Analysis of genes mapping within rare genic TS CNVs show significant enrichment for a variety of pathways involved in CNS development and function (Table 1; Figure S6 in Supplement 1). However, after correcting for the impact of gene family clusters mapping within large CNVs, only histaminergic signaling was identified by multiple algorithms. The result is a particularly intriguing, given our recent discovery of a dense TS pedigree segregating a rare loss-of-function mutation in the HDC gene (22), the rate-limiting enzyme in histamine biosynthesis. HA signaling in the central nervous system is mediated by four G protein-coupled receptors, located both presynaptically (predominantly H3 as well as H4) and postsynaptically (H1-H3). Presynaptic HA receptors regulate not only the release of HA, but also a variety of other neurotransmitters, including dopamine. Several lines of evidence suggest that HA acts in a counter-regulatory fashion, with increased HA resulting in decreased DA signaling and vice versa (62, 63). H2 and H3 receptors are enriched in the striatum and cortex, regions of the brain implicated in TS (64), and studies of rodents with decreased brain HA
