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Phenotypes
Original article
Kabuki syndrome: international consensus diagnostic criteria
  1. Margaret P Adam1,
  2. Siddharth Banka2,3,
  3. Hans T Bjornsson4,5,6,7,
  4. Olaf Bodamer8,9,
  5. Albert E Chudley10,11,
  6. Jaqueline Harris12,
  7. Hiroshi Kawame13,
  8. Brendan C Lanpher14,15,
  9. Andrew W Lindsley16,17,
  10. Giuseppe Merla18,
  11. Noriko Miyake19,
  12. Nobuhiko Okamoto20,
  13. Constanze T Stumpel21,
  14. Norio Niikawa22
  15. the Kabuki Syndrome Medical Advisory Board
  1. 1 Division of Genetic Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, USA
  2. 2 Manchester Centre for Genomic Medicine, Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
  3. 3 Manchester Centre for Genomic Medicine, St Mary’s Hospital, Manchester University NHS Foundation Trust, Health Innovation Manchester, Manchester, UK
  4. 4 McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  5. 5 Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  6. 6 Faculty of Medicine, University of Iceland, Reykjavik, Iceland
  7. 7 Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland
  8. 8 Division of Genetics and Genomics, Department of Medicine, Boston Children’s Hospital/Harvard Medical School, Boston, Massachusetts, USA
  9. 9 Division of Genetics and Genomics, Broad Institute of MIT and Harvard University, Cambridge, Massachusetts, USA
  10. 10 Department of Pediatrics and Child Health, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
  11. 11 Department of Biochemistry and Medical Genetics, Max Rady College of Medicine, Rady Faculty Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
  12. 12 Departments of Neurology and Pediatrics, Kennedy Krieger Institute, Baltimore, Maryland, USA
  13. 13 Department of Education and Training, Tohoku University School of Medicine, Sendai, Japan
  14. 14 Center for Individualized Medicine, Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA
  15. 15 Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
  16. 16 Division of Allergy and Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, USA
  17. 17 Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio, USA
  18. 18 Division of Medical Genetics, IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, Italy
  19. 19 Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan
  20. 20 Department of Medical Genetics, Osaka Women’s and Children’s Hospital, Izumi, Japan
  21. 21 Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands
  22. 22 President, the Research Institute of Personalized Health Sciences, Health Sciences University of Hokkaido, Hokkaido, Japan
  1. Correspondence to Dr Margaret P Adam, Division of Genetic Medicine, University of Washington School of Medicine, Seattle, WA 98105, USA; margaret.adam{at}seattlechildrens.org

Abstract

Background Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in KMT2D or KDM6A. Understanding the function of these genes opens the door to targeted therapies. The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal.

Methods An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed.

Results The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in KMT2D or KDM6A; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented.

Conclusion As targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.

  • kabuki syndrome
  • kabuki make-up syndrome
  • Kmt2d
  • Kdm6a
  • consensus diagnostic criteria

https://doi.org/10.1136/jmedgenet-2018-105625

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    Footnotes

    • Contributors MPA, SB, HTB, OF, AEC, CTS and NN planned the study and created the study design, including reviewing and compiling relevant clinical and molecular features of large cohorts of individuals with Kabuki syndrome. JH, HK, BCL, AWL, GM, NM and NO reviewed and interpreted the data. Based on the data, JH, HK, BCL, AWL, GM, NM, NO, MPA, SB, HTB, OF, AEC, CTS and NN constructed the diagnostic criteria, including multiple discussions around using a scoring system versus a system of major and minor criteria. JH, HK, BCL, AWL, GM, NM, NO, MPA, SB, HTB, OF, AEC, CTS and NN also determined which features should be listed in table 2, which outlines supportive findings in those who do not qualify for a definitive diagnosis of Kabuki syndrome based on major criteria. The Kabuki Syndrome Medical Advisory Board approved the consensus diagnostic criteria as presented in this manuscript. MPA wrote majority of the manuscript and is responsible for manuscript submission.

    • Funding The financial support of Telethon - Italy (grant no GGP13231), Jérôme Lejeune Foundation and Daunia Plast to GM is gratefully acknowledged.

    • Competing interests The clinical and molecular genetic experts on Kabuki syndrome who collaborated on this manuscript were all participants of the Kabuki Syndrome Medical Advisory Board organised and sponsored by Takeda in January 2018. Although the meeting was facilitated and organised by Takeda, Takeda did not have any influence on the content of this report.

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Data sharing statement There are no unpublished data from this study.