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
- consensus diagnostic criteria
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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.