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

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Title: The contribution of X-linked coding variation to severe developmental disorders
Authors: Martin, Hilary C.Gardner, Eugene J.Samocha, Kaitlin E.Green, Andrewet al.
Permanent link: http://hdl.handle.net/10197/13041
Date: 27-Jan-2021
Online since: 2022-08-05T09:22:28Z
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.
Funding Details: UK Research Ethics Committee
Cambridge South Research Ethics Committee
Republic of Ireland Research Ethics Committee
Health Innovation Challenge Fund
Wellcome Trust and the UK Department of Health
Wellcome Trust Sanger Institute
National Institutes for Health Research
Type of material: Journal Article
Publisher: Springer
Journal: Nature Communications
Volume: 12
Start page: 1
End page: 13
Copyright (published version): 2021 The Authors
Keywords: X chromosome burden analysisX-linked disordersDevelopmental disorder rates
DOI: 10.1038/s41467-020-20852-3
Language: en
Status of Item: Peer reviewed
ISSN: 2041-1723
This item is made available under a Creative Commons License: https://creativecommons.org/licenses/by-nc-nd/3.0/ie/
Appears in Collections:Medicine Research Collection

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