期刊
NEURON
卷 94, 期 3, 页码 486-+出版社
CELL PRESS
DOI: 10.1016/j.neuron.2017.04.024
关键词
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资金
- National Institute of Mental Health [R01MH092290, R01MH092291, R01MH092292, R01MH092293, R01MH092513, R01MH092516, R01MH092520, R01MH092289, K08MH099424, K23MH085057]
- National Institute of Neurological Disorders and Stroke [U01NS40024-09S1, K02 NS085048]
- Harvard Clinical and Translational Science Center [UL TR001102]
- Tourette Association of America
- New Jersey Center for Tourette Syndrome and Associated Disorders (NJCTS)
- Overlook International Fund
- Instituto de Salud Carlos III [PI10/01674, PI13/01461]
- Consejeria de Economia, Innovacion, Ciencia y Empresa de la Junta de Andalucia [CVI-02526, CTS-7685]
- Consejeria de Salud y Bienestar Social de la Junta de Andalucia [PI-0741/2010, PI-0437-2012, PI-0471-2013]
- Sociedad Andaluza de Neurologia
- Fundacion Alicia Koplowitz
- Fundacion Mutua Madrilena
- Jaques and Gloria Gossweiler Foundation
- Deutsche Forschungsgemeinschaft [DFG: MU 1692/3-1, MU1692/4-1, SFB 936]
- NIHR Great Ormond Street Hospital Biomedical Research Centre (GOSH BRC)
- Informatics Starter Grant from the PhRMA Foundation
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 genedisrupting (LGD) variants (rate ratio [RR] 2.32, p = 0.002). Additionally, de novo damaging variants (LGD and probably damaging missense) are over-represented 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 vari-ants in approximately 400 genes contribute risk in 12% of clinical cases.
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