CHD2 variants are a risk factor for photosensitivity in epilepsy.
CHD2 variants are a risk factor for photosensitivity in epilepsy.
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DOI：
10.1093/brain/awv052
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发表时间：
2015-05
期刊：
影响因子：
--
通讯作者：
Sisodiya SM
中科院分区：
文献类型：
--
作者：
Galizia EC;Myers CT;Leu C;de Kovel CG;Afrikanova T;Cordero-Maldonado ML;Martins TG;Jacmin M;Drury S;Krishna Chinthapalli V;Muhle H;Pendziwiat M;Sander T;Ruppert AK;Møller RS;Thiele H;Krause R;Schubert J;Lehesjoki AE;Nürnberg P;Lerche H;EuroEPINOMICS CoGIE Consortium;Palotie A;Coppola A;Striano S;Gaudio LD;Boustred C;Schneider AL;Lench N;Jocic-Jakubi B;Covanis A;Capovilla G;Veggiotti P;Piccioli M;Parisi P;Cantonetti L;Sadleir LG;Mullen SA;Berkovic SF;Stephani U;Helbig I;Crawford AD;Esguerra CV;Kasteleijn-Nolst Trenité DG;Koeleman BP;Mefford HC;Scheffer IE;Sisodiya SM
癫痫的光敏性很常见，具有很高的遗传性，但其遗传基础尚不清楚。Galizia等人。揭示CHD2的独特变体在光敏性癫痫中的过度表达，并表明斑马鱼中的CHD2基因敲除导致光敏。癫痫的光敏性很常见，具有很高的遗传性，但其遗传基础尚不清楚。Galizia等人。揭示CHD2的独特变体在光敏性癫痫中的过度表达，并表明斑马鱼中的CHD2基因敲除导致光敏。光敏性是一种可遗传的皮质对闪烁光的异常反应，表现为特殊的脑电变化，有或没有癫痫发作。光敏性在一种非常罕见的癫痫脑病中表现突出，这是由于CHD2的从头突变，但也可以在癫痫脑病中看到，由于其他基因突变。我们确定了CHD2变异是否在普通癫痫、特殊光敏性癫痫和无癫痫发作的光敏性个体中是光敏的基础。我们研究了580例癫痫患者和55例有光发作反应但无癫痫发作的患者。我们将CHD2序列数据与34427名未强化癫痫患者的公开数据进行了比较。我们调查了在整个数据集中只出现一次的独特变体的作用。我们在238个家族性遗传性全面性癫痫外显子中寻找CHD2变异体，并在其他公开的外显子数据集中寻找CHD2变异体。我们在580名光敏性癫痫患者中发现了11个独特的变异，在34427名对照中发现了128个独特的变异：在所有病例中，独特的CHD2变异过多(P=2.17×10−5)。在癫痫综合征中，典型的光敏性癫痫综合征、眼睑肌阵挛缺失(P=3.50×10−4)存在独特的CHD2变异(3/36例)。CHD2变异在无癫痫发作的光阵发性反应中没有过度表现。对CHD2基因敲除的斑马鱼幼体进行了光敏性测试。CHD2基因敲除显著增强了斑马鱼幼体的光敏性。CHD2突变是典型的全身性光敏性癫痫综合征，即眼睑肌阵挛缺失的第一个被确认的原因。独特的CHD2变异也与常见癫痫的光敏性有关。CHD2不编码离子通道，为研究人类大脑皮层兴奋性开辟了新的途径。
Photosensitivity in epilepsy is common and has high heritability, but its genetic basis remains uncertain. Galizia et al. reveal an overrepresentation of unique variants of CHD2 — which encodes the transcriptional regulator ‘chromodomain helicase DNA-binding protein 2’ — in photosensitive epilepsies, and show that chd2 knockdown in zebrafish causes photosensitivity. Photosensitivity in epilepsy is common and has high heritability, but its genetic basis remains uncertain. Galizia et al. reveal an overrepresentation of unique variants of CHD2 — which encodes the transcriptional regulator ‘chromodomain helicase DNA-binding protein 2’ — in photosensitive epilepsies, and show that chd2 knockdown in zebrafish causes photosensitivity. 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.
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影响因子：
2.2
作者：
de Kovel, C. G. F.;Pinto, D.;Koeleman, B. P. C.
通讯作者：
Koeleman, B. P. C.
影响因子：
30.8
作者：
Kircher, Martin;Witten, Daniela M.;Jain, Preti;O'Roak, Brian J.;Cooper, Gregory M.;Shendure, Jay
通讯作者：
Shendure, Jay
DOI：
10.1073/pnas.1309438111
发表时间：
2014-04-08
影响因子：
11.1
作者：
Cnossen, Wybrich R.;te Morsche, Rene H. M.;Drenth, Joost P. H.
通讯作者：
Drenth, Joost P. H.
影响因子：
5.6
作者：
Sadleir, Lynette G.;Vears, Danya;Scheffer, Ingrid E.
通讯作者：
Scheffer, Ingrid E.
影响因子：
4.5
作者：
Petrovski S;Wang Q;Heinzen EL;Allen AS;Goldstein DB
通讯作者：
Goldstein DB