Epileptic encephalopathies are a phenotypically and genetically heterogeneous group of severe epilepsies accompanied by intellectual disability and other neurodevelopmental features. 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.

] Center for Genomics and Transcriptomics Tübingen Germany [2] Division of Human Genetics University Children's Hospital Inselspital Bern Switzerland [3] Swiss Epilepsy Center Zürich Switzerland

] Danish Epilepsy Center Dianalund Denmark [2] Institute for Regional Health Services University of Southern Denmark Odense Denmark

] Department of Clinical and Experimental Epilepsy University College London Institute of Neurology Queen Square London UK [2] Epilepsy Society Chalfont St Peter Bucks UK

] Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany [2] German Research Center for Neurodegenerative Diseases Tübingen Germany

] Department of Neurodegenerative Diseases Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany [2] German Research Center for Neurodegenerative Diseases Tübingen Germany [3] Dr J T MacDonald Department for Human Genetics Hussman Institute for Human Genomics University of Miami Miami Florida USA

] Department of Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany [2] Department of Neurology University of Tübingen Tübingen Germany

] Department of Neuropediatrics Christian Albrechts University of Kiel Kiel Germany [2] Division of Neurology Children's Hospital of Philadelphia Philadelphia Pennsylvania USA

] Department of Women and Child Health Hospital for Children and Adolescents University of Leipzig Leipzig Germany [2] Division of Human Genetics University Children's Hospital Inselspital Bern Switzerland [3] Institute of Human Genetics University of Leipzig Leipzig Germany

] Folkhälsan Institute of Genetics Helsinki Finland [2] Neuroscience Center University of Helsinki Helsinki Finland [3] Research Programs Unit Molecular Neurology University of Helsinki Helsinki Finland

] Institute for Molecular Medicine Finland University of Helsinki Helsinki Finland [2] Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton UK [3] Psychiatric and Neurodevelopmental Genetics Unit Department of Psychiatry Massachusetts General Hospital Boston Massachusetts USA

] Neurogenetics Group Department of Molecular Genetics VIB Antwerp Belgium [2] Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium

] Neurogenetics Group Department of Molecular Genetics VIB Antwerp Belgium [2] Laboratory of Neurogenetics Institute Born Bunge University of Antwerp Antwerp Belgium [3] Department of Neurology Antwerp University Hospital University of Antwerp Antwerp Belgium

] Neurology Laboratory and Epilepsy Unit Department of Neurology Instituto de Investigatión Sanitaria Fundación Jiménez Díaz Universidad Autónoma de Madrid Madrid Spain [2] Centro de Investigación Biomédica en Red de Enfermedades Raras Madrid Spain

] Pediatric Neurology Clinic 2 Department of Neurology Pediatric Neurology Psychiatry and Neurosurgery 'Carol Davila' University of Medicine Bucharest Romania [2] Pediatric Neurology Clinic 'Professor Doctor Alexandru Obregia' Clinical Hospital Bucharest Romania

Center for Genomics and Transcriptomics Tübingen Germany

Child and Adolescent Department Pediatric Neurology University Hospitals Geneva Switzerland

Cologne Center for Genomics University of Cologne Cologne Germany

Department of Child Neurology 2nd Faculty of Medicine Charles University Motol Hospital Prague Czech Republic

Department of Medical Genetics Institute of Mother and Child Warsaw Poland

Department of Molecular Biology and Genetics Bo[gcaron]aziçi University Istanbul Turkey

Department of Neurology and Epileptology Hertie Institute for Clinical Brain Research University of Tübingen Tübingen Germany

Department of Neuropediatrics University of Tübingen Tübingen Germany

Department of Pediatric Neurology Children's Hospital University of Helsinki and Helsinki University Hospital Helsinki Finland

Department of Women and Child Health Hospital for Children and Adolescents University of Leipzig Leipzig Germany

Division of Child Neurology Gulhane Military Medical School Ankara Turkey

Division of Human Genetics University Children's Hospital Inselspital Bern Switzerland

Division of Neuropediatrics University Children's Hospital Inselspital Bern Switzerland

Division of Pediatric Endocrinology University Children's Hospital Inselspital Bern Switzerland

Dr J T MacDonald Department for Human Genetics Hussman Institute for Human Genomics University of Miami Miami Florida USA

Luxembourg Centre for Systems Biomedicine University of Luxembourg Esch sur Alzette Luxembourg

Swiss Epilepsy Center Zürich Switzerland

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