Supplementary Figure 13: Gene set based evaluation of RVIS.
From: Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability
The box plots indicate the distribution of median RVIS (Residual Variation Intolerance Score) based on 100,000 permutations of equal sized gene sets (see Online Methods). Gene sets analyzed include loss-of-function tolerant (LoFT) genes (light blue; N=161), genes with at least one functional de novo mutation in healthy control set (pink box; N=1,262),), House-keeping (HK) genes (yellow box; N=397), dominant ID genes (blue box; N=412), and novel candidate ID genes (green box, N=9). 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 RVIS per category. Based on the simulations, depicted by the boxplots, we could identified a significant higher median RVIS for the LoFT genes which is in line with the tolerant nature of this gene set (Observed: 85.04; simulated distribution: μ=50.01, σ=2.48; empirical p-value: <1x10−5; Z-value: 14.14). For the healthy control set the observed median RVIS was significantly lower than the expected median RVIS (observed: 37.05; simulated distribution: μ=50.01, σ=1.36; empirical p-value: <1x10−5; Z-value=-9.56). For the House-keeping and dominant ID gene sets the observed median RVIS is significantly lower than the simulated distribution of median RVIS (HK genes: observed: 32.80; simulated distribution: μ=50.01, σ=2.48; empirical p-value <1x10−5; Z-value: -6.95; and Dominant ID genes: observed: 18.92; simulated distribution: μ=50.02, σ=2.43; empirical p-value <1x10−5; Z-value: -12.82). The set of novel candidate ID genes has an observed median RVIS of 8.47 (simulated distribution: μ=50.05, σ=15.08; empirical p-value = 4.60x10−4; Z-value: -2.76). For the 21 dominant ‘missense only’ genes (with at least 3 missense mutations in the absence of LoF mutations) we observe the lowest median RVIS of 3.56 (simulated distribution: μ=50.02, σ=10.42; empirical p-value <1x10−5; Z-value: -4.46) again illustrating that those known and novel candidate dominant ID genes that harbor only missense variants are among the most intolerant ID genes.
