Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features1,2,3,4,5,6. Using next-generation sequencing, we identified four different de novo mutations in KCNA2, encoding the potassium channel KV1.2, in six isolated patients with epileptic encephalopathy (one mutation recurred three times independently). Four individuals presented with febrile and multiple afebrile, often focal seizure types, multifocal epileptiform discharges strongly activated by sleep, mild to moderate intellectual disability, delayed speech development and sometimes ataxia. Functional studies of the two mutations associated with this phenotype showed almost complete loss of function with a dominant-negative effect. Two further individuals presented with a different and more severe epileptic encephalopathy phenotype. They carried mutations inducing a drastic gain-of-function effect leading to permanently open channels. These results establish KCNA2 as a new gene involved in human neurodevelopmental disorders through two different mechanisms, predicting either hyperexcitability or electrical silencing of KV1.2-expressing neurons.
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NCBI Reference Sequence
We thank all patients and family members for their participation in this study, S. Grissmer (Ulm University) for providing the human cDNA clone of KCNA2, and F. Lang and his colleagues (University of Tübingen) for providing Xenopus oocytes. J.R.L. (32EP30_136042/1), J.M.S. (EUI-EURC2011-4325), H. Lerche (DFG Le1030/11-1), P.D.J. (G.A.136.11.N, FWO/ESF-ECRP), H.S.C. (TUBITAK 110S518) and I.H. (DFG HE 5415 3-1) received financial support within the EuroEPINOMICS RES and EuroEPINOMICS CoGIE networks (http://www.euroepinomics.org/), a Eurocores project of the European Science Foundation. R.S. received funding from the European Union (E-Rare JTC grants 01GM1408B and PIOF-GA-2012-326681). J.M.S. received further support from the Ministerio de Economía y Competitividad (SAF2010-18586). H. Lerche, S.B. and S. Maljevic received further support from the Federal Ministry for Education and Research (BMBF, program on rare diseases, IonNeurONet: 01GM1105A). S.Z. received support from the US National Institutes of Health (R01NS072248). S.M.S. received support from the Wellcome Trust (084730), National Institute for Health Research (NIHR) University College London Hospital Biomedical Research Centre and Epilepsy Society, UK. M. Synofzik received support from the Interdisciplinary Center for Clinical Research (IZKF) Tübingen (2191-0-0). A.S. received funding for a postdoctoral fellowship from the Fonds Wetenschappelijk Onderzoek. T. Djémié is a PhD fellow of the Institute of Science and Technology (IWT).