Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 93, Issue 5, Pages 967-975Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2013.09.017
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Funding
- European Science Foundation
- state budget of Romania
- Scientific and Technological Research Council of Turkey
- National Science Centre Poland [800/N-ESF-EuroEPINOMICS/10/2011/0]
- MH CZ-DRO, University Hospital Motol, Prague [00064203]
- Investissements d'avenir [ANR-10-IAIHU-06]
- Academy of Finland [141549, 251704]
- Folkhalsan Research Foundation
- Wellcome Trust [WT089062, 098051]
- Academy of Finland Center of Excellence in Complex Disease Genetics grants [213506, 129680]
- European Community [HEALTH-F4-2007-201413]
- Synaptic Systems grant [242167]
- Sigrid Juselius Foundation
- European Commission [261123]
- Federal Ministry of Education and Research [NGENplus/EMINet 01GS08123, IonNeurONet 01GM1105A]
- German Research Foundation (DFG) [Le1030/11-1]
- German Society for Epileptology
- Fund for Scientific Research Flanders (FWO)
- Flemish government Methusalem excellence grant
- University of Antwerp
- Academy of Finland (AKA) [141549, 141549] Funding Source: Academy of Finland (AKA)
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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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