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Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X

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Leitão, Elsa, Schröder, Christopher, Parenti, Ilaria, Dalle, Carine, Rastetter, Agnès, Kühnel, Theresa, Kuechler, Alma, Kaya, Sabine +29 more·2022·Nature Communications
DOI 10.1038/s41467-022-34264-yPMC PMC9630267

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Abstract

Disease 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.

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Cited by

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Authors
Leitão, E., Schröder, C., Parenti, I., Dalle, C., Rastetter, A., Kühnel, T., Kuechler, A., Kaya, S., Gérard, B., Schaefer, E., Nava, C., Drouot, N., Engel, C., Piard, J., Duban-Bedu, B., Villard, L., Stegmann, A. P. A., Vanhoutte, E. K., Verdonschot, J. A. J., Kaiser, F. J., Tran Mau-Them, F., Scala, M., Striano, P., Frints, S. G. M., Argilli, E., Sherr, E. H., Elder, F., Buratti, J., Keren, B., Mignot, C., Héron, D., Mandel, J.-L., Gecz, J., Kalscheuer, V. M., Horsthemke, B., Piton, A., & Depienne, C.
Affiliations
  • Essen University Hospital (DE)
  • Centre National de la Recherche Scientifique (FR)
  • Hôpitaux Universitaires de Strasbourg (FR)
  • Inserm (FR)
  • Maastricht University Medical Centre (NL)
  • Istituto Giannina Gaslini (IT)
  • University of California, San Francisco (US)
  • Sorbonne Université (FR)
  • Max Planck Institute for Molecular Genetics (DE)
Corresponding author
Depienne, Christel
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2022-11-02
Volume
13
Issue
1
Pages
6570-6570
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-022-34264-y
PMC
PMC9630267
OpenAlex
W4308147265
Cited by
47
References
6
Citations by year
2026: 9 · 2025: 10 · 2024: 20 · 2023: 6 · 2022: 2
FWCI
5.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • HAL AMU (submittedVersion, other-oa)
  • RePEc: Research Papers in Economics (submittedVersion)
  • Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DuEPublico (University of Duisburg-Essen) (submittedVersion, cc-by)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (R01NS058721)
  • 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
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Keywords
X chromosome, monogenic disorders, X-linked inheritance, disease gene prediction, gene-disease association, intellectual disability, autism spectrum disorder, CDK16, TRPC5, genetic conservation, gene expression, paralogs, machine learning classification, seizures
MeSH terms
Autism Spectrum Disorder, Humans, Intellectual Disability, Databases, Genetic, Chromosomes, Human, X, Genes, X-Linked

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