Table 2.

Burden of UR variants in the targets of DN LGD mutation

DN LGD targets	Gene count	Proportion expected to be causal	No. of UR syn mutations	No. of UR LGD mutations	LGD/syn mutations	P value	Expected no. of UR LGD mutations	Class vulnerability	Causal class vulnerability
sib	173	0.02	7,372	881	0.12	0.9842	881	1.00	1.00
rec in aut	39	0.90	2,568	79	0.03	<0.0001	307	0.26	0.17
autL	204	0.44	10,244	790	0.08	0.0011	1,224	0.65	0.19
autH	151	0.30	7,039	678	0.10	0.1066	841	0.81	0.35
aut	509	0.36	24,758	2,062	0.08	0.0009	2,959	0.70	0.15

Target classes of DN LGD mutations occurring in “sib” (unaffected sibling), “autL” (affected, lower nonverbal IQ half), “autH” (affected, higher nonverbal IQ half), “aut” (all affected), and “rec in aut” (targets hit in >1 affected) are shown. For each class, we report the gene count, and the proportion expected to be causal, as determined by the ascertainment differential (Methods). In successive columns, the numbers of observed UR synonymous and LGD variants are reported, as well as the ratio of the latter to former for each class. Based on permutations of labels, we compute the P value of the observed ratios on the assumption that they arise from a gene class similar to the sibling targets. Target classes from affected children show a markedly lower load for UR LGD variants than the class from siblings, although this difference is not significant for the affected children of higher IQ. We also derived the expected loads in the gene classes by multiplying the fourth column (number of UR syn) by 0.12, the ratio of LGD mutations to synonymous mutations in the unaffected sibling class. The expected loads allow us to compute class vulnerability as the ratio of observed to expected and, more importantly, to use a linear model to compute vulnerability of causal genes within classes (Methods). The estimates of the causal class vulnerability for the true autism genes based on the rec in aut, autL, and aut values are close (0.17, 0.19 and 0.15, respectively) and quite low.