identify de novo single-nucleotide variants (SNVs) and insertion-deletion variants (indels). We observe significant evidence for the contribution of de novo likely gene-disrupting (LGD) variants (insertion of premature stop codon, frameshift, or canonical splice-site variant) to TD. We then replicate these findings in WES data from 186 parent-child trios (173 after quality control) from the Tourette Syndrome Association International Consortium for Genetics (TSAICG; https://www.findtsgene.org/). We also observe evidence for the contribution of de novo damaging variants (LGD and probably damaging missense). Overall, we estimate that 12% of clinical cases will carry a de novo damaging variant (LGD and probably damaging missense) mediating TD risk and that approximately 400 genes are vulnerable to these variants. Finally, a combined analysis identifies one high-confidence TD (hcTD) risk gene (false discovery rate [FDR] < 0.1), WWC1 (WW and C2 domain containing 1), and three additional probable TD (pTD) risk genes (FDR < 0.3) CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). See Figure 1 for an overview of this study.
