Willsey, A. J., Fernandez, T. V., Yu, D., King, R. A., Dietrich, A., Xing, J., Sanders, S. J., Mandell, J. D., Huang, A. Y., Richer, P., Smith, L., Dong, S., Samocha, K. E., Neale, B. M., Coppola, G., Mathews, C. A., Tischfield, J. A., Scharf, J. M., State, M. W., Heiman, G. A. (May 2017) De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron, 94 (3). 486-499.e9. ISSN 0896-6273
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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Adult Cadherins/*genetics 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 TIC Genetics Tsaicg Tourette disorder Tourette syndrome de novo variants gene discovery whole-exome sequencing |
| Subjects: | bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > de novo mutation diseases & disorders > mental disorders > Tourette Syndrome |
| CSHL Authors: | |
| Communities: | CSHL labs > Lyon lab |
| Depositing User: | Matt Covey |
| Date: | 3 May 2017 |
| Date Deposited: | 31 Jul 2017 20:42 |
| Last Modified: | 07 Jul 2021 18:57 |
| PMCID: | PMC5769876 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/35077 |
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