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Title: CHD2 variants are a risk factor for photosensitivity in epilepsy.
Austin Authors: Galizia, Elizabeth C;Myers, Candace T;Leu, Costin;de Kovel, Carolien G F;Afrikanova, Tatiana;Cordero-Maldonado, Maria Lorena;Martins, Teresa G;Jacmin, Maxime;Drury, Suzanne;Krishna Chinthapalli, V;Muhle, Hiltrud;Pendziwiat, Manuela;Sander, Thomas;Ruppert, Ann-Kathrin;Møller, Rikke S;Thiele, Holger;Krause, Roland;Schubert, Julian;Lehesjoki, Anna-Elina;Nürnberg, Peter;Lerche, Holger;Palotie, Aarno;Coppola, Antonietta;Striano, Salvatore;Gaudio, Luigi Del;Boustred, Christopher;Schneider, Amy L ;Lench, Nicholas;Jocic-Jakubi, Bosanka;Covanis, Athanasios;Capovilla, Giuseppe;Veggiotti, Pierangelo;Piccioli, Marta;Parisi, Pasquale;Cantonetti, Laura;Sadleir, Lynette G;Mullen, Saul A ;Berkovic, Samuel F ;Stephani, Ulrich;Helbig, Ingo;Crawford, Alexander D;Esguerra, Camila V;Kasteleijn-Nolst Trenité, Dorothee G A;Koeleman, Bobby P C;Mefford, Heather C;Scheffer, Ingrid E ;Sisodiya, Sanjay M
Institutional Author: EuroEPINOMICS CoGIE Consortium
Affiliation: Department of Paediatrics, University of Washington, USA
NIHR Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
North East Thames Regional Genetics Laboratories, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
NIHR Biomedical Research Centre Department of Clinical and Experimental Epilepsy, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK 2 Epilepsy Society, Bucks, UK
Department of Medical Genetics Research, University Medical Centre Utrecht, The Netherlands.
Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
Department of Neuropaediatrics, University Medical Centre Schleswig-Holstein and Christian-Albrechts-University of Kiel, Kiel, Germany.
Cologne Centre for Genomics, University of Cologne, Cologne, Germany.
Danish Epilepsy Centre, Dianalund, Denmark 10 Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
Department of Neurology and Epileptology, Hertie Institut for Clinical Brain Research, Tübingen, Germany.
Folkhälsan Institute of Genetics and Neuroscience Centre, University of Helsinki, Helsinki, Finland
Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, USA
Epilepsy Centre, Neurology Department, Federico II University of Naples, Naples, Italy
Department of Child Neurology, Paediatric Clinic, Clinical Centre Nis, Serbia
Department of Paediatric Neurology, Paediatric Clinic, Al Sabah Hospital, Kuwait
Neurology Department, The Children's Hospital Agia Sophia, Athens, Greece
Epilepsy Centre 'C. Poma Hospital', Mantova, Italy
Department of Child Neurology and Psychiatry C. Mondino National Neurological Institute, Via Mondino, 2, 27100, Pavia, Italy
Brain and Behaviour Department, University of Pavia, Pavia, Italy
Neurophysiopathology Unit, San Filippo Neri Hospital, Rome, Italy
Child Neurology, NESMOS Department, Faculty of Medicine and Psychology, Sapienza University, Rome, Italy
Neurorehabilitation Unit, Department of Neuroscience and Neurorehabilitation, IRCCS, Bambino Gesu' Children's Hospital, Rome, Italy
Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand
Florey Institute of Neurosciences and Mental Health, and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia
Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia
Epilepsy Society, Bucks, UK
Chemical Neuroscience Group, Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway
Laboratory for Molecular Biodiscovery, University of Leuven, Leuven, Belgium
Department of Medical Genetics Research, University Medical Centre Utrecht, The Netherlands
Issue Date: 17-Mar-2015
Publication information: Brain : A Journal of Neurology 2015; 138(Pt 5): 1198-207
Abstract: Photosensitivity is a heritable abnormal cortical response to flickering light, manifesting as particular electroencephalographic changes, with or without seizures. Photosensitivity is prominent in a very rare epileptic encephalopathy due to de novo CHD2 mutations, but is also seen in epileptic encephalopathies due to other gene mutations. We determined whether CHD2 variation underlies photosensitivity in common epilepsies, specific photosensitive epilepsies and individuals with photosensitivity without seizures. We studied 580 individuals with epilepsy and either photosensitive seizures or abnormal photoparoxysmal response on electroencephalography, or both, and 55 individuals with photoparoxysmal response but no seizures. We compared CHD2 sequence data to publicly available data from 34 427 individuals, not enriched for epilepsy. We investigated the role of unique variants seen only once in the entire data set. We sought CHD2 variants in 238 exomes from familial genetic generalized epilepsies, and in other public exome data sets. We identified 11 unique variants in the 580 individuals with photosensitive epilepsies and 128 unique variants in the 34 427 controls: unique CHD2 variation is over-represented in cases overall (P = 2·17 × 10(-5)). Among epilepsy syndromes, there was over-representation of unique CHD2 variants (3/36 cases) in the archetypal photosensitive epilepsy syndrome, eyelid myoclonia with absences (P = 3·50 × 10(-4)). CHD2 variation was not over-represented in photoparoxysmal response without seizures. Zebrafish larvae with chd2 knockdown were tested for photosensitivity. Chd2 knockdown markedly enhanced mild innate zebrafish larval photosensitivity. CHD2 mutation is the first identified cause of the archetypal generalized photosensitive epilepsy syndrome, eyelid myoclonia with absences. Unique CHD2 variants are also associated with photosensitivity in common epilepsies. CHD2 does not encode an ion channel, opening new avenues for research into human cortical excitability.
Gov't Doc #: 25783594
DOI: 10.1093/brain/awv052
PubMed URL: 25783594
Type: Journal Article
Subjects: eyelid myoclonia with absences
Appears in Collections:Journal articles

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