title: De novo loss-of-function mutations in CHD2 cause a fever-sensitive myoclonic epileptic encephalopathy sharing features with Dravet syndrome.
abstract: 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.
authors.affiliation: Neurogenetics group, Department of Molecular Genetics, VIB, 2610 Antwerp, Belgium; Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, 2610 Antwerp, Belgium.
authors.forename: Arvid
authors.initials: A
authors.lastname: Suls
authors.forename: Johanna A
authors.initials: JA
authors.lastname: Jaehn
authors.forename: Angela
authors.initials: A
authors.lastname: Kecskés
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Weber
authors.forename: Sarah
authors.initials: S
authors.lastname: Weckhuysen
authors.forename: Dana C
authors.initials: DC
authors.lastname: Craiu
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Siekierska
authors.forename: Tania
authors.initials: T
authors.lastname: Djémié
authors.forename: Tatiana
authors.initials: T
authors.lastname: Afrikanova
authors.forename: Padhraig
authors.initials: P
authors.lastname: Gormley
authors.forename: Sarah
authors.initials: S
authors.lastname: von Spiczak
authors.forename: Gerhard
authors.initials: G
authors.lastname: Kluger
authors.forename: Catrinel M
authors.initials: CM
authors.lastname: Iliescu
authors.forename: Tiina
authors.initials: T
authors.lastname: Talvik
authors.forename: Inga
authors.initials: I
authors.lastname: Talvik
authors.forename: Cihan
authors.initials: C
authors.lastname: Meral
authors.forename: Hande S
authors.initials: HS
authors.lastname: Caglayan
authors.forename: Beatriz G
authors.initials: BG
authors.lastname: Giraldez
authors.forename: José
authors.initials: J
authors.lastname: Serratosa
authors.forename: Johannes R
authors.initials: JR
authors.lastname: Lemke
authors.forename: Dorota
authors.initials: D
authors.lastname: Hoffman-Zacharska
authors.forename: Elzbieta
authors.initials: E
authors.lastname: Szczepanik
authors.forename: Nina
authors.initials: N
authors.lastname: Barisic
authors.forename: Vladimir
authors.initials: V
authors.lastname: Komarek
authors.forename: Helle
authors.initials: H
authors.lastname: Hjalgrim
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.forename: Tarja
authors.initials: T
authors.lastname: Linnankivi
authors.forename: Petia
authors.initials: P
authors.lastname: Dimova
authors.forename: Pasquale
authors.initials: P
authors.lastname: Striano
authors.forename: Federico
authors.initials: F
authors.lastname: Zara
authors.forename: Carla
authors.initials: C
authors.lastname: Marini
authors.forename: Renzo
authors.initials: R
authors.lastname: Guerrini
authors.forename: Christel
authors.initials: C
authors.lastname: Depienne
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Baulac
authors.forename: Gregor
authors.initials: G
authors.lastname: Kuhlenbäumer
authors.forename: Alexander D
authors.initials: AD
authors.lastname: Crawford
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.forename: Peter A M
authors.initials: PA
authors.lastname: de Witte
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.forename: Holger
authors.initials: H
authors.lastname: Lerche
authors.forename: Camila V
authors.initials: CV
authors.lastname: Esguerra
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Ingo
authors.initials: I
authors.lastname: Helbig
mesh_terms: D000818:Animals; D002648:Child; D003072:Cognition Disorders / Q000235:genetics / Q000473:pathology; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D004831:Epilepsies, Myoclonic / Q000235:genetics* / Q000473:pathology; D059472:Exome; D005260:Female; D055785:Gene Knockdown Techniques; D057895:Haploinsufficiency; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D007814:Larva / Q000235:genetics; D008297:Male; D062550:NAV1.1 Voltage-Gated Sodium Channel / Q000235:genetics; D010641:Phenotype; D003294:Seizures, Febrile / Q000235:genetics / Q000473:pathology; D055815:Young Adult; D015027:Zebrafish
chemical_list: C575189:CHD2 protein, human; D004268:DNA-Binding Proteins; D062550:NAV1.1 Voltage-Gated Sodium Channel; C568242:SCN1A protein, human