As noted, our initial pathway analysis also identified enrichment of GABA-A receptor life cycle and GABA receptor signaling genes; however, the finding was accounted for by a single large multigenic de novo CNV (Figure 3A). Consequently, the implications are not clear: on the one hand, the clustering of gene families in genomic segments, as well as the relatively large target sizes of neuronal genes, has the potential to bias pathway analyses (58); on the other hand, there is strong evidence from prior studies of neurodevelopmental disorders, including ASD (38), that large de novo genic events are very likely to be pathogenic. As 447 genes map within the chromosome 5 de novo event, conclusions regarding which gene or genes may be contributing to TS in this instance are not possible. However, in light of two recent post mortem studies highlighting the GABA system in TS (10, 11), further study of genes within this interval and attention to the GABA system in general will be of particular interest in large-scale sequencing and follow-up CNV studies.
