De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with dravet syndrome

Arvid Suls, Johanna A. Jaehn, Angela Kecskés, Yvonne Weber, Sarah Weckhuysen, Dana C. Craiu, Aleksandra Siekierska, Tania Djémie, Tatiana Afrikanova, Padhraig Gormley, Sarah Von Spiczak, Gerhard Kluger, Catrinel M. Iliescu, Tiina Talvik, Inga Talvik, Cihan Meral, Hande S. Caglayan, Beatriz G. Giraldez, José Serratosa, Johannes R. LemkeDorota Hoffman-Zacharska, Elzbieta Szczepanik, Nina Barisic, Vladimir Komarek, Helle Hjalgrim, Rikke S. Møller, Tarja Linnankivi, Petia Dimova, Pasquale Striano, Federico Zara, Carla Marini, Renzo Guerrini, Christel Depienne, Stéphanie Baulac, Gregor Kuhlenbäumer, Alexander D. Crawford, Anna Elina Lehesjoki, Peter A M De Witte, Aarno Palotie, Holger Lerche, Camila V. Esguerra, Peter De Jonghe, Ingo Helbig

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)967-975
Number of pages9
JournalAmerican Journal of Human Genetics
Issue number5
Publication statusPublished - Nov 7 2013

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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