Fig. 5: Application of transcript-expression based annotation to de novo variant analyses in ASD and DD/ID.

a, b, Transcript-expression-based analyses in patients with DD/ID (a) or ASD (b). We find that de novo pLoF variants found on near-constitutively expressed regions in GTEx brain tissues have larger effect sizes than de novo LoF variants in weakly expressed regions in both disorders. Notably, de novo pLoF variants found on regions with little evidence for expression are as equally distributed in cases versus controls as de novo synonymous variants, which suggests that such variants can be removed from analyses of gene burden testing to boost discovery power. The high pext expression bin contains 46.1%, 42.3% and 11.4%, and the low-expression bin contains 4.0%, 6.0% and 11.4% of 1,249, 752 and 166 de novo pLoF variants found in patients with DD/ID, ASD and controls, respectively. Points represent rate ratio estimate and error bars represent 95% confidence interval from the Poisson exact test.