De Novo Coding Variants Are Strongly Associated with Tourette Disorder

A Jeremy Willsey, Thomas V Fernandez, Dongmei Yu, Robert A King, Andrea Dietrich, Jinchuan Xing, Stephan J Sanders, Jeffrey D Mandell, Alden Y Huang, Petra Richer, Louw Smith, Shan Dong, Kaitlin E Samocha, Benjamin M Neale, Giovanni Coppola, Carol A Mathews, Jay A Tischfield, Jeremiah M Scharf, Matthew W State, Gary A HeimanTourette International Collaborative Genetics (TIC Genetics)

Research output: Contribution to JournalArticleAcademicpeer-review


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.

Original languageEnglish
Pages (from-to)486-499.e9
Issue number3
Publication statusPublished - 3 May 2017
Externally publishedYes


This research was also supported in part by an Informatics Starter Grant from the PhRMA Foundation (to Y. Bromberg). We thank all of the individuals involved in recruitment and assessment of the subjects reported in this study: Denmark: Nikoline Frost and Heidi B. Biernat (Copenhagen); Germany: Stephanie Enghardt, Yvonne Friedrich, Christiane Michel (Dresden), Jenny Schmalfeld (Lübeck), Hanife Kling, and Ariane Saccarello (Ulm); Spain: María T. Cáceres, Fátima Carrillo, Marta Correa, Pilar Gómez-Garre, and Laura Vargas (Sevilla); the Netherlands: Vivian op de Beek (Amsterdam), Marieke Messchendorp (Groningen), Nicole Driessen, Nadine Schalk (Nijmegen), Noor Tromp (Alkmaar), Els van den Ban (Utrecht), Jolanda Blom, Rudi Bruggemans, and MariAnne Overdijk (Barendrecht); UK: Anup Kharod (London GOSH); USA: Sarah Jacobson (Cincinnati), Angie Cookman (Iowa City), Zoey Shaw (Mount Sinai/NKI), Julia Brillante, Daniela B. Colognori, Joseph Conerty, Alycia Davis, Joanne O'Brien, Carolyn Spiro, Donna Tischfield (Rutgers), Shannon Granillo, and JD Sandhu (Seattle Children's). Finally, we thank Adife Gulhan Ercan-Sencicek (Yale), Xin He (University of Chicago), Kathryn Roeder (CMU), Bernie Devlin (University of Pittsburgh), Helen Willsey (UCSF), the Willsey lab (UCSF), and all who may not have been mentioned.

FundersFunder number
Angie Cookman
Hanife Kling
Helen Willsey
Kathryn Roeder
MariAnne Overdijk
Vivian op de Beek
National Institute of Mental HealthR01MH092289
Pharmaceutical Research and Manufacturers of America Foundation
University of Chicago
University of Pittsburgh
Carnegie Mellon University
University of California, San Francisco


    • Adult
    • Cadherins
    • Child
    • Cohort Studies
    • Female
    • Fibronectins
    • Genetic Predisposition to Disease
    • Genetic Variation
    • Humans
    • Intracellular Signaling Peptides and Proteins
    • Journal Article
    • Male
    • Mutation
    • Odds Ratio
    • Parents
    • Phosphoproteins
    • Proteins
    • Receptors, Cell Surface
    • Sequence Analysis, DNA
    • Tourette Syndrome
    • Video-Audio Media


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