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 language | English |
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Pages (from-to) | 486-499.e9 |
Journal | Neuron |
Volume | 94 |
Issue number | 3 |
DOIs | |
Publication status | Published - 3 May 2017 |
Externally published | Yes |
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