Friedman Daniel, Kannan Kasthuri, Faustin Arline, Shroff Seema, Thomas Cheddhi, Heguy Adriana, Serrano Jonathan, Snuderl Matija, Devinsky Orrin
1Comprehensive Epilepsy Center, NYU Langone Medical Center, New York, NY USA.
2Department of Neurology, NYU Langone Medical Center, New York, NY USA.
NPJ Genom Med. 2018 Mar 27;3:9. doi: 10.1038/s41525-018-0048-5. eCollection 2018.
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in µ-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including , , , , , , , and . In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including , , , , , and , which were not present in living epilepsy controls. Our data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk.
癫痫猝死（SUDEP）是年轻成年人癫痫相关死亡的主要原因。确切机制尚不清楚，但死亡通常发生在全面强直阵挛发作之后。提出的机制包括与癫痫发作相关的呼吸、心脏、自主神经和觉醒功能障碍。SUDEP风险的潜在遗传驱动因素在很大程度上尚不清楚。为了识别潜在的SUDEP风险基因，我们比较了来自8例死于SUDEP的癫痫患者的福尔马林固定石蜡包埋手术脑标本的全外显子序列（WES）与7例在手术年龄、性别、手术年份和切除脑叶方面相匹配的存活对照。我们比较了两组中鉴定出的变异体，从公开数据中过滤已知的多态性，并扫描癫痫和候选SUDEP基因。在SUDEP队列中，我们在参与μ-阿片信号传导、γ-氨基丁酸（GABA）和谷氨酸介导的突触信号传导的基因中鉴定出相互排斥的变异体，包括 、 、 、 、 、 、 、 和 。在SUDEP患者中，我们还在与心律失常相关的基因中鉴定出变异体，包括 、 、 、 、 和 ，这些变异体在存活的癫痫对照中不存在。我们的数据表明，对为控制癫痫发作而切除的脑组织进行基因组分析可以识别SUDEP风险的潜在遗传生物标志物。
