The contribution of X-linked coding variation to severe developmental disorders

Abstract

Over 130 X-linked genes have been robustly associated with developmental disorders, and X-linked causes have been hypothesised to underlie the higher developmental disorder rates in males. Here, we evaluate the burden of X-linked coding variation in 11,044 developmental disorder patients, and find a similar rate of X-linked causes in males and females (6.0% and 6.9%, respectively), indicating that such variants do not account for the 1.4-fold male bias. We develop an improved strategy to detect X-linked developmental disorders and identify 23 significant genes, all of which were previously known, consistent with our inference that the vast majority of the X-linked burden is in known developmental disorder-associated genes. Importantly, we estimate that, in male probands, only 13% of inherited rare missense variants in known developmental disorder-associated genes are likely to be pathogenic. Our results demonstrate that statistical analysis of large datasets can refine our understanding of modes of inheritance for individual X-linked disorders.

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Item Type:	Article
Authors/Creators:	Martin, H.C. Gardner, E.J. Samocha, K.E. Kaplanis, J. Akawi, N. Sifrim, A. Eberhardt, R.Y. Tavares, A.L.T. Neville, M.D.C. Niemi, M.E.K. Gallone, G. McRae, J. Wright, C.F. FitzPatrick, D.R. Firth, H.V. Hurles, M.E.
Copyright, Publisher and Additional Information:	© The Author(s) 2021. 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/.
Keywords:	Chromosomes, Human, X; Developmental Disabilities; Female; Genes, Recessive; Genes, X-Linked; Genetic Diseases, X-Linked; Genetic Variation; Humans; Inheritance Patterns; Male; Multifactorial Inheritance; Mutation; Phenotype; Sex Characteristics
Dates:	Published: 27 January 2021 Published (online): 27 January 2021 Accepted: 8 December 2020
Institution:	The University of Sheffield
Academic Units:	The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Human Metabolism (Sheffield) The University of Sheffield > Faculty of Medicine, Dentistry and Health (Sheffield) > Department of Oncology (Sheffield)
Depositing User:	Symplectic Sheffield
Date Deposited:	18 Mar 2021 13:19
Last Modified:	18 Mar 2021 13:19
Status:	Published
Publisher:	Springer Science and Business Media LLC
Refereed:	Yes
Identification Number:	10.1038/s41467-020-20852-3
Related URLs:	PubMed URL
Open Archives Initiative ID (OAI ID):	oai:eprints.whiterose.ac.uk:172113

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The contribution of X-linked coding variation to severe developmental disorders

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