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

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Kaplanis, Joanna 
Akawi, Nadia 


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.



Chromosomes, Human, X, Developmental Disabilities, Female, Genes, Recessive, Genes, X-Linked, Genetic Diseases, X-Linked, Genetic Variation, Humans, Inheritance Patterns, Male, Multifactorial Inheritance, Mutation, Phenotype, Sex Characteristics

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Nat Commun

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Springer Science and Business Media LLC