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

Hilary C. Martin (Lead / Corresponding author), Eugene J. Gardner, Kaitlin E. Samocha, Joanna Kaplanis, Nadia Akawi, Alejandro Sifrim, Ruth Y. Eberhardt, Ana Lisa Taylor Tavares, Matthew D. C. Neville, Mari E. K. Niemi, Giuseppe Gallone, Jeremy McRae, , Caroline F. Wright, David R. Fitzpatrick, Helen V. Firth, Matthew E. Hurles

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21 Citations (Scopus)
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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.

Original languageEnglish
Article number627
Number of pages13
JournalNature Communications
Early online date27 Jan 2021
Publication statusPublished - Dec 2021


  • Genetic association study
  • Medical genetics
  • Neurodevelopmental disorders

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)


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