We observed significant enrichment of both deletion and duplication events overlapping FMRP and PSD targets, indicating that altered dosage of these genes can underlie ASD susceptibility. This is consistent with evidence that FMRP targets belong to multiple signaling and interconnected pathways such as PI3K-Akt-TSC-PTEN-mTOR and PI3K-RAS-MAPK,59,60 which have been linked to ASD through both underexpression and overexpression of genes in these pathways. Although both deletions and duplications can contribute to risk, we found that deletions can have a stronger impact when highly-brain-expressed genes, genes conferring dominant phenotypes in humans and mice, or genes with a high pHI are considered. We also found that ASD risk increases as a function of the number of brain-expressed genes affected by rare de novo and pathogenic CNVs, consistent with an additive model of risk underlying ASD etiology.