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，心脏和大脑中共同表达的缺陷离子通道是癫痫猝死（SUDEP）的重要分子危险因素。我们提出了一种新的基于阵列的分析SUDEP病例及其家族样本中的候选SUDEP基因。该建议补充了我们正在进行的工作，以支持我们的中心假设：“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发作表型的基础，并可能最终导致SUDEP。”许多年轻人的特发性心律失常与离子通道病有关，离子通道基因的突变是公认的致痫性原因。猝死症是一种病因不明的癫痫的灾难性并发症。基于文献的证据和来自我们实验室的小鼠模型数据表明，心脏和大脑共同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，并使用我们定制的离子通道基因特异性比较杂交阵列（ICCH阵列）对包括所有主要心律失常基因在内的250多个离子通道亚基进行了分析。我们发现拷贝数变异（CNVs）可能在SUDEP病理生理中起关键作用。基于这些积极的试点结果，我建议使用我们的ICCH平台分析来自SUDEP家族的样本，以确定(1)已知与遗传性恶性心律失常相关的所有主要离子通道亚基基因的CNVs，(2)所有非心律失常离子通道基因的CNVs，以及(3)在神经-心脏轴内绘制目标2中鉴定的突变的新型离子通道基因。此外，通过与NIH科里埃尔库合作，我为开发第一个集中的公开访问的高质量新鲜冷冻SUDEP样本库奠定了基础。我期望找到许多变异，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谱。我们的发现将在临床上用于启动预防策略的猝死。

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.