Under the assumption that different genes harboring suspected causative mutations for the same disorder often physically interact, we sought to evaluate protein-protein interactions (PPIs) encoded by genes known to be implicated in ASD and genes affected by rare CNVs or SNVs (data drawn from our de novo CNVs and published de novo ASD LoF SNVs; Figures 5A, 5B, and S5). The union set of 336 unique genes (Table S15) analyzed by DAPPLE37 resulted in a network of direct PPIs encoded by 151 genes (Figure 5A) from each of the three main lists: 54/92 (58.7%) genes involved in ASD, 64/113 (56.6%) de novo CNV genes, and 41/122 (33.6%) de novo LoF SNV genes. The number of direct PPIs was 1.5-fold higher than expected (p < 0.001, Figure 5B), suggesting that many of the de novo CNV or SNV genes and ASD-implicated genes function cooperatively. Overrepresentation analysis identified convergent functional themes related to neuronal development and axon guidance, signaling pathways, and chromatin and transcription regulation. Overall, these findings are consistent among the three different types of analyses shown in Figures 4A, 4B, and 5.