Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X
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Published:2022-11-02
Issue:1
Volume:13
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Leitão ElsaORCID, Schröder Christopher, Parenti IlariaORCID, Dalle Carine, Rastetter Agnès, Kühnel TheresaORCID, Kuechler Alma, Kaya Sabine, Gérard Bénédicte, Schaefer Elise, Nava CarolineORCID, Drouot Nathalie, Engel Camille, Piard JulietteORCID, Duban-Bedu Bénédicte, Villard LaurentORCID, Stegmann Alexander P. A.ORCID, Vanhoutte Els K., Verdonschot Job A. J.ORCID, Kaiser Frank J., Tran Mau-Them FrédéricORCID, Scala Marcello, Striano PasqualeORCID, Frints Suzanna G. M., Argilli Emanuela, Sherr Elliott H., Elder FikretORCID, Buratti JulienORCID, Keren Boris, Mignot Cyril, Héron Delphine, Mandel Jean-Louis, Gecz JozefORCID, Kalscheuer Vera M.ORCID, Horsthemke BernhardORCID, Piton AmélieORCID, Depienne ChristelORCID
Abstract
AbstractDisease gene discovery on chromosome (chr) X is challenging owing to its unique modes of inheritance. We undertook a systematic analysis of human chrX genes. We observe a higher proportion of disorder-associated genes and an enrichment of genes involved in cognition, language, and seizures on chrX compared to autosomes. We analyze gene constraints, exon and promoter conservation, expression, and paralogues, and report 127 genes sharing one or more attributes with known chrX disorder genes. Using machine learning classifiers trained to distinguish disease-associated from dispensable genes, we classify 247 genes, including 115 of the 127, as having high probability of being disease-associated. We provide evidence of an excess of variants in predicted genes in existing databases. Finally, we report damaging variants in CDK16 and TRPC5 in patients with intellectual disability or autism spectrum disorders. This study predicts large-scale gene-disease associations that could be used for prioritization of X-linked pathogenic variants.
Funder
U.S. Department of Health & Human Services | National Institutes of Health Broad Institute Deutsche Forschungsgemeinschaft UK Essen, University Duisburg-Essen, Tom-Wahlig-Stiftung (TWS), the Deutsche Stiftung Neurologie (DSN), and Assistance Publique des Hôpitaux de Paris
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary
Reference85 articles.
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