TY - JOUR
T1 - De Novo Coding Variants Are Strongly Associated with Tourette Disorder
AU - Tourette International Collaborative Genetics (TIC Genetics)
AU - Tourette Syndrome Association International Consortium for Genetics (TSAICG)
AU - Willsey, A. Jeremy
AU - Fernandez, Thomas V.
AU - Yu, Dongmei
AU - King, Robert A.
AU - Dietrich, Andrea
AU - Xing, Jinchuan
AU - Sanders, Stephan J.
AU - Mandell, Jeffrey D.
AU - Huang, Alden Y.
AU - Richer, Petra
AU - Smith, Louw
AU - Dong, Shan
AU - Samocha, Kaitlin E.
AU - Abdulkadir, Mohamed
AU - Bohnenpoll, Julia
AU - Bromberg, Yana
AU - Brown, Lawrence W.
AU - Cheon, Keun Ah
AU - Coffey, Barbara J.
AU - Deng, Li
AU - Dietrich, Andrea
AU - Dong, Shan
AU - Elzerman, Lonneke
AU - Fernandez, Thomas V.
AU - Fründt, Odette
AU - Garcia-Delgar, Blanca
AU - Gedvilaite, Erika
AU - Gilbert, Donald L.
AU - Grice, Dorothy E.
AU - Hagstrøm, Julie
AU - Hedderly, Tammy
AU - Heiman, Gary A.
AU - Heyman, Isobel
AU - Hoekstra, Pieter J.
AU - Hong, Hyun Ju
AU - Huyser, Chaim
AU - Ibanez-Gomez, Laura
AU - Kim, Young Key
AU - Kim, Young Shin
AU - King, Robert A.
AU - Koh, Yun Joo
AU - Kook, Sodahm
AU - Kuperman, Samuel
AU - Lamerz, Andreas
AU - Leventhal, Bennett
AU - Ludolph, Andrea G.
AU - Lühr da Silva, Claudia
AU - Madruga-Garrido, Marcos
AU - Münchau, Alexander
AU - Tübing, Jennifer
PY - 2017/5/3
Y1 - 2017/5/3
N2 - 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 [Figure presented]
AB - 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 [Figure presented]
UR - http://www.scopus.com/inward/record.url?scp=85018748582&partnerID=8YFLogxK
U2 - 10.1016/j.neuron.2017.04.024
DO - 10.1016/j.neuron.2017.04.024
M3 - Journal articles
C2 - 28472652
AN - SCOPUS:85018748582
VL - 94
SP - 486-499.e9
JO - Neuron
JF - Neuron
SN - 0896-6273
IS - 3
ER -