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De Novo Loss-of-Function Mutations in CHD2 Cause a Fever-Sensitive Myoclonic Epileptic Encephalopathy Sharing Features with Dravet Syndrome
Open accessAbstract
Dravet syndrome is a severe epilepsy syndrome characterized by infantile onset of therapy-resistant, fever-sensitive seizures followed by cognitive decline. Mutations in SCN1A explain about 75% of cases with Dravet syndrome; 90% of these mutations arise de novo. We studied a cohort of nine Dravet-syndrome-affected individuals without an SCN1A mutation (these included some atypical cases with onset at up to 2 years of age) by using whole-exome sequencing in proband-parent trios. In two individuals, we identified a de novo loss-of-function mutation in CHD2 (encoding chromodomain helicase DNA binding protein 2). A third CHD2 mutation was identified in an epileptic proband of a second (stage 2) cohort. All three individuals with a CHD2 mutation had intellectual disability and fever-sensitive generalized seizures, as well as prominent myoclonic seizures starting in the second year of life or later. To explore the functional relevance of CHD2 haploinsufficiency in an in vivo model system, we knocked down chd2 in zebrafish by using targeted morpholino antisense oligomers. chd2-knockdown larvae exhibited altered locomotor activity, and the epileptic nature of this seizure-like behavior was confirmed by field-potential recordings that revealed epileptiform discharges similar to seizures in affected persons. Both altered locomotor activity and epileptiform discharges were absent in appropriate control larvae. Our study provides evidence that de novo loss-of-function mutations in CHD2 are a cause of epileptic encephalopathy with generalized seizures.
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“Mutations in CHD2 have been detected in individuals with a diagnosis of ASD (22), ID (73) or epilepsy (82,83,87,89)”
From Genetics and genomics of autism spectrum disorder: embracing complexity (2015) · cites this paper as [82]
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Metadata
- Authors
- Suls, A., Jaehn, J. A., Kecskés, A., Weber, Y., Weckhuysen, S., Craiu, D. C., Siekierska, A., Djémié, T., Afrikanova, T., Gormley, P., von Spiczak, S., Kluger, G., Iliescu, C. M., Talvik, T., Talvik, I., Meral, C., Caglayan, H. S., Giraldez, B. G., Serratosa, J., Lemke, J. R., Hoffman-Zacharska, D., Szczepanik, E., Barisic, N., Komarek, V., Hjalgrim, H., Møller, R. S., Linnankivi, T., Dimova, P., Striano, P., Zara, F., Marini, C., Guerrini, R., Depienne, C., Baulac, S., Kuhlenbäumer, G., Crawford, A. D., Lehesjoki, A.-E., de Witte, P. A. M., Palotie, A., Lerche, H., Esguerra, C. V., De Jonghe, P., Helbig, I., Hendrickx, R., Holmgren, P., Stephani, U., Muhle, H., Pendiziwiat, M., Appenzeller, S., Selmer, K., Brilstra, E., Koeleman, B., Rosenow, F., Leguern, E., Sterbova, K., Magdalena, B., Rodica, G., Arsene, O. T., Diana, B., Guerrero-Lopez, R., Ortega, L., Todorova, A. P., Kirov, A. V., Robbiano, A., Arslan, M., Yiş, U., & Ivanović, V.
- Affiliations
- University of Antwerp (BE)
- Hertie Institute for Clinical Brain Research (DE)
- Carol Davila University of Medicine and Pharmacy (RO)
- KU Leuven (BE)
- Wellcome Sanger Institute (GB)
- Schön Klinik Vogtareuth (DE)
- Tartu University Hospital (EE)
- GATA Haydarpaşa Eğitim Hastanesi (TR)
- Centre for Biomedical Network Research on Rare Diseases (ES)
- University Hospital of Bern (CH)
- University of Southern Denmark (DK)
- University of Helsinki (FI)
- Istituto Giannina Gaslini (IT)
- Meyer Children's Hospital (IT)
- Centre National de la Recherche Scientifique (FR)
- Christian-Albrechts-Universität zu Kiel (DE)
- University of Luxembourg (LU)
- Broad Institute (US)
- ORCID
- Suls, Arvid
- Weber, Yvonne
- Weckhuysen, Sarah
- Craiu, Dana C.
- Siekierska, Aleksandra
- Gormley, Padhraig
- Kluger, Gerhard
- Iliescu, Catrinel M.
- Serratosa, José
- Lemke, Johannes R.
- Hjalgrim, Helle
- Møller, Rikke S.
- Linnankivi, Tarja
- Dimova, Petia
- Striano, Pasquale
- Zara, Federico
- Marini, Carla
- Guerrini, Renzo
- Depienne, Christel
- Baulac, Stéphanie
- Kuhlenbäumer, Gregor
- Lehesjoki, Anna-Elina
- Palotie, Aarno
- Lerche, Holger
- Esguerra, Camila V.
- Helbig, Ingo
- Hendrickx, Rik
- Stephani, Ulrich
- Appenzeller, Silke
- Selmer, Kaja
- Brilstra, Eva
- Koeleman, Bobby
- Rosenow, Felix
- Arslan, Mutluay
- Yiş, Uluç
- Ivanović, Vanja
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-11
- Volume
- 93
- Issue
- 5
- Pages
- 967-975
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3824114
- OpenAlex
- W2069010410
- Cited by
- 219
- References
- 36
- Citations by year
- 2026: 4 · 2025: 12 · 2024: 17 · 2023: 18 · 2022: 13 · 2021: 20 · 2020: 16 · 2019: 12 · 2018: 15 · 2017: 19 · 2016: 19 · 2015: 29 · 2014: 23
- FWCI
- 17.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Lirias (submittedVersion, other-oa)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Florence Research (University of Florence) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Funders
- European Science Foundation
- Deutsche Forschungsgemeinschaft (Le1030/11-1)
- Academy of Finland (141549)
- Deutsche Gesellschaft für Epileptologie
- Folkhälsanin Tutkimussäätiö
- Vlaamse regering
- European Commission (261123)
- Sigrid Juséliuksen Säätiö
- Wellcome Trust (098051, 129680, 213506, 251704, WT089062)
- Universiteit Antwerpen
- Seventh Framework Programme (FP7/2007-2013, HEALTH-F4-2007- 201413)
- Fonds Wetenschappelijk Onderzoek
- Narodowe Centrum Nauki (800/N-ESF-EuroEPINOMICS/10/2011/0)
- Türkiye Bilimsel ve Teknolojik Araştirma Kurumu
- Topics
- Health Sciences › Medicine › Clinical Neurology › Epilepsy research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Pharmacological Effects and Toxicity Studies
- Keywords
- CHD2, Dravet syndrome, myoclonic epilepsy, haploinsufficiency, intellectual disability, epileptiform discharges, locomotor activity
- MeSH terms
- Animals, Child, Cognition Disorders, Seizures, Febrile, DNA-Binding Proteins, Epilepsies, Myoclonic, Female, Humans, Larva, Male, Intellectual Disability, Phenotype, Zebrafish, Cohort Studies, Gene Knockdown Techniques, Young Adult, Haploinsufficiency, Exome, NAV1.1 Voltage-Gated Sodium Channel
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