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

De Novo Coding Variants Are Strongly Associated with Tourette Disorder.

Author information

1
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA; Institute for Neurodegenerative Diseases, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA.
2
Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA.
3
Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
4
University of Groningen, University Medical Center Groningen, Department of Child and Adolescent Psychiatry, 9713GZ Groningen, the Netherlands.
5
Rutgers, the State University of New Jersey, Department of Genetics and the Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA.
6
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA.
7
Department of Neurology, University of California Los Angeles, Los Angeles, California, CA 90095, USA; Department of Psychiatry and Biobehavioral Sciences, University of California Los Angeles, Los Angeles, CA 90095, USA.
8
Yale Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT 06520, USA; Sewanee: The University of the South, Sewanee, TN 37383, USA.
9
Department of Psychiatry, University of Florida School of Medicine, Gainesville, FL 32611, USA.
10
Center for Genomic Medicine, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA. Electronic address: jscharf@partners.org.
11
Department of Psychiatry, UCSF Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: matthew.state@ucsf.edu.
12
Rutgers, the State University of New Jersey, Department of Genetics and the Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA. Electronic address: heiman@dls.rutgers.edu.

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.

KEYWORDS:

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

PMID:
28472652
PMCID:
PMC5769876
DOI:
10.1016/j.neuron.2017.04.024
[Indexed for MEDLINE]
Free PMC Article

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