PMC:4067558 / 29713-31388 JSONTXT

{"project":"2_test","denotations":[{"id":"24768552-21658583-2047138","span":{"begin":490,"end":492},"obj":"21658583"},{"id":"24768552-21658583-2047139","span":{"begin":1673,"end":1675},"obj":"21658583"}],"text":"De novo deletions (52 in European affected subjects) were found to be significantly enriched within each gene set or pathway cluster (for 85 of the 86 gene sets or pathways), as well as across clusters (chi-square test p = 9.8 × 10−9) (Table S12B), prompting us to search for enriched biological functions within de novo events separately. Taking into account our observations of a significant multigene burden in ASD subjects (Figures 3C and 3D), we analyzed de novo events by using NETBAG36 to identify up to two ASD candidate genes per CNV among 102 de novo events in 99 subjects. NETBAG identifies networks of genes under the premise that if genomic regions are perturbed by genetic variants associated with the same phenotype, they will contain genes forming connected clusters. The NETBAG analysis resulted in a network of 113 genes (global cluster p value = 0.02; Figure 4B). Ten genes have been previously implicated in autosomal-dominant or X-linked forms of ASD and ID (UBE3A [MIM 601623], NRXN1, SHANK2, EHMT1, SYNGAP1 [MIM 603384], and SMARCA2 [MIM 600014]) or ID only (ZEB2 [MIM 605802], FLNA [MIM 300017], SKI [MIM 164780], and IKBKG [MIM 300248]). On the basis of cumulative evidence from various sources, an additional 68% (67/98) are likely to affect ASD risk (Tables S14A–S14E); 27/67 of these are either FMRP targets or PSD genes. Compared to all other genes within de novo CNVs (or deletion CNVs only), genes in the network exhibited a significantly higher pHI (Wilcoxon rank sum p = 7.07 × 10−8), and 55% (59/107 [6 without information]) had a pHI \u003e 0.35. A similar NETBAG analysis of de novo CNVs in control subjects did not yield significant results.36"}