CHD2 variants are a risk factor for photosensitivity in epilepsy

被引：94

作者：

Galizia, Elizabeth C. ^{[1
,2
]}

Myers, Candace T. ^{[3
]}

Leu, Costin ^{[1
,2
]}

de Kovel, Carolien G. F. ^{[4
]}

Afrikanova, Tatiana ^{[5
]}

Cordero-Maldonado, Maria Lorena ^{[5
]}

Martins, Teresa G. ^{[5
]}

Jacmin, Maxime ^{[5
]}

Drury, Suzanne ^{[6
]}

Chinthapalli, V. Krishna ^{[1
,2
]}

Muhle, Hiltrud ^{[7
,8
]}

Pendziwiat, Manuela ^{[7
,8
]}

Sander, Thomas ^{[9
]}

Ruppert, Ann-Kathrin ^{[9
]}

Moller, Rikke S. ^{[10
,11
]}

Thiele, Holger ^{[9
]}

Krause, Roland ^{[5
]}

Schubert, Julian ^{[12
]}

Lehesjoki, Anna-Elina ^{[13
,14
,15
]}

Nuernberg, Peter ^{[9
]}

Lerche, Holger ^{[12
]}

Palotie, Aarno ^{[16
,17
,18
,19
]}

Coppola, Antonietta ^{[1
,2
,20
]}

Striano, Salvatore ^{[20
]}

Del Gaudio, Luigi ^{[20
]}

Boustred, Christopher ^{[6
]}

Schneider, Amy L. ^{[21
]}

Lench, Nicholas ^{[6
]}

Jocic-Jakubi, Bosanka ^{[22
,23
]}

Covanis, Athanasios ^{[24
]}

Capovilla, Giuseppe ^{[25
]}

Veggiotti, Pierangelo ^{[26
,27
]}

Piccioli, Marta ^{[28
]}

Parisi, Pasquale ^{[29
]}

Cantonetti, Laura ^{[30
]}

Sadleir, Lynette G. ^{[31
]}

Mullen, Saul A. ^{[32
,33
]}

Berkovic, Samuel F. ^{[21
]}

Stephani, Ulrich ^{[7
,8
]}

Helbig, Ingo ^{[7
,8
]}

Crawford, Alexander D. ^{[5
]}

Esguerra, Camila V. ^{[34
,35
]}

Trenite, Dorothee G. A. Kasteleijn-Nolst ^{[4
]}

Koeleman, Bobby P. C. ^{[4
]}

Mefford, Heather C. ^{[3
]}

Scheffer, Ingrid E. ^{[21
,32
,33
]}

Sisodiya, Sanjay M. ^{[1
,2
]}

机构：

[1] UCL, Dept Clin & Expt Epilepsy, Natl Hosp Neurol & Neurosurg, NIHR Biomed Res Ctr,Inst Neurol, London WC1N 3BG, England

[2] Epilepsy Soc, Gerrards Cross, Bucks, England

[3] Univ Washington, Dept Paediat, Seattle, WA 98195 USA

[4] Univ Med Ctr Utrecht, Dept Med Genet Res, NL-3584 CG Utrecht, Netherlands

[5] Univ Luxembourg, Luxembourg Ctr Syst Biomed, Esch Sur Alzette, Luxembourg

[6] Great Ormond St Hosp Children NHS Fdn Trust, North East Thames Reg Genet Labs, London, England

[7] Univ Med Ctr Schleswig Holstein, Dept Neuropaediat, Kiel, Germany

[8] Univ Kiel, Kiel, Germany

[9] Univ Cologne, Cologne Ctr Genom, D-50931 Cologne, Germany

[10] Danish Epilepsy Ctr, Dianalund, Denmark

[11] Univ So Denmark, Inst Reg Hlth Serv, Odense, Denmark

[12] Hertie Inst Clin Brain Res, Dept Neurol & Epileptol, Tubingen, Germany

[13] Univ Helsinki, Folkhalsan Inst Genet, Helsinki, Finland

[14] Univ Helsinki, Ctr Neurosci, Helsinki, Finland

[15] Univ Helsinki, Res Programs Unit, Mol Neurol, Helsinki, Finland

[16] Wellcome Trust Sanger Inst, Hinxton, Cambs, England

[17] Univ Helsinki, Inst Mol Med Finland, Helsinki, Finland

[18] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[19] Broad Inst MIT & Harvard, Genet Anal Platform, Cambridge, MA USA

[20] Univ Naples Federico II, Epilepsy Ctr, Dept Neurol, Naples, Italy

[21] Univ Melbourne, Dept Med, Austin Hlth, Melbourne, Vic, Australia

[22] Clin Ctr Nis, Paediat Clin, Dept Child Neurol, Nish, Serbia

[23] Al Sabah Hosp, Paediat Clin, Dept Paediat Neurol, Kuwait, Kuwait

[24] Childrens Hosp Agia Sophia, Dept Neurol, Athens, Greece

[25] C Poma Hosp, Epilepsy Ctr, Mantua, Italy

[26] C Mondino Natl Neurol Inst, Dept Child Neurol & Psychiat, I-27100 Pavia, Italy

[27] Univ Pavia, Brain & Behav Dept, I-27100 Pavia, Italy

[28] San Filippo Neri Hosp, Neurophysiopathol Unit, Rome, Italy

[29] Univ Roma La Sapienza, Fac Med & Psychol, NESMOS Dept, Child Neurol, I-00185 Rome, Italy

[30] Bambino Gesu Pediat Hosp, IRCCS, Dept Neurosci & Neurorehabil, Neurorehabil Unit, Rome, Italy

[31] Univ Otago, Dept Paediat & Child Hlth, Sch Med & Hlth Sci, Wellington, New Zealand

[32] Univ Melbourne, Florey Inst Neurosci & Mental Hlth, Royal Childrens Hosp, Melbourne, Vic, Australia

[33] Univ Melbourne, Royal Childrens Hosp, Dept Paediat, Melbourne, Vic, Australia

[34] Univ Oslo, Biotechnol Ctr Oslo, Chem Neurosci Grp, Oslo, Norway

[35] Univ Leuven, Lab Mol Biodiscovery, Leuven, Belgium

来源：

BRAIN | 2015年 / 138卷

基金：

英国医学研究理事会; 英国惠康基金; 美国国家卫生研究院;

关键词：

photosensitive; seizure; eyelid myoclonia with absences; IDIOPATHIC GENERALIZED EPILEPSY; JUVENILE MYOCLONIC EPILEPSY; LENNOX-GASTAUT SYNDROME; COPY NUMBER VARIANTS; DE-NOVO MUTATIONS; INTELLECTUAL DISABILITY; GENETIC DISSECTION; FAMILY; ENCEPHALOPATHIES; MICRODELETION;

D O I：

10.1093/brain/awv052

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

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.

引用

页码：1198 / 1207

页数：10

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