Supplementary Figure 8: Intolerance to loss-of-function (LoF) variation for ID genes.

The box plots indicate the distribution of median pLI (probability LoF intolerant) based on 100,000 permutations of equal sized gene sets (see Online Methods). Gene sets analyzed include genes with at least one functional de novo mutation in healthy control set (pink box; N=1,300), dominant ID genes (blue box; N=423), and novel candidate ID genes (green box, N=10). In orange, all genes (n=21, all known dominant ID genes) were used for which we observed at least three amino missense DNM - and no loss-of-function - mutations, suggestive for genes with gain-of-function and/or dominant negative effect. The red diamonds show the observed median pLI per category. The closer a pLI is to 1 the more intolerant a gene is to LoF variants. A pLI >= 0.9 is considered as an extremely LoF intolerant set of genes (Lek, M., et al. Preprint at bioRxiv http://dx.doi.org/10.1101/030338 (2016)) For the control genes, the observed median pLI matched the simulated distribution of median pLI (Observed: 0.03; simulated distribution: μ=0.03, σ=0.01; empirical p-value: 0.31; Z-value = 0.39). For the set of dominant ID genes and ten novel candidate ID genes, the observed median pLI is significantly higher than the simulated distribution of median pLI (Dominant ID genes: observed: 0.87; simulated distribution: μ=0.03, σ=0.01; empirical p-value <1x10⁻⁵; Z-value: 61.54 and Novel candidate ID genes: Observed 0.99; simulated distribution: μ= 0.14, σ= 0.20; empirical p-value <1x10⁻⁵; Z-value = 4.28). For the dominant ‘missense only’ genes (with at least 3 missense mutations in the absence of LoF mutations). we observed the highest median pLI of all evaluated gene sets (Observed: 0.9999; simulated distribution: μ=0.09, σ=0.14; empirical p-value <1x10⁻⁵; Z-value = 6.70)