CHD2 variants are a risk factor for photosensitivity in epilepsy.

Galizia EC1, Myers CT2, Leu C3, de Kovel CG4, Afrikanova T5, Cordero-Maldonado ML5, Martins TG5, Jacmin M5, Drury S6, Krishna Chinthapalli V3, Muhle H7,Pendziwiat M7, Sander T8, Ruppert AK8, Møller RS9, Thiele H8, Krause R5, Schubert J10, Lehesjoki AE11, Nürnberg P8, Lerche H10; EuroEPINOMICS CoGIE Consortium, Palotie A12, Coppola A13, Striano S14, Gaudio LD14, Boustred C6, Schneider AL15, Lench N6, Jocic-Jakubi B16, Covanis A17, Capovilla G18,Veggotti P19, Piccioli M20, Parisi P21, Cantonetti L22, Sadleir LG23, Mullen SA24, Berkovic SF15, Stephani U7, Helbig I7, Crawford AD5, Esguerra CV25,Kasteleijn-Nolst Trenité DG4, Koeleman BP26, Mefford HC27, Scheffer IE28, Sisodiya SM1.

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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.