendrell T, van der Burgt I, van Lier B, Zweier C, Reymond A, Trembath RC, Perez-Jurado L, Dupont J, de Vries BB, Brunner HG, Veltman JA, Merla G, Antonarakis SE, Hoischen A. MLL2 mutation detected in 86 patients with Kabuki syndrome; a genotype-phenotype study. Clin Genet. 2013;84:539-45. [PubMed: 23320472]
• McVeigh TP, Banka S, Reardon W. (2015) Kabuki syndrome: expanding the phenotype to include microphthalmia and anophthalmia. Clin Dysmorphol. 24:135-9. [PubMed: 26049589]
• Micale L, Augello B, Fusco C, Selicorni A, Loviglio MN, Silengo MC, Reymond A, Gumiero B, Zucchetti F, D'Addetta EV, Belligni E, Calcagnì A, Digilio MC, Dallapiccola B, Faravelli F, Forzano F, Accadia M, Bonfante A, Clementi M, Daolio C, Douzgou S, Ferrari P, Fischetto R, Garavelli L, Lapi E, Mattina T, Melis D, Patricelli MG, Priolo M, Prontera P, Renieri A, Mencarelli MA, Scarano G, Monica MD, Toschi B, Turolla L, Vancini A, Zatterale A, Gabrielli O, Zelante L, Merla G (2011) Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients. Orphanet J Rare Dis. 6:38. [PMC free article: PMC3141365] [PubMed: 21658225]
• Miyake N, Mizuno S, Okamoto N, Ohashi H, Shiina M, Ogata K, Tsurusaki Y, Nakashima M, Saitsu H, Niikawa N, Matsumoto N (2013) KDM6A point mutations cause Kabuki syndrome. Hum Mutat 34:108-10. [PubMed: 23076834]
• Morgan AT, Mei C, Da Costa A, Fifer J, Lederer D, Benoit V, McMillin MJ, Buckingham KJ, Bamshad MJ, Pope K, White SM (2015) Speech and language in a genotyped cohort of individuals with Kabuki syndrome. Am J Med Genet A. 2015;167:1483-92. [PubMed: 25755104]
• Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, Yamada Y, Fujita M, Umemoto H, Yoshimitsu Fukushima Y, Nako Y, Matsui I, Urakami T, Aritaki S, Hara M, Suzuki Y, Chyo H, Sugio Y, Hasegawa T, Yamanaka T, Tsukino R, Yoshida A, Nomoto N, Kawahito S, Aihara R, Toyota S, Ieshima A, Funaki H, Ishitobi K, Ogura S, Furumae T, Yoshino M, Tsuji Y, Kondoh T, Matsumoto T, Abe K, Harada N, Miike T, Ohdo S, Naritomi K, Abushwereb AK, Braun OH, Schmid E (1988) Kabuki make-up (Niikawa-Kuroki) syndrome: A study of 62 patients. Am J Med Genet 31:565-89. [PubMed: 3067577]
• Paděrová J, Holubová A, Simandlová M, Puchmajerová A, Vlčková M, Malíková M, Pourová R, Vejvalková S, Havlovicová M, Šenkeříková M, Ptáková N, Drábová J, Geryk J, Maver A, Křepelová A, Macek M Jr (2016) Molecular genetic analysis in 14 Czech Kabuki syndrome patients is confirming the utility of phenotypic scoring. Clin Genet 90:230-7. [PubMed: 26841933]
• Paik JM, Lim SY. (2016) Kabuki syndrome with cleft palate. Arch Plast Surg 43:474-6. [PMC free article: PMC5040853] [PubMed: 27689058]
• Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, Smeets EE, Wagemans A, Schrander JJ, van den Boogaard MJ, van der Smagt J, van Haeringen A, Stolte-Dijkstra I, Kerstjens-Frederikse WS, Mancini GM, Wessels MW, Hennekam RC, Vreeburg M, Geraedts J, de Ravel T, Fryns JP, Smeets HJ, Devriendt K, Schrander-Stumpel CT (2011) MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Hum Mutat. 32:E2018-25. [PubMed: 21280141]
• Porntaveetus T, Abid MF, Theerapanon T, Srichomthong C, Ohazama A, Kawasaki K, Kawasaki M, Suphapeetiporn K, Sharpe PT, Shotelersuk V (2018) Expanding the Oro-Dental and Mutational Spectra of Kabuki Syndrome and Expression of KMT2D and KDM6A in Human Tooth Germs. Int J Biol Sci 14:381-9. [PMC free article: PMC5930470] [PubMed: 29725259]
• Rao RC, Dou Y (2015) Hijacked in cancer: the KMT2 (MLL) family of methyltransferases. Nat Rev Cancer 15:334-46. [PMC free article: PMC4493861] [PubMed: 25998713]
• Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405-24. [PMC free article: PMC4544753] [PubMed: 25741868]
• Riess A, Dufke A, Riess O, Beck-Woedl S, Fode B, Skladny H, Klaes R, Tzschach A (2012) Mirror-image asymmetry in monozygotic twins with kabuki syndrome. Mol Syndromol 3:94-7. [PMC free article: PMC3542933] [PubMed: 23326255]
• Roma D, Palma P, Capolino R, Figà-Talamanca L, Diomedi-Camassei F, Lepri FR, Digilio MC, Marras CE, Messina R, Carai A, Randi F, Mastronuzzi A. Spinal ependymoma in a patient with Kabuki syndrome: a case report. BMC Med Genet. 2015;16:80. [PMC free article: PMC4560867] [PubMed: 26341229]
• Sakata S, Okada S, Aoyama K, HaraK, Tani C, Kagawa R, Utsunomiya-Nakamura A, Miyagawa S, Ogata T, Mizuno H, Kobayashi M (2017) Individual clinically diagnosed with CHARGE syndrome but with a mutation in KMT2D, a gene associated with Kabuki syndrome: a case report. Front Genet 8:210. [PMC free article: PMC5732153] [PubMed: 29321794]
• Schott DA, Blok MJ, Gerver WJ, Devriendt K, Zimmermann LJ, Stumpel CT (2016a) Growth pattern in Kabuki syndrome with a KMT2D mutation. Am J Med Genet A. 170:3172-9. [PubMed: 27530205]
• Schott DA, Gerver WJM, Stumpel CTRM (2016b) Growth hormone stimulation tests in children with Kabuki syndromeome. Horm Res Paediatr 86:319-24. [PubMed: 27649541]
• Schulz WA, Lang A, Koch J, Greife A. The histone demethylase UTX/KDM6A in cancer: progress and puzzles. Int J Cancer. 2019;145:614-20. [PubMed: 30628063]
• Sertçelik M, Uğur Ç, Şahin Aközel A, Gürkan CK (2016) A child with Kabuki syndrome and autism spectrum disorder. Noro Psikiyatr Ars 53:280-2. [PMC free article: PMC5378211] [PubMed: 28373809]
• Siminas S, Baillie CT, Turnock R (2015) Kabuki syndrome and anorectal malformations: implications for diagnosis and treatment. European J Pediatr Surg Rep 3:54-8. [PMC free article: PMC4487125] [PubMed: 26171318]
• Teranishi H, Koga Y, Nakashima K, Morihana E, Ishii K, Sakai Y, Taguchi T, Oda Y, Miyake N, Matsumoto N, Ohga S (2018) Cancer management in Kabuki syndrome: the first case of Wilms tumor and a literature review. J Pediatr Hematol Oncol 40:391-4. [PubMed: 29489735]
• Van Laarhoven PM, Neitzel LR, Quintana AM, Geiger EA, Zackai EH, Clouthier DE, Artinger KB, Ming JE, Shaikh TH. Kabuki syndrome genes KMT2D and KDM6A: functional analyses demonstrate critical roles in craniofacial, heart and brain development. Hum Mol Genet. 2015;24:4443-53. [PMC free article: PMC4492403] [PubMed: 25972376]
• Vesseur A, Cillessen E, Mylanus E (2016) Cochlear implantation in a patient with Kabuki syndrome. J Int Adv Otol 12:129-31. [PubMed: 27341000]
• White SM, Thompson EM, Kidd A, Savarirayan R, Turner A, Amor D, Delatycki MB, Fahey M, Baxendale A, White S, Haan E, Gibson K, Halliday JL, Bankier A (2004) Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome. Am J Med Genet A 127A:118-27. [PubMed: 15108197]
• Yap KL, Johnson AEK, Fischer D, Kandikatla P, Deml J, Nelakuditi V, Halbach S, Jeha GS, Burrage LC, Bodamer O, Benavides VC, Lewis AM, Ellard S, Shah P, Cody D, Diaz A, Devarajan A, Truong L, Greeley SAW, De Leó-Crutchlow DD, Edmondson AC, Das S, Thornton P, Waggoner D, Del Gaudio D. Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals. Genet Med. 2019;21:262-5. [PubMed: 30097611]
• Zarate YA, Zhan H, Jones JR. (2012) Infrequent manifestations of Kabuki syndrome in a patient with novel MLL2 mutation. Mol Syndromol 3:180-4. [PMC free article: PMC3507269] [PubMed: 23239960]