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Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2


Title: Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2
Author: Faundes, Víctor
Goh, Stephanie
Akilapa, Rhoda
Bezuidenhout, Heidre
Björnsson, Hans Tómas
Bradley, Lisa
Brady, Angela F.
Brischoux-Boucher, Elise
Brunner, Han
Bulk, Saskia
... 34 more authors Show all authors
Date: 2021-07
Language: English
Scope: 9
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: Genetics in Medicine; 23(7)
ISSN: 1098-3600
DOI: https://doi.org/10.1038/s41436-021-01119-8
Subject: Erfðafræði; Kabuki heilkenni; Kabuki heilkenni; Histone demethylases; Intellectual disability; Genetics; Sex characteristics; Kabuki make-up syndrome; Genetics (clinical)
URI: https://hdl.handle.net/20.500.11815/2897

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Citation:

Faundes , V , Goh , S , Akilapa , R , Bezuidenhout , H , Björnsson , H T , Bradley , L , Brady , A F , Brischoux-Boucher , E , Brunner , H , Bulk , S , Canham , N , Cody , D , Dentici , M L , Digilio , M C , Elmslie , F , Fry , A E , Gill , H , Hurst , J , Johnson , D , Julia , S , Lachlan , K , Lebel , R R , Byler , M , Gershon , E , Lemire , E , Gnazzo , M , Lepri , F R , Marchese , A , McEntagart , M , McGaughran , J , Mizuno , S , Okamoto , N , Rieubland , C , Rodgers , J , Sasaki , E , Scalais , E , Scurr , I , Suri , M , van der Burgt , I , Matsumoto , N , Miyake , N , Benoit , V , Lederer , D & Banka , S 2021 , ' Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2 ' , Genetics in Medicine , vol. 23 , no. 7 , pp. 1202-1210 . https://doi.org/10.1038/s41436-021-01119-8

Abstract:

Purpose: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. Methods: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. Results: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. Conclusion: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.

Description:

We are thankful to all the individuals and their families for taking part in the study. V.F. acknowledges to CONICYT, Chile’s National Commission for Scientific and Technological Research, for its scholarship support (grant number 72160007). S.B. acknowledges the Kabuki Research Fund 629396 at Manchester University NHS Foundation Trust. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003). This study makes use of DECIPHER (http://decipher.sanger.ac.uk), which is funded by the Wellcome Trust. See Nature PMID: 25533962 or www.ddduk.org/access.html for full acknowledgement. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network, UK. H.T.B. is supported by a grant by the Louma G. Foundation. We thank AKABE (Belgian Kabuki association) for their funding for systematic panel gene analysis of patients with suspected Kabuki syndrome. We are also grateful to Kabuki Syndrome Network (kabukisyndrome.com) for the connection with new families affected by KDM6A variants. This work is also supported in part by AMED under grant numbers JP20ek0109280, JP20dm0107090, JP20ek0109301, JP20ek0109348, and JP20kk0205012, by JSPS KAKENHI under grant numbers JP17H01539 and JP19H06321, and by Ministero della Salute (RC2020, to M.L.D.). Publisher Copyright: © 2021, The Author(s).

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