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Journal Articles Nature Communications Year : 2022

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

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

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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Dates and versions

hal-03959490 , version 1 (27-01-2023)

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Elsa Leitão, Christopher Schröder, Ilaria Parenti, Carine Dalle, Agnès Rastetter, et al.. Systematic analysis and prediction of genes associated with monogenic disorders on human chromosome X. Nature Communications, 2022, 13 (1), pp.6570. ⟨10.1038/s41467-022-34264-y⟩. ⟨hal-03959490⟩

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