Copy Number Variants of Neuro-Cardiac Ion Channel Genes and the Risk of SUDEP

描述(由申请人提供)：我们的数据表明，在心脏和大脑中共表达的离子通道缺陷是癫痫猝死(SUDEP)的重要分子风险因素。我们提出了一种新的基于阵列的候选SUDEP基因分析方法，该方法来自SUDEP病例及其家族。这一建议补充了我们正在进行的支持我们的中心假说的工作：“在心脏和大脑中共同表达的离子通道基因突变是心律失常和癫痫的表型基础，并可能最终导致SUDEP。”许多年轻人的特发性心律失常与通道病有关，离子通道基因的突变是公认的致痫原因。SUDEP是不明原因癫痫的灾难性并发症。来自本实验室的文献证据和小鼠模型数据表明，心脏和脑中共表达的缺陷离子通道是SUDEP的重要分子危险因素。我们对47例癫痫患者进行了可行性研究，并使用自制的离子通道基因特异性比较杂交阵列(ICCH阵列)查询了超过250个离子通道亚基，包括所有主要的心律失常基因，并分析了几个SUDEP病例。我们鉴定了拷贝数变异(CNV)，它可能在SUDEP的病理生理学中起关键作用。基于这些积极的试点结果，我建议使用我们的ICCH平台来分析SUDEP家族的样本中的CNV，(1)所有已知与遗传性恶性心律失常相关的主要离子通道亚单位基因，(2)所有非心律失常离子通道基因，以及(3)将AIM 2中发现的突变新离子通道基因定位在神经心轴内。此外，我还通过与NIH Coriell存储库合作，为开发第一个可公开访问的高质量新鲜SUDEP样本的集中式SUDEP存储库奠定了基础。我希望找到许多变异，从而发现新的基因，更好地理解SUDEP的分子机制，并定义癫痫高危人群的基因图谱。我们的发现将在临床上用于启动SUDEP的预防策略。 公共卫生相关性：我们使用新的基于阵列的分析来确定神经-心脏离子通道基因的结构突变、拷贝数变异(CNV)，这是癫痫猝死(SUDEP)的候选分子危险因素。我们非常重要的试点数据表明，拟议的研究将导致更好地了解SUDEP生物学，定义SUDEP的风险患者，并启动预防策略。

DESCRIPTION (provided by applicant): Our data incriminate defective ion channels co-expressed in heart and brain as important molecular risk factors for sudden unexpected death in epilepsy (SUDEP). We propose a novel array-based analysis of candidate SUDEP genes in samples from SUDEP cases and their families. This proposal complements our ongoing work in support of our central hypothesis: "Mutations in ion channel genes co-expressed in heart and brain underlie the phenotype of cardiac arrhythmias and seizures and may ultimately lead to SUDEP." Many idiopathic cardiac arrhythmias in the young are linked to channelopathies and mutations of ion channel genes are recognized causes of epileptogenicity. SUDEP is a catastrophic complication of epilepsy of unknown cause. The literature-based evidence and mouse model data originating from our laboratory indicate that defective ion channels co-expressed in heart and brain are important molecular risk factors for SUDEP. We performed a feasibility study on a cohort of 47 patients with epilepsy and analyzed several SUDEP cases using our custom built ion channel gene-specific comparative hybridization array (ICCH array) interrogating over 250 ion channel subunits, including all main cardiac arrhythmia genes. We identified copy number variants (CNVs) which may play a critical role in the SUDEP pathophysiology. Based on these positive pilot results I propose using our ICCH platform to analyze samples from SUDEP families for CNVs in (1) all major ion channel subunit genes known to be associated with inherited malignant cardiac arrhythmias, (2) in all non-arrhythmia ion channel genes, and (3) to map mutant novel ion channel genes identified in aim 2 within the neuro-cardiac axis. In addition, I have laid ground work for the development of the first centralized publicly accessible SUDEP repository of high quality fresh frozen SUDEP samples by working with the NIH Coriell Repository. I expect to find many variants leading to the discovery of novel genes and a better understanding of molecular mechanisms of SUDEP and definition of a gene profile of the epilepsy population at risk. Our discoveries will be of clinical use in the initiation of preventative strategies in SUDEP. PUBLIC HEALTH RELEVANCE: We used novel array based analysis to identify structural mutations, copy number variations (CNVs), in neuro-cardiac ion channel genes, candidate molecular risk factors for sudden unexpected death in epilepsy (SUDEP). Our very important pilot data indicate that the proposed research will lead to better understanding of the SUDEP biology, definition of patients at risk for SUDEP, and initiation of preventative strategies.