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

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.

Fig. 1. Results from burden analysis of rare and de novo coding variants on the X chromosome.

a Fraction of males and females attributable to rare inherited and de novo coding variants on the X chromosome. Note that in the males, the overall attributable fraction was estimated from the case/control analysis of all male probands (7136 cases versus 8551 controls), whereas that for de novo mutations (DNMs) was estimated only in the 5138 male trio probands. In the females, only de novos were considered since we were assuming full penetrance. b Relative fraction of protein-truncating variants (PTVs) versus missense/inframe variants amongst ClinVar likely pathogenic or pathogenic variants in X-linked DDG2P genes, versus the fraction inferred in the burden analysis in DDD. c Estimated attributable fraction versus positive predictive value for DNMs and inherited variants in males in X-linked DDG2P genes. Inherited missense variants are split according to CADD (Combined Annotation Dependent Depletion) 21 and MPC (missense badness, PolyPhen, constraint) 22 scores. In a, c the coloured bars (a) or points (c) show the point estimate and the error bars show 95% confidence intervals calculated as described in the ‘Methods’.

Fig. 2. Sex-specific de novo burden analysis.

a Burden of damaging de novo mutations (DNMs) (protein truncating variants (PTVs) + missense/inframe) in females versus males, per gene. Shown are the 23 X-linked genes that passed multiple-testing correction. The text colour indicates whether the gene was classed in the consensus of genes from the Developmental Disorders Gene-to-Phenotype list (DDG2P) and Online Mendelian Inheritance in Man (OMIM) (see ‘Methods’) as X-linked dominant only (orange), X-linked recessive only (green) or both/uncertain (blue). P-values for the genes under different tests are shown in Supplementary Data 3. b Burden of damaging (PTV + missense/inframe) DNMs for males and females in the indicated gene sets. p: p-value from upper-tailed Poisson test. f_att: attributable fraction for DNMs in this gene set. The colored bars show the point estimates and error bars show 95% confidence intervals calculated as described in the ‘Methods’.