The contribution of X-linked coding variation to severe developmental disorders
Hilary C Martin,
Eugene J Gardner,
Kaitlin E Samocha,
Ruth Y. Eberhardt,
Ana Lisa Taylor Tavares,
Matthew D. C. Neville,
Mari EK Niemi,
Caroline F Wright,
David R. FitzPatrick,
Helen V Firth,
Matthew E Hurles,
on behalf of the Deciphering Developmental Disorders study
Posted 23 Mar 2020
medRxiv DOI: 10.1101/2020.03.18.20037960
Posted 23 Mar 2020
Over 130 X-linked genes have been robustly associated with developmental disorders (DDs), and X-linked causes have been hypothesised to underlie the higher DD rates in males. We evaluated the burden of X-linked coding variation in 11,046 DD patients, and found 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 developed an improved strategy to detect novel X-linked DDs and identified 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 DD-associated genes. Importantly, we estimated that, in male probands, only 13% of inherited rare missense variants in known DD-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.
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