Genomic tics in tourette syndrome.

1 I t is a striking observation that studies of copy number variation (CNV) in neurodevelopmental phenotypes continue to report an excess of rare variants in case populations. This astonishing esult has been observed and replicated in studies of intellectual isability (1), autism (2), schizophrenia (3), and epilepsy (4). In a tudy published this month in Biological Psychiatry, Tourette synrome (TS) is now added to this growing list (5). In their newly published study, Fernandez et al. (5) found a 2.45-fold excess of de novo CNV in cases compared with controls. They also found that these CNVs are larger and affect more genes than de novo events present in controls. Although these results are not statistically significant, owing to the small sample size under study, this trend is similar to what has been seen for other neurodevelopmental phenotypes, including autism. Additionally, TS case CNVs are enriched for autism candidate genes, such as contactin-associated protein-like 2 (CNTNAP2), fragile histidine triad protein (FHIT), and astrotactin 2 (ASTN2). This result does reach statistical significance, suggesting that there is a shared pathway between TS and autism. The shared-pathway hypothesis is supported by a prior report of a neuroligin 4 (NLGN4) deletion discovered in an autistic proband. In this pedigree, a brother of the autistic proband who shares the NLGN4 deletion has TS (6). One interpretation of these data is that inherited susceptibility alleles give rise to a core neurobiological insult that could result in any of a range of phenotypes. Current evidence suggests that this range includes both TS and autism, with environmental influences or modifier genes mediating the specific phenotypic manifestation. These intriguing hypotheses will require additional investigation in larger cohorts of TS patients. The authors chose to explore the qualitative nature of genes affected by rare CNV in their TS cases, using well-known methods to identify biological pathways or processes that might be commonly affected in their TS cases. They find evidence for involvement of the histamine receptor-signaling pathway. This dovetails with prior work of these authors, in which they investigated a Mendelian form of TS. In a pedigree with nine affected individuals, in which TS is segregating in a dominant fashion, linkage analysis, and subsequent sequencing of all genes in the linkage interval identified a rare stop codon mutation in the gene for L-histidine decarboxylase, the rate-limiting enzyme in histamine production (7). The authors showed that this mutation led to a decrease in both enzyme activity and histamine concentration, suggesting that a decrease in histamine transmission may underlie some forms of TS. In a very recent case report of an adult male with TS and narcolepsy, a pharmacologic intervention was tailored based on the results of the pedigree analysis discussed above. The patient had been treated with various agents, and although some were successful in treating his narcolepsy, they simultaneously in-