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

Martin, H. C. et al. (2021) The contribution of X-linked coding variation to severe developmental disorders. Nature Communications, 12, 627. (doi: 10.1038/s41467-020-20852-3) (PMID:33504798) (PMCID:PMC7840967)

Abstract

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Tobias, Professor Edward
• Authors: Martin, H. C., Gardner, E. J., Samocha, K. E., Kaplanis, J., Akawi, N., Sifrim, A., Eberhardt, R. Y., Taylor Tavares, A. L., Neville, M. D.C., Niemi, M. E.K., Gallone, G., McRae, J., Deciphering Developmental Disorders Study, ., Wright, C. F., FitzPatrick, D. R., Firth, H. V., and Hurles, M. E.
• College/School: College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
• Journal Name: Nature Communications
• Publisher: Nature Research
• ISSN: 2041-1723
• ISSN (Online): 2041-1723
• Copyright Holders: Copyright © The Author(s) 2021
• First Published: First published in Nature Communications 12(1):627
• Publisher Policy: Reproduced in accordance with the publisher copyright policy