Abstract
Introduction
Kabuki syndrome (KS) is a rare disorder characterized by typical facial features, skeletal anomalies, fetal fingertip pad persistence, postnatal growth retardation, and intellectual disabilities. Heterozygous variants of the KMT2D and KDM6A genes are major genetic causes of KS. This study aimed to report the clinical and genetic characteristics of KS.
Methods
This study included 28 Korean patients (14 boys and 14 girls) with KS through molecular genetic testing, including direct Sanger sequencing, whole-exome sequencing, or whole-genome sequencing.
Results
The median age at clinical diagnosis was 18.5 months (IQR 7–58 months), and the median follow-up duration was 80.5 months (IQR 48–112 months). Molecular genetic testing identified different pathogenic variants of the KMT2D (n = 23) and KDM6A (n = 3) genes, including 15 novel variants. Patients showed typical facial features (100%), such as long palpebral fissure and eversion of the lower eyelid; intellectual disability/developmental delay (96%); short stature (79%); and congenital cardiac anomalies (75%). Although 71% experienced failure to thrive in infancy, 54% of patients showed a tendency toward overweight/obesity in early childhood. Patients with KDM6A variants demonstrated severe genotype-phenotype correlation.
Conclusion
This study enhances the understanding of the clinical and genetic characteristics of KS.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Data availability
The datasets used and/or analyzed in this study are available from the corresponding author upon reasonable request.
References
Niikawa N, Kuroki Y, Kajii T, Matsuura N, Ishikiriyama S, Tonoki H, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am J Med Genet. 1988;31:565–89.
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;99:570–3.
Matsumoto N, Niikawa N. Kabuki make-up syndrome: a review. Am J Med Genet C Semin Med Genet. 2003;117C:57–65.
White SM, Thompson EM, Kidd A, Savarirayan R, Turner A, Amor D, et al. Growth, behavior, and clinical findings in 27 patients with Kabuki (Niikawa-Kuroki) syndrome. Am J Med Genet A. 2004;127A:118–27.
Adam MP, Hudgins L. Kabuki syndrome: a review. Clin Genet. 2005;67:209–19.
Ng SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet. 2010;42:790–3.
Issaeva I, Zonis Y, Rozovskaia T, Orlovsky K, Croce CM, Nakamura T, et al. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol Cell Biol. 2007;27:1889–903.
Bogershausen N, Gatinois V, Riehmer V, Kayserili H, Becker J, Thoenes M, et al. Mutation Update for Kabuki Syndrome Genes KMT2D and KDM6A and Further Delineation of X-Linked Kabuki Syndrome Subtype 2. Hum Mutat. 2016;37:847–64.
Cocciadiferro D, Augello B, De Nittis P, Zhang J, Mandriani B, Malerba N, et al. Dissecting KMT2D missense mutations in Kabuki syndrome patients. Hum Mol Genet. 2018;27:3651–68.
Yap KL, Johnson AEK, Fischer D, Kandikatla P, Deml J, Nelakuditi V, et al. Correction: “Congenital hyperinsulinism as the presenting feature of Kabuki syndrome: clinical and molecular characterization of 10 affected individuals. ”. Genet Med. 2019;21:262–5.
Bogershausen N, Wollnik B. Unmasking Kabuki syndrome. Clin Genet. 2013;83:201–11.
Lederer D, Grisart B, Digilio MC, Benoit V, Crespin M, Ghariani SC, et al. Deletion of KDM6A, a histone demethylase interacting with MLL2, in three patients with Kabuki syndrome. Am J Hum Genet. 2012;90:119–24.
Schuettengruber B, Chourrout D, Vervoort M, Leblanc B, Cavalli G. Genome regulation by polycomb and trithorax proteins. Cell. 2007;128:735–45.
Prasad R, Zhadanov AB, Sedkov Y, Bullrich F, Druck T, Rallapalli R, et al. Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax. Oncogene. 1997;15:549–60.
Dubuc AM, Remke M, Korshunov A, Northcott PA, Zhan SH, Mendez-Lago M, et al. Aberrant patterns of H3K4 and H3K27 histone lysine methylation occur across subgroups in medulloblastoma. Acta Neuropathol. 2013;125:373–84.
Greenfield A, Carrel L, Pennisi D, Philippe C, Quaderi N, Siggers P, et al. The UTX gene escapes X inactivation in mice and humans. Hum Mol Genet. 1998;7:737–42.
Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, et al. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum. Eur J Hum Genet. 2012;20:381–8.
Kim JH, Yun S, Hwang SS, Shim JO, Chae HW, Lee YJ, et al. The 2017 Korean National Growth Charts for children and adolescents: development, improvement, and prospects. Korean J Pediatr. 2018;61:135–49.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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.
Seo GH, Kim T, Choi IH, Park JY, Lee J, Kim S, et al. Diagnostic yield and clinical utility of whole exome sequencing using an automated variant prioritization system, EVIDENCE. Clin Genet. 2020;98:562–70.
Faundes V, Goh S, Akilapa R, Bezuidenhout H, Bjornsson HT, Bradley L, et al. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2. Genet Med. 2021;23:1202–10.
Armstrong L, Abd El Moneim A, Aleck K, Aughton DJ, Baumann C, Braddock SR, et al. Further delineation of Kabuki syndrome in 48 well-defined new individuals. Am J Med Genet A. 2005;132A:265–72.
Cheon CK, Sohn YB, Ko JM, Lee YJ, Song JS, Moon JW, et al. Identification of KMT2D and KDM6A mutations by exome sequencing in Korean patients with Kabuki syndrome. J Hum Genet. 2014;59:321–5.
Schott DA, Blok MJ, Gerver WJ, Devriendt K, Zimmermann LJ, Stumpel CT. Growth pattern in Kabuki syndrome with a KMT2D mutation. Am J Med Genet A. 2016;170:3172–9.
Schott DA, Gerver WJ, Stumpel CT. Growth hormone stimulation tests in children with kabuki syndrome. Horm Res Paediatr. 2016;86:319–24.
van Montfort L, Gerver WJM, Kooger BLS, Plat J, Bierau J, Stumpel C, et al. Follow-up study of growth hormone therapy in children with kabuki syndrome: two-year treatment results. Horm Res Paediatr. 2021;94:285–96.
Huether R, Dong L, Chen X, Wu G, Parker M, Wei L, et al. The landscape of somatic mutations in epigenetic regulators across 1,000 paediatric cancer genomes. Nat Commun. 2014;5:3630.
Scala M, Morana G, Sementa AR, Merla G, Piatelli G, Capra V, et al. Aggressive desmoid fibromatosis in Kabuki syndrome: Expanding the tumor spectrum. Pediatr Blood Cancer. 2019;66:e27831.
Barry KK, Tsaparlis M, Hoffman D, Hartman D, Adam MP, Hung C, et al. From genotype to phenotype-a review of kabuki syndrome. Genes. 2022;13:1761.
Richet C, Maza A, Dreyfus I, Bourrat E, Mazereeuw-Hautier J. Childhood pilomatricomas: associated anomalies. Pediatr Dermatol. 2018;35:548–51.
Bernier FE, Schreiber A, Coulombe J, Hatami A, Marcoux D. Pilomatricoma associated with kabuki syndrome. Pediatr Dermatol. 2017;34:e26–e7.
Sierra J, Yoshida T, Joazeiro CA, Jones KA. The APC tumor suppressor counteracts beta-catenin activation and H3K4 methylation at Wnt target genes. Genes Dev. 2006;20:586–600.
Philip N, Meinecke P, David A, Dean J, Ayme S, Clark R, et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 16 non-Japanese cases. Clin Dysmorphol. 1992;1:63–77.
Ilyina H, Lurie I, Naumtchik I, Amoashy D, Stephanenko G, Fedotov V, et al. Kabuki make-up (Niikawa-Kuroki) syndrome in the Byelorussian register of congenital malformations: ten new observations. Am J Med Genet. 1995;56:127–31.
Vaux KK, Jones KL, Jones MC, Schelley S, Hudgins L. Developmental outcome in Kabuki syndrome. Am J Med Genet A. 2005;132A:263–4.
Hannibal MC, Buckingham KJ, Ng SB, Ming JE, Beck AE, McMillin MJ, et al. Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet A. 2011;155A:1511–6.
van Dongen LCM, Wingbermuhle PAM, van der Veld WM, Stumpel C, Kleefstra T, Egger JIM. Exploring the cognitive phenotype of Kabuki (Niikawa-Kuroki) syndrome. J Intellect Disabil Res. 2019;63:498–506.
Lehman N, Mazery AC, Visier A, Baumann C, Lachesnais D, Capri Y, et al. Molecular, clinical and neuropsychological study in 31 patients with Kabuki syndrome and KMT2D mutations. Clin Genet. 2017;92:298–305.
Paulussen AD, Stegmann AP, Blok MJ, Tserpelis D, Posma-Velter C, Detisch Y, et al. MLL2 mutation spectrum in 45 patients with Kabuki syndrome. Hum Mutat. 2011;32:E2018–25.
Miyake N, Koshimizu E, Okamoto N, Mizuno S, Ogata T, Nagai T, et al. MLL2 and KDM6A mutations in patients with Kabuki syndrome. Am J Med Genet A. 2013;161A:2234–43.
Micale L, Augello B, Maffeo C, Selicorni A, Zucchetti F, Fusco C, et al. Molecular analysis, pathogenic mechanisms, and readthrough therapy on a large cohort of Kabuki syndrome patients. Hum Mutat. 2014;35:841–50.
Makrythanasis P, van Bon BW, Steehouwer M, Rodriguez-Santiago B, Simpson M, Dias P, et al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. Clin Genet. 2013;84:539–45.
Choufani S, McNiven V, Cytrynbaum C, Jangjoo M, Adam MP, Bjornsson HT, et al. An HNRNPK-specific DNA methylation signature makes sense of missense variants and expands the phenotypic spectrum of Au-Kline syndrome. Am J Hum Genet. 2022;109::1867–84.
Murakami H, Tsurusaki Y, Enomoto K, Kuroda Y, Yokoi T, Furuya N, et al. Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome. Am J Med Genet A. 2020;182:2333–44.
Acknowledgements
We are grateful to the patients and their families for their sincere participation in this study.
Funding
This study was supported in part by the Bio and Medical Technology Development Program of the National Research Foundation (NRF), funded by the Korean government (grant number: NRF‐NRF-2022R1A2C2091689) and the Asan Institute for Life Sciences (Seoul, Republic of Korea) (2022IP0017).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
None of the authors declared Financial and Non-Financial Relationships and Activities, and Conflicts of Interest regarding this manuscript.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Yoon, JH., Hwang, S., Bae, H. et al. Clinical and molecular characteristics of Korean patients with Kabuki syndrome. J Hum Genet (2024). https://doi.org/10.1038/s10038-024-01258-1
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1038/s10038-024-01258-1
