To investigate the contribution of de novo variants to Tourette disorder (TD) probands in China. Whole-exome sequencing (WES) conducted on 15 child-parent trios (45 samples) detected 25 coding de novo variants, including 2 de novo Likely Gene Disrupting (LGD) variants and 6 Missense3 variants. The de novo LGD variants were consistently associated with TD risk (Fisher's exact test OR 2.69; p = 0.1952), although statistical significance was not achieved due to the small sample size. We then assessed the relationship between the genetic events and phenotypic data by comparing Yale Global Tic Severity Scale (YGTSS) scores. The TD probands with damaging variants (defined as LGD variants and Mis3 variants) had significantly higher YGTSS scores, suggesting more severe tic symptoms (p = 0.019). We also observed a hit for a damaging compound heterozygous (CH) mutation in CELSR3, a high-confidence TD risk gene, in one of the TD probands. To our knowledge, this is the first study to investigate de novo variants in TD in a Chinese population. Our results showed that de novo LGD variants contributed to TD risk in our cohort and that TD probands with de novo damaging variants have more severe symptoms. Furthermore, our observation of damaging CH mutations in CELSR3 in an individual affected with TD further strengthened the confidence in a role for this gene in TD etiology.
Keywords: Tourette disorder; YGTSS score; de novo variants; whole-exome sequencing.