Neuron · 2017
De Novo Coding Variants Are Strongly Associated with Tourette Disorder.
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Willsey A Jeremy, Fernandez Thomas V, Yu Dongmei, King Robert A, Dietrich Andrea, Xing Jinchuan, Sanders Stephan J, Mandell Jeffrey D, Huang Alden Y, Richer Petra, Smith Louw, Dong Shan, Samocha Kaitlin E, Tourette International Collaborative Genetics (TIC Genetics), Tourette Syndrome Association International Consortium for Genetics (TSAICG), Neale Benjamin M, Coppola Giovanni, Mathews Carol A, Tischfield Jay A, Scharf Jeremiah M, State Matthew W, Heiman Gary A
Аннотация
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. VIDEO ABSTRACT.