Article (Scientific journals)
De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome
Suls, A.; Jaehn, J. A.; Kecskés, A. et al.
2013In American Journal of Human Genetics, 93 (5), p. 967-975
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Keywords :
DNA binding protein; DNA fragment; Animals; Child; Cognition Disorders; Cohort Studies; DNA-Binding Proteins; Epilepsies, Myoclonic; Exome; Female; Gene Knockdown Techniques; Haploinsufficiency; Humans; Intellectual Disability; Larva; Male; NAV1.1 Voltage-Gated Sodium Channel; Phenotype; Seizures, Febrile; Young Adult; Zebrafish; Danio rerio
Abstract :
[en] 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 feversensitive 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. © 2013 by The American Society of Human Genetics. All rights reserved.
Research center :
Luxembourg Centre for Systems Biomedicine (LCSB): Chemical Biology (Crawford Group)
Disciplines :
Human health sciences: Multidisciplinary, general & others
Identifiers :
eid=2-s2.0-84890151248
Author, co-author :
Suls, A.;  Neurogenetics group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Jaehn, J. A.;  University Medical Center Schleswig-Holstein, Christian-Albrechts University, 24105 Kiel, Germany
Kecskés, A.;  Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, 3000 Leuven, Belgium
Weber, Y.;  Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
Weckhuysen, S.;  Neurogenetics group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Craiu, D. C.;  Pediatric Neurology Clinic 2, Departments of Neurology, Pediatric Neurology, 050474 Bucharest, Romania, Pediatric Neurology Clinic, 041914 Bucharest, Romania
Siekierska, A.;  Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, 3000 Leuven, Belgium
Djémie, T.;  Neurogenetics group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Afrikanova, T.;  Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, 3000 Leuven, Belgium
Gormley, P.;  Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom
Von Spiczak, S.;  University Medical Center Schleswig-Holstein, Christian-Albrechts University, 24105 Kiel, Germany
Kluger, G.;  Neuropädiatrie und Neurologische Rehabilitation, Epilepsiezentrum für Kinder und Jugendliche, Tagesklinik für Neuropädiatrie, 83569 Vogtareuth, Germany
Iliescu, C. M.;  Pediatric Neurology Clinic 2, Departments of Neurology, Pediatric Neurology, 050474 Bucharest, Romania, Pediatric Neurology Clinic, 041914 Bucharest, Romania
Talvik, T.;  Department of Pediatrics, University of Tartu, 51014 Tartu, Estonia, Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, 50406 Tartu, Estonia
Talvik, I.;  Department of Pediatrics, University of Tartu, 51014 Tartu, Estonia, Department of Neurology and Neurorehabilitation, Children's Clinic, Tartu University Hospital, 50406 Tartu, Estonia
Meral, C.;  Department of Pediatric Neurology, GATA Haydarpasa Teaching Hospital, 34668 Istanbul, Turkey
Caglayan, H. S.;  Department of Molecular Biology and Genetics, Bogazici University, 34342 Istanbul, Turkey
Giraldez, B. G.;  Epilepsy Unit, Hospital Universitario Fundación Jiménez Diaz, Centro De Investigación Biomédica En Red De Enfermedades Raras, 28040 Madrid, Spain
Serratosa, J.;  Epilepsy Unit, Hospital Universitario Fundación Jiménez Diaz, Centro De Investigación Biomédica En Red De Enfermedades Raras, 28040 Madrid, Spain
Lemke, J. R.;  Division of Human Genetics, University Children's Hospital Inselspital, 3010 Bern, Switzerland
Hoffman-Zacharska, D.;  Department of Medical Genetics, Institute of Mother and Child, 01211 Warsaw, Poland
Szczepanik, E.;  Clinic of Neurology of Child and Adolescents, Institute of Mother and Child, 01211 Warsaw, Poland
Barisic, N.;  Department of Paediatrics, University of Zagreb School of Medicine, University Hospital Centre Zagreb, 10000 Zagreb, Croatia
Komarek, V.;  Child Neurology Department, University Hospital Motol, 150 06 Praha, Czech Republic
Hjalgrim, H.;  Danish Epilepsy Centre, 4293 Dianalund, Denmark, Institute for Regional Health research, University of Southern Denmark, 5230 Odense, Denmark
Møller, R. S.;  Danish Epilepsy Centre, 4293 Dianalund, Denmark
Linnankivi, T.;  Pediatric Neurology, Children's Hospital, University of Helsinki and Helsinki University Central Hospital, 00029 Helsinki, Finland
Dimova, P.;  Clinic of Child Neurology, St. Naum University Hospital of Neurology and Psychiatry, 1113 Sofia, Bulgaria
Striano, P.;  Pediatric Neurology and Muscular Diseases Unit, Departments of Neurosciences, Genetics, and Maternal and Child Health, 16147 Genova, Italy
Zara, F.;  Laboratory of Neurogenetics, Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, 16147 Genova, Italy
Marini, C.;  Pediatric Neurology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50132 Florence, Italy
Guerrini, R.;  Pediatric Neurology Unit and Laboratories, Meyer Children's Hospital, University of Florence, 50132 Florence, Italy
Depienne, C.;  Institut National de la Santé et de la Recherche Médicale U975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France, Centre National de la Recherche Scientifique 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France, Département de Génétique et de Cytogéné tique, Unité Fonctionnelle de Neurogénétique Moléculaire et Cellulaire, Assistance Publique - Hôpitaux de Paris, 75013 Paris, France
Baulac, S.;  Institut National de la Santé et de la Recherche Médicale U975, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France, Centre National de la Recherche Scientifique 7225, Centre de Recherche de l'Institut du Cerveau et de la Moelle Epinière, 75013 Paris, France, Université Pierre et Marie Curie (Paris VI), 75013 Paris, France
Kuhlenbäumer, G.;  Department of Neurology, Institute of Experimental Medicine, Christian-Albrechts University of Kiel, 24105 Kiel, Germany
Crawford, Alexander Dettmar ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
Lehesjoki, A.-E.;  Folkhälsan Institute of Genetics, 00290 Helsinki, Finland, Research Programs Unit, Molecular Neurology, University of Helsinki, 00290 Helsinki, Finland, Neuroscience Center, University of Helsinki, 00290 Helsinki, Finland
De Witte, P. A. M.;  Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, 3000 Leuven, Belgium
Palotie, A.;  Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, United Kingdom, Institute for Molecular Medicine Finland, University of Helsinki, 00290 Helsinki, Finland, Program inMedical and Population Genetics and Genetic Analysis Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States
Lerche, H.;  Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, 72076 Tübingen, Germany
Esguerra, C. V.;  Laboratory for Molecular Biodiscovery, Department of Pharmaceutical and Pharmacological Sciences, University of Leuven, 3000 Leuven, Belgium
De Jonghe, P.;  Neurogenetics group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium, Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium
Helbig, I.;  University Medical Center Schleswig-Holstein, Christian-Albrechts University, 24105 Kiel, Germany
More authors (33 more) Less
External co-authors :
yes
Language :
English
Title :
De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome
Publication date :
2013
Journal title :
American Journal of Human Genetics
ISSN :
0002-9297
Volume :
93
Issue :
5
Pages :
967-975
Peer reviewed :
Peer reviewed
Funders :
ESF, European Science Foundation; WT089062, Wellcome Trust; 098051, Wellcome Trust; 261123, EC, European Commission; DFG, Deutsche Forschungsgemeinschaft
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