Suls, Arvid3; Jaehn, Johanna A4; Kecskés, Angela5; Weber, Yvonne6; Weckhuysen, Sarah3; Craiu, Dana C7; Siekierska, Aleksandra5; Djémié, Tania3; Afrikanova, Tatiana5; Gormley, Padhraig8; von Spiczak, Sarah4; Kluger, Gerhard9; Iliescu, Catrinel M10; Talvik, Tiina11; Talvik, Inga11; Meral, Cihan12; Caglayan, Hande S13; Giraldez, Beatriz G14; Serratosa, José15; Lemke, Johannes R16; Hoffman-Zacharska, Dorota17; Szczepanik, Elzbieta17; Barisic, Nina18; Komarek, Vladimir19; Hjalgrim, Helle28; Møller, Rikke S28; Linnankivi, Tarja20; Dimova, Petia21; Striano, Pasquale22; Zara, Federico23; Marini, Carla24; Guerrini, Renzo24; Depienne, Christel25; Baulac, Stéphanie25; Kuhlenbäumer, Gregor4; Crawford, Alexander D5; Lehesjoki, Anna-Elina26; de Witte, Peter A M5; Palotie, Aarno8; Lerche, Holger6; Esguerra, Camila V5; De Jonghe, Peter3; Helbig, Ingo4
1 Danish Epilepsy Centre, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU2 Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU3 Neurogenetics Group, Department of Molecular Genetics, VIB, Antwerp, Belgium4 Christian-Albrechts-Universität zu Kiel5 University of Leuven6 University of Tübingen7 ‘‘Carol Davila’’ University of Medicine8 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK9 Schön Klinik Vogtareuth10 ‘‘Carol Davila’’ University of Medicine11 University of Tartu12 GATA Haydarpasa Teaching Hospital13 Bogazici University14 Hospital Universitario Fundación Jiménez Diaz15 Hospital Universitario Fundación Jiménez Diaz16 University Children’s Hospital Inselspital17 Institute of Mother and Child18 University Hospital Centre Zagreb19 University Hospital Motol20 University of Helsinki21 St. Naum University Hospital of Neurology and Psychiatry22 U. Genova23 Giannina Gaslini Institute, Genova, Italy24 University of Florence25 Hôpital Pitié-Salpêtrière26 Folkhälsan Institute of Genetics27 unknown28 Danish Epilepsy Centre, Institute of Regional Health Research, Det Sundhedsvidenskabelige Fakultet, SDU
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.
American Journal of Human Genetics, 2013, Vol 93, Issue 5, p. 967-75