The distribution of missense Z scores and Z scores of de novo loss-of-function mutations identified in unaffected individuals, autism spectrum disorder (ASD) cases, and intellectual disability cases. (a) The distribution of missense Z scores. The red line indicates a Z score of 3.09, or the threshold for inclusion into the set of 1,003 constrained genes. (b) The missense Z scores for genes containing de novo LoF in unaffected individuals, ASD cases, and intellectual disability cases–,,,. Black bars indicate the mean Z score of each group: 0.94, 1.68, and 2.46 for unaffected individuals, ASD cases, and intellectual disability cases, respectively. While the missense Z scores of the de novo LoF mutations found in unaffected siblings matched the overall distribution (Wilcoxon p=0.8325, n.s. = not significant), de novo LoF mutations found in both ASD and intellectual disability cases were significantly shifted towards more extreme constraint values (p < 10−6 for both). All p-values for deviation from the overall distribution are listed on the right side of the figure in bold. In addition, the distribution of missense Z scores between each of the three de novo lists were all individually significant at p < 0.05.