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

Abstract

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
JournalNeuron
Volume94
Issue number3
DOIs
Publication statusPublished - 3 May 2017
Externally publishedYes

Keywords

  • 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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