Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses.
Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses.
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DOI：
10.1136/jmedgenet-2018-105319
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发表时间：
2018-09
影响因子：
4
通讯作者：
Pal DK
中科院分区：
文献类型：
--
作者：
Addis L;Sproviero W;Thomas SV;Caraballo RH;Newhouse SJ;Gomez K;Hughes E;Kinali M;McCormick D;Hannan S;Cossu S;Taylor J;Akman CI;Wolf SM;Mandelbaum DE;Gupta R;van der Spek RA;Pruna D;Pal DK
罗兰性癫痫是最常见的遗传性儿童癫痫，包括局灶性夜间癫痫发作和言语、语言、识字和注意力方面频繁的神经发育障碍。大多数病例被认为是复杂的遗传病因，GRIN2A的单基因突变占病例的0.5%。为了确定RE患者中罕见的、有因果关系的CNV，我们使用高密度SNP阵列分析了来自英国、美国、撒丁岛、阿根廷和印度喀拉拉邦的186例RE患者中罕见CNV的存在。我们确定了84例具有一种或多种罕见CNVs的患者，其中14例（7.5%）具有复发性危险因素CNVs， 15例（8.0%）具有可能的致病性CNVs。9名患者携带复发性热点CNVs，包括在16p13.11和1p36，最引人注目的发现是4名个体（3名来自撒丁岛）在Xp22.31位点携带重复，1名携带缺失。5例RE患者携带一种罕见的CNV，这种CNV破坏了与其他癫痫相关的基因（KCTD7、ARHGEF15、CACNA2D1、GRIN2A和ARHGEF4）， 17例携带的CNV破坏了与其他神经系统疾病相关的基因或参与神经元信号/发育的基因。对脑内高表达基因的网络分析发现，在胆碱能突触、鸟嘌呤交换因子激活和哺乳动物雷帕霉素靶蛋白的通路中显著富集。我们的研究结果提供了一个种族多样化的RE患者队列的CNV概况，揭示了新的研究重点领域，并强调了研究非西欧人群在少源性疾病中的重要性，以揭示风险变化的全图。
Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases. To identify rare, causal CNV in patients with RE. We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India. We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin. Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.
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影响因子：
30.8
作者：
Carvill, Gemma L.;Regan, Brigid M.;Yendle, Simone C.;O'Roak, Brian J.;Lozovaya, Natalia;Bruneau, Nadine;Burnashev, Nail;Khan, Adiba;Cook, Joseph;Geraghty, Eileen;Sadleir, Lynette G.;Turner, Samantha J.;Tsai, Meng-Han;Webster, Richard;Ouvrier, Robert;Damiano, John A.;Berkovic, Samuel F.;Shendure, Jay;Hildebrand, Michael S.;Szepetowski, Pierre;Scheffer, Ingrid E.;Mefford, Heather C.
通讯作者：
Mefford, Heather C.
影响因子：
30.8
作者：
Helbig I;Mefford HC;Sharp AJ;Guipponi M;Fichera M;Franke A;Muhle H;de Kovel C;Baker C;von Spiczak S;Kron KL;Steinich I;Kleefuss-Lie AA;Leu C;Gaus V;Schmitz B;Klein KM;Reif PS;Rosenow F;Weber Y;Lerche H;Zimprich F;Urak L;Fuchs K;Feucht M;Genton P;Thomas P;Visscher F;de Haan GJ;Møller RS;Hjalgrim H;Luciano D;Wittig M;Nothnagel M;Elger CE;Nürnberg P;Romano C;Malafosse A;Koeleman BP;Lindhout D;Stephani U;Schreiber S;Eichler EE;Sander T
通讯作者：
Sander T
影响因子：
9.9
作者：
Bouma, PAD;Bovenkerk, AC;Brouwer, OF
通讯作者：
Brouwer, OF
DOI：
10.1212/nxg.0000000000000056
发表时间：
2016-04
期刊：
Neurology. Genetics
影响因子：
--
作者：
Addis L;Rosch RE;Valentin A;Makoff A;Robinson R;Everett KV;Nashef L;Pal DK
通讯作者：
Pal DK
影响因子：
3.7
作者：
Lal D;Reinthaler EM;Altmüller J;Toliat MR;Thiele H;Nürnberg P;Lerche H;Hahn A;Møller RS;Muhle H;Sander T;Zimprich F;Neubauer BA
通讯作者：
Neubauer BA