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

In Nature communications ; h5-index 260.0

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.

Leitão Elsa, Schröder Christopher, Parenti Ilaria, Dalle Carine, Rastetter Agnès, Kühnel Theresa, Kuechler Alma, Kaya Sabine, Gérard Bénédicte, Schaefer Elise, Nava Caroline, Drouot Nathalie, Engel Camille, Piard Juliette, Duban-Bedu Bénédicte, Villard Laurent, Stegmann Alexander P A, Vanhoutte Els K, Verdonschot Job A J, Kaiser Frank J, Tran Mau-Them Frédéric, Scala Marcello, Striano Pasquale, Frints Suzanna G M, Argilli Emanuela, Sherr Elliott H, Elder Fikret, Buratti Julien, Keren Boris, Mignot Cyril, Héron Delphine, Mandel Jean-Louis, Gecz Jozef, Kalscheuer Vera M, Horsthemke Bernhard, Piton Amélie, Depienne Christel

2022-Nov-02