De Novo Coding Variants Are Strongly Associated with Tourette Disorder

Neuron. 2017 May 3;94(3):486-499.e9. doi: 10.1016/j.neuron.2017.04.024.


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.

Keywords: TIC Genetics; TSAICG; Tourette disorder; Tourette syndrome; de novo variants; gene discovery; whole-exome sequencing.

Publication types

  • Video-Audio Media

MeSH terms

  • Adult
  • Cadherins / genetics*
  • Cell Cycle Proteins
  • Child
  • Cohort Studies
  • Female
  • Fibronectins / genetics*
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Male
  • Mutation
  • Odds Ratio
  • Parents
  • Phosphoproteins / genetics*
  • Proteins / genetics*
  • Receptors, Cell Surface / genetics*
  • Sequence Analysis, DNA
  • Tourette Syndrome / genetics*


  • Cadherins
  • Cell Cycle Proteins
  • Celsr3 protein, human
  • FN1 protein, human
  • Fibronectins
  • Intracellular Signaling Peptides and Proteins
  • NIPBL protein, human
  • Phosphoproteins
  • Proteins
  • Receptors, Cell Surface
  • WWC1 protein, human