De Novo Coding Variants Are Strongly Associated with Tourette Disorder

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. (2017) De Novo Coding Variants Are Strongly Associated with Tourette Disorder. Neuron, 94 (3). 486-499.e9. ISSN 0896-6273

URL: https://www.ncbi.nlm.nih.gov/pubmed/28472652
DOI: 10.1016/j.neuron.2017.04.024

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 Deposited: 31 Jul 2017 20:42
Last Modified: 31 Jul 2017 20:42
Related URLs:
URI: http://repository.cshl.edu/id/eprint/35077

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