De Novo Sequence and Copy Number Variants are Strongly Associated with Tourette Disorder and Implicate Cell Polarity in Pathogenesis

We previously established the contribution of de novo damaging sequence variants to Tourette disorder (TD) through whole exome sequencing of 511 trios. Here, we sequence an additional 291 TD trios and analyze the combined set of 802 trios. We observe an overrepresentation of de novo damaging variants in simplex but not multiplex families; we identify two new high confidence TD risk genes, CELSR3 (Cadherin EGF LAG Seven-Pass G-Type Receptor 3) and OPA1 (Mitochondrial Dynamin-Like GTPase); we find that the genes mutated in TD patients are enriched for those related to cell polarity, suggesting a common pathway underlying pathobiology; and we confirm a statistically significant excess of de novo copy number variants in TD. Finally, we identify significant overlap of de novo sequence variants between TD and obsessive-compulsive disorder, and de novo copy number variants between TD and autism spectrum disorder, consistent with shared genetic risk.