Network Analysis Links Exonic Deletions to Neurodevelopmental Processes
We performed a gene-set enrichment analysis6 on our expanded sample set after refining our criteria to consider only exonic events (see Supplemental Data for details) and found only deletions to be significantly enriched in gene sets in affected versus control subjects (Figure 4A). We found 86 significantly enriched gene sets, including MAPK signaling components and neuronal synaptic functions and processes, in 42.5% (335/789) of affected subjects with exonic deletions (Figure 4A; Tables S12A–S12D). Enrichment of synaptic functioning has also been reported among inherited events in the AGRE families47 and among de novo events in the Simons Simplex Collection.36 Enriched sets delineate candidate genes disrupted by deletions not found in control subjects; these genes notably include those in the KEGG glutamatergic pathway (e.g., GRIK2 [MIM 138244], GRM5 [MIM 604102], SHANK1 [MIM 604999], SHANK2 [MIM 603290], and SHANK3 [MIM 606230]; Figure S2A and Tables S13A–S13D), the KEGG cholinergic pathway (e.g., KCNJ12 [MIM 602323], CHAT [MIM 118490], and SLC18A3 [MIM 600336], the latter two of which are within a recurrent 10q11.21–q11.23 deletion, recently reported in individuals with ID and ASD;48 Figure S2B and Tables S13A–S13D), or in both pathways (e.g., GNG13 [MIM 607298], PRKACB [MIM 176892], PLCB1 [MIM 607120], CAMK2G [MIM 602123 ], and PPP3CB [MIM 114106]). When analyzing human homologs of mouse genes, we also found enrichment of phenotypes mostly related to the brain, including abnormal telencephalon morphology, neuron morphology, behavior, and nervous system physiology (Table S12D).