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. 2013 Nov 7;93(5):967-75.
doi: 10.1016/j.ajhg.2013.09.017. Epub 2013 Oct 24.

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

Arvid Suls  1 , Johanna A Jaehn, Angela Kecskés, Yvonne Weber, Sarah Weckhuysen, Dana C Craiu, Aleksandra Siekierska, Tania Djémié, 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 Lemke, Dorota 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; EuroEPINOMICS RES Consortium
Collaborators, Affiliations

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

Arvid Suls et al. Am J Hum Genet. .

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.

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Figures

Figure 1
Figure 1
chd2 Knockdown: E2I2 MO Causes Missplicing of Zebrafish chd2 (A) Schematic cartoon showing predicted splicing events in the pre-mRNA of chd2 E2I2-MO- and ctrl-MO-injected fish. The exons are represented by colored boxes (E1, E2, and E3), and the introns are represented by solid black lines (I1 and I2). The splice MO binding site (E2I2 MO) and the primer binding sites (P1 and P2) used for qPCR are indicated. According to the predictions, PCR products of 384 and 149 bp were expected for ctrl-MO- and E2I2-MO-injected larvae, respectively. In the case of a partial knockdown, both products should be present. (B) qPCR analysis of MO-knockdown larvae. Normal splicing in ctrl-MO-injected larvae resulted in the predicted 384 bp product, indicating the presence of wild-type mRNA. Abnormal splicing in E2I2-MO-injected larvae resulted in two products: 384 bp (corresponding to the wild-type mRNA) and ∼300 bp (an abnormal mRNA), indicating partial knockdown. The larger-than-expected size of the PCR product could have been a result of the activation of a cryptic splice site. The aberrant mRNA was present from 1–5 dpf and was accompanied by the wild-type 384 bp fragment.
Figure 2
Figure 2
Representative Pictures of 4-Day-Old chd2 Knockdown and Control Larvae chd2 E2I2-MO-injected larvae displayed pericardial edema, microcephaly, body curvature, absent swim bladder, and stunted growth (A). Ctrl-MO-injected (B) and uninjected (C) larvae developed normally. The experiment was performed at least three times with 100 embryos injected per condition.
Figure 3
Figure 3
Electrographic Activity of 4-Day-Old chd2 Knockdown and Control Larvae (A) Uninjected larva. (B) chd2 E2I2-MO-injected larva displaying ictal-like discharges. (C) Ctrl-MO-injected larva. One-minute fragments are shown. The y axis shows a 4 mV span. Ictal-like events shown in (B) (more than 3 s in duration) were observed in five out of seven fish larvae in the chd2 E2I2-MO-injected group. Seven, six, and five fish were analyzed for the chd2 E2I2 MO, ctrl MO, and uninjected larvae, respectively.
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