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Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2

Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2


Title: Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2
Author: Reynisdottir, Tinna
Anderson, Kimberley Jade
Boukas, Leandros
Bjornsson, Hans Tomas
Date: 2022-06-21
Language: English
Scope:
University/Institute: Landspitali - The National University Hospital of Iceland
Department: Faculty of Medicine
Clinical Laboratory Services, Diagnostics and Blood Bank
Series: PLoS Genetics; 18(6)
ISSN: 1553-7390
DOI: https://doi.org/10.1371/journal.pgen.1010278
Subject: Lífefna- og sameindalíffræði; Abnormalities, Multiple; Craniofacial Abnormalities; Growth Disorders; Hypertrichosis; Intellectual Disability; Myeloid-Lymphoid Leukemia Protein; Ecology, Evolution, Behavior and Systematics; Molecular Biology; Genetics; Genetics (clinical); Cancer Research
URI: https://hdl.handle.net/20.500.11815/3474

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Citation:

Reynisdottir , T , Anderson , K J , Boukas , L & Bjornsson , H T 2022 , ' Missense variants causing Wiedemann-Steiner syndrome preferentially occur in the KMT2A-CXXC domain and are accurately classified using AlphaFold2 ' , PLoS Genetics , vol. 18 , no. 6 , e1010278 . https://doi.org/10.1371/journal.pgen.1010278

Abstract:

Wiedemann-Steiner syndrome (WDSTS) is a neurodevelopmental disorder caused by de novo variants in KMT2A, which encodes a multi-domain histone methyltransferase. To gain insight into the currently unknown pathogenesis of WDSTS, we examined the spatial distribution of likely WDSTS-causing variants across the 15 different domains of KMT2A. Compared to variants in healthy controls, WDSTS variants exhibit a 61.9-fold overrepresentation within the CXXC domain–which mediates binding to unmethylated CpGs–suggesting a major role for this domain in mediating the phenotype. In contrast, we find no significant overrepresentation within the catalytic SET domain. Corroborating these results, we find that hippocampal neurons from Kmt2a-deficient mice demonstrate disrupted histone methylation (H3K4me1 and H3K4me3) preferentially at CpG-rich regions, but this has no systematic impact on gene expression. Motivated by these results, we combine accurate prediction of the CXXC domain structure by AlphaFold2 with prior biological knowledge to develop a classification scheme for missense variants in the CXXC domain. Our classifier achieved 92.6% positive and 92.9% negative predictive value on a hold-out test set. This classification performance enabled us to subsequently perform an in silico saturation mutagenesis and classify a total of 445 variants according to their functional effects. Our results yield a novel insight into the mechanistic basis of WDSTS and provide an example of how AlphaFold2 can contribute to the in silico characterization of variant effects with very high accuracy, suggesting a paradigm potentially applicable to many other Mendelian disorders.

Description:

Funding Information: This work was supported by a grant from the Wiedemann-Steiner Foundation to HTB (salary coverage of TR). HTB is also supported by the Louma G. Foundation, the Icelandic Research Fund (#217988, #195835, #206806) and the Icelandic Technology Development Fund (#2010588). Research reported in this publication was supported by the National Institute of General Medical Sciences of the National Institutes of Health (#R01GM121459 to LB). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: © 2022 Reynisdottir et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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