Recognizing that results from pathway analysis tools can be biased by the clustering of gene families within structural variants (58), we next removed CNVs containing large numbers of genes, defined by exceeding three standard deviations from the mean of all genic TS CNVs (mean = 2.3, SD = 13.3). Two duplications, one involving 447 RefSeq genes on chromosome 5q and the other involving 56 genes on chromosome 22q11, met this criterion. An analysis of the remaining list of 2,143 genes resulted in the elimination of the GABA receptor signaling findings and ranked the histamine receptor signaling pathway as having the smallest relative p-value (Table S4 in Supplement 1). We found no evidence that enrichment of histamine receptor signaling could have been the result of similar clustering. The histamine pathways identified by both PA and MC were composed of between 4 and 9 genes from rare CNVs found in 10 (PA) or 17 (MC) TS subjects (Table 1; Table S4 in Supplement 1). No single CNV contributed more than one gene to the histamine pathways results.
