title: CHD2 variants are a risk factor for photosensitivity in epilepsy.
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.
authors.affiliation: 1 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 s.sisodiya@ucl.ac.uk scheffer@unimelb.edu.au hmefford@uw.edu b.p.c.koeleman@umcutrecht.nl.
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authors.initials: EC
authors.lastname: Galizia
authors.affiliation: 3 Department of Paediatrics, University of Washington, USA.
authors.forename: Candace T
authors.initials: CT
authors.lastname: Myers
authors.affiliation: 1 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.
authors.forename: Costin
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authors.lastname: Leu
authors.affiliation: 4 Department of Medical Genetics Research, University Medical Centre Utrecht, The Netherlands.
authors.forename: Carolien G F
authors.initials: CG
authors.lastname: de Kovel
authors.affiliation: 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Tatiana
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authors.lastname: Afrikanova
authors.affiliation: 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Maria Lorena
authors.initials: ML
authors.lastname: Cordero-Maldonado
authors.affiliation: 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Teresa G
authors.initials: TG
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authors.affiliation: 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Maxime
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authors.affiliation: 6 North East Thames Regional Genetics Laboratories, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
authors.forename: Suzanne
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authors.lastname: Drury
authors.affiliation: 1 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.
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authors.affiliation: 7 Department of Neuropaediatrics, University Medical Centre Schleswig-Holstein and Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Hiltrud
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authors.affiliation: 7 Department of Neuropaediatrics, University Medical Centre Schleswig-Holstein and Christian-Albrechts-University of Kiel, Kiel, Germany.
authors.forename: Manuela
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authors.lastname: Pendziwiat
authors.affiliation: 8 Cologne Centre for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Thomas
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authors.affiliation: 8 Cologne Centre for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Ann-Kathrin
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authors.affiliation: 9 Danish Epilepsy Centre, Dianalund, Denmark 10 Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark.
authors.forename: Rikke S
authors.initials: RS
authors.lastname: Møller
authors.affiliation: 8 Cologne Centre for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Holger
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authors.affiliation: 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Roland
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authors.affiliation: 11 Deptartment of Neurology and Epileptology, Hertie Institut for Clinical Brain Research, Tübingen, Germany.
authors.forename: Julian
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authors.lastname: Schubert
authors.affiliation: 12 Folkhälsan Institute of Genetics and Neuroscience Centre, University of Helsinki, Helsinki, Finland 13 Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland.
authors.forename: Anna-Elina
authors.initials: AE
authors.lastname: Lehesjoki
authors.affiliation: 8 Cologne Centre for Genomics, University of Cologne, Cologne, Germany.
authors.forename: Peter
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authors.affiliation: 11 Deptartment of Neurology and Epileptology, Hertie Institut for Clinical Brain Research, Tübingen, Germany.
authors.forename: Holger
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authors.lastname: Lerche
authors.affiliation: 14 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire, UK 15 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland 16 Program in Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, USA.
authors.forename: Aarno
authors.initials: A
authors.lastname: Palotie
authors.affiliation: 1 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 17 Epilepsy Centre, Neurology Department, Federico II University of Naples, Naples, Italy.
authors.forename: Antonietta
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authors.affiliation: 17 Epilepsy Centre, Neurology Department, Federico II University of Naples, Naples, Italy.
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authors.affiliation: 17 Epilepsy Centre, Neurology Department, Federico II University of Naples, Naples, Italy.
authors.forename: Luigi Del
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authors.affiliation: 6 North East Thames Regional Genetics Laboratories, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
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authors.affiliation: 28 Department of Paediatrics and Child Health, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.
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authors.initials: SF
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authors.forename: Ingo
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authors.affiliation: 5 Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg.
authors.forename: Alexander D
authors.initials: AD
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authors.affiliation: 30 Chemical Neuroscience Group, Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway 31 Laboratory for Molecular Biodiscovery, University of Leuven, Leuven, Belgium.
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authors.initials: CV
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authors.affiliation: 4 Department of Medical Genetics Research, University Medical Centre Utrecht, The Netherlands s.sisodiya@ucl.ac.uk scheffer@unimelb.edu.au hmefford@uw.edu b.p.c.koeleman@umcutrecht.nl.
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authors.initials: BP
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authors.forename: Heather C
authors.initials: HC
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authors.affiliation: 18 Department of Medicine, University of Melbourne, Austin Health, Melbourne, Australia 29 Florey Institute of Neurosciences and Mental Health, and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Australia s.sisodiya@ucl.ac.uk scheffer@unimelb.edu.au hmefford@uw.edu b.p.c.koeleman@umcutrecht.nl.
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Scheffer
authors.affiliation: 1 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 s.sisodiya@ucl.ac.uk scheffer@unimelb.edu.au hmefford@uw.edu b.p.c.koeleman@umcutrecht.nl.
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mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics*; D004569:Electroencephalography; D020195:Epilepsy, Reflex / Q000235:genetics*; D055785:Gene Knockdown Techniques / Q000379:methods; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010775:Photic Stimulation / Q000379:methods; D012307:Risk Factors; D015027:Zebrafish
chemical_list: C575189:CHD2 protein, human; D004268:DNA-Binding Proteins
keywords: eyelid myoclonia with absences; photosensitive; seizure