TY - JOUR
T1 - CHD2 variants are a risk factor for photosensitivity in epilepsy
AU - Galizia, Elizabeth C.
AU - Myers, Candace T.
AU - Leu, Costin
AU - de Kovel, Carolien G F
AU - Afrikanova, Tatiana
AU - Cordero-Maldonado, Maria Lorena
AU - Martins, Teresa G.
AU - Jacmin, Maxime
AU - Drury, Suzanne
AU - Chinthapalli, V. Krishna
AU - Muhle, Hiltrud
AU - Pendziwiat, Manuela
AU - Sander, Thomas
AU - Ruppert, Ann-Kathrin
AU - Moller, Rikke S.
AU - Thiele, Holger
AU - Krause, Roland
AU - Schubert, Julian
AU - Lehesjoki, Anna-Elina
AU - Nuernberg, Peter
AU - Lerche, Holger
AU - Palotie, Aarno
AU - Coppola, Antonietta
AU - Striano, Salvatore
AU - Del Gaudio, Luigi
AU - Boustred, Christopher
AU - Schneider, Amy L.
AU - Lench, Nicholas
AU - Jocic-Jakubi, Bosanka
AU - Covanis, Athanasios
AU - Capovilla, Giuseppe
AU - Veggiotti, Pierangelo
AU - Piccioli, Marta
AU - Parisi, Pasquale
AU - Cantonetti, Laura
AU - Sadleir, Lynette G.
AU - Mullen, Saul A.
AU - Berkovic, Samuel F.
AU - Stephani, Ulrich
AU - Helbig, Ingo
AU - Crawford, Alexander D.
AU - Esguerra, Camila V.
AU - Kasteleijn-Nolst Trenite, Dorothee G. A.
AU - Koeleman, Bobby P. C.
AU - Mefford, Heather C.
AU - Scheffer, Ingrid E.
AU - Sisodiya, Sanjay M.
PY - 2015/5/1
Y1 - 2015/5/1
N2 - 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 x 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 x 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.
AB - 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 x 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 x 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.
KW - photosensitive
KW - seizure
KW - eyelid myoclonia with absences
KW - IDIOPATHIC GENERALIZED EPILEPSY
KW - JUVENILE MYOCLONIC EPILEPSY
KW - LENNOX-GASTAUT SYNDROME
KW - COPY NUMBER VARIANTS
KW - DE-NOVO MUTATIONS
KW - INTELLECTUAL DISABILITY
KW - GENETIC DISSECTION
KW - FAMILY
KW - ENCEPHALOPATHIES
KW - MICRODELETION
U2 - 10.1093/brain/awv052
DO - 10.1093/brain/awv052
M3 - Article
C2 - 25783594
SN - 0006-8950
VL - 138
SP - 1198
EP - 1207
JO - Brain
JF - Brain
ER -