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A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome.

Cuvertino, S; Hartill, V; Colyer, A; Garner, T; Nair, N; Al-Gazali, L; Canham, N; Faundes, V; Flinter, F; Hertecant, J; et al. 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 (2020) A restricted spectrum of missense KMT2D variants cause a multiple malformations disorder distinct from Kabuki syndrome. Genet Med, 22 (5). pp. 867-877. ISSN 1530-0366 https://doi.org/10.1038/s41436-019-0743-3
SGUL Authors: Southgate, Laura

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Abstract

PURPOSE: To investigate if specific exon 38 or 39 KMT2D missense variants (MVs) cause a condition distinct from Kabuki syndrome type 1 (KS1). METHODS: Multiple individuals, with MVs in exons 38 or 39 of KMT2D that encode a highly conserved region of 54 amino acids flanked by Val3527 and Lys3583, were identified and phenotyped. Functional tests were performed to study their pathogenicity and understand the disease mechanism. RESULTS: The consistent clinical features of the affected individuals, from seven unrelated families, included choanal atresia, athelia or hypoplastic nipples, branchial sinus abnormalities, neck pits, lacrimal duct anomalies, hearing loss, external ear malformations, and thyroid abnormalities. None of the individuals had intellectual disability. The frequency of clinical features, objective software-based facial analysis metrics, and genome-wide peripheral blood DNA methylation patterns in these patients were significantly different from that of KS1. Circular dichroism spectroscopy indicated that these MVs perturb KMT2D secondary structure through an increased disordered to ɑ-helical transition. CONCLUSION: KMT2D MVs located in a specific region spanning exons 38 and 39 and affecting highly conserved residues cause a novel multiple malformations syndrome distinct from KS1. Unlike KMT2D haploinsufficiency in KS1, these MVs likely result in disease through a dominant negative mechanism.

Item Type: Article
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. © The Author(s) 2020 Correction available at https://doi.org/10.1038/s41436-020-0784-7
Keywords: KMT2D, Kabuki syndrome, histone 3 lysine 4 methyltransferase, intrinsically disordered region, multiple congenital anomaly, Genomics England Research Consortium, multiple congenital anomaly, Kabuki syndrome, KMT2D, histone 3 lysine 4 methyltransferase, intrinsically disordered region, KMT2D, Kabuki syndrome, histone 3 lysine 4 methyltransferase, intrinsically disordered region, multiple congenital anomaly, 0604 Genetics, 1103 Clinical Sciences, Genetics & Heredity
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Journal or Publication Title: Genet Med
ISSN: 1530-0366
Language: eng
Dates:
DateEvent
May 2020Published
17 January 2020Published Online
24 December 2019Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
16-17/10Newlife - The Charity for Disabled ChildrenUNSPECIFIED
102627/Z/13/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
FS/13/32/30069British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
JTA/09Sir Jules Thorn Charitable Trusthttp://dx.doi.org/10.13039/501100000282
213312/Z/18/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
72160007Chile's National Commission for Scientific and Technological ResearchUNSPECIFIED
GGP13231Telethon - ItalyUNSPECIFIED
062164/Z/00/ZWellcome Trusthttp://dx.doi.org/10.13039/100004440
HICF-1009–003Health Innovation Challenge FundUNSPECIFIED
PubMed ID: 31949313
Web of Science ID: WOS:000508167800002
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/111581
Publisher's version: https://doi.org/10.1038/s41436-019-0743-3

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