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

Nat Commun. 2021 Jan 27;12(1):627. doi: 10.1038/s41467-020-20852-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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