De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Whole-exome sequencing (WES) and de novo variant detection have proven a powerful approach to gene discovery in complex neurodevelopmental disorders. We have completed WES of 325 Tourette disorder trios from the Tourette International Collaborative Genetics cohort and a replication sample of 186 trios from the Tourette Syndrome Association International Consortium on Genetics (511 total). We observe strong and consistent evidence for the contribution of de novo likely gene-disrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are overrepresented in probands (RR 1.37, p = 0.003). We identify four likely risk genes with multiple de novo damaging variants in unrelated probands: WWC1 (WW and C2 domain containing 1), CELSR3 (Cadherin EGF LAG seven-pass G-type receptor 3), NIPBL (Nipped-B-like), and FN1 (fibronectin 1). Overall, we estimate that de novo damaging variants in approximately 400 genes contribute risk in 12% of clinical cases. [Display omitted] •Exome sequencing links damaging de novo sequence variants with Tourette disorder•De novo variants in approximately 400 genes contribute risk in 12% of clinical cases•Recurrent de novo variants identify one high-confidence TD risk gene: WWC1•Gene discovery will exponentially increase as additional cohorts are sequenced Gene discovery by identifying recurrent de novo variants with whole-exome sequencing has proven effective in neurodevelopmental disorders like autism, epilepsy, and intellectual disability. Willsey et al. apply this approach to Tourette disorder, associate de novo variants, and identify genes.