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

Journal article

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

Authors: Martin, HC; Gardner, EJ; Samocha, KE; Kaplanis, J; Akawi, N

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Nature Research
• Journal: Nature Communications
• Volume: 12
• Issue: 1
• Pages: 627-627
• Article number: 627
• Publication date: 2021-01-27
• DOI: 10.1038/s41467-020-20852-3
• EISSN: 2041-1723
• ISSN: 2041-1723
• Language: English
• Keywords: Phenotype; Gene; Biology; Medicine; Developmental disorder; Intellectual disability; Missense mutation; Proband; Mutation; Autism; Psychiatry; Genetics