Isolating SUDEP Risk conferred by genomic co-variation in candidate SUDEP genes

项目总结/摘要 SCN 1A（钠通道基因的原型）的致病性变异是热性惊厥表型的基础 从轻度遗传性癫痫伴热性惊厥附加综合征（GEFS+）到难治性Dravet 综合征（DS）。人类和实验研究表明，SCN 1A的致病性变异是导致SCN 1A感染的危险因素。 大约4%的DS患者发生癫痫猝死（SUDEP），比例未知 受轻度GEFS+表型影响的个体。虽然大多数SCN 1A运营商逃脱了SUDEP，但它 目前尚不清楚基于SCN 1A基因的变异何时成为过早死亡的一种责任， SCN 1A特性和SUDEP风险之间的相关性从未被评估过。实验和人体 对癫痫和SUDEP的研究表明，修饰等位基因可能通过基因内或 寡基因机制或通过基因相互作用网络。我们的中心假设是， 对SUDEP的易感性取决于（a）基于基因内SCN 1A基因的常见变异模式， 阈下效应与新发和遗传性罕见致病性变体在功能上共分离 表现为癫痫表型，和/或（B）新发和遗传性罕见致病性 其他已知的SUDEP基因的变体。在这项试点研究中，我们计划应用新的计算方法， 探讨三个问题，（i）常见和罕见SCN 1A基因变异的综合作用是否足够， 是否有必要导致致病性SCN 1A变体携带者发生SUDEP（目的1）？(ii)SUDEP风险是否已调整 通过已知的猝死基因（SUDEP基因）的共变异（aim 2）？(iii)SUDEP基因的共变异 独立于SCN 1A基因影响热性癫痫表型患者的死亡风险（目的3）？我们计划 通过评估临床特征和结果数据以及基于外显子组和拷贝数来解决问题 两个患者队列中62个已知SUDEP基因的变异体（a）超过300个致病性变异体携带者， 将SCN 1A基因提交给贝勒遗传诊断实验室（BG）进行全外显子组临床测序 (aims 1和2）和B）在172例先证者和68例FEBrile癫痫持续状态研究的家族对照中 （FEBSTAT）队列。该试点项目的目标是开发急需的生物信息学工具， SUDEP风险分层。结果将对SUDEP患者的风险分层产生直接影响， 癫痫由于SCN 1A基因致病变异，他们将告知未来的生物信息学和统计设计 当分析临床上非常常见的热性惊厥表型患者的SUDEP风险时， 在现有SUDEP病例集合中评价因果关系时。

PROJECT SUMMARY/ABSTRACT Pathogenic variations in SCN1A, the prototypical sodium channel gene, underlie a febrile seizure phenotype ranging from mild genetic epilepsy with febrile seizures plus syndrome (GEFS+) to treatment resistant Dravet Syndrome (DS). Human and experimental research show that pathogenic variation in SCN1A is a risk factor for sudden unexpected death in epilepsy (SUDEP) in about 4% of individuals affected by DS and in unknown fraction of individuals affected by the milder GEFS+ phenotype. While the majority of SCN1A carriers escape SUDEP, it remains unclear when the SCN1A gene based variation becomes a liability for premature mortality and a correlation among SCN1A properties and SUDEP risk has never been evaluated. Experimental and human research in epilepsy and SUDEP suggests that modifier alleles may exert their effects through intragenic or oligogenic mechanism or through gene interaction networks. It is our central hypothesis that SCN1A gene based liability to SUDEP rests either in (a) an intragenic SCN1A gene based patterns of common variants with subthreshold effect co-segregating with de novo and inherited rare pathogenic variants functionally manifest in the epileptic phenotype, and/or in (b) co-occurrence of de novo and inherited rare pathogenic variants in other known SUDEP genes. In this pilot study we plan to apply novel computational methods to probe three questions, (i) is the combined effects of common and rare SCN1A gene variants sufficient and necessary to result in SUDEP in carriers of pathogenic SCN1A variants (aim 1)? (ii) is SUDEP risk modulated by co-variation in known sudden death genes (SUDEP genes) (aim2)? (iii) does co-variation in SUDEP genes affect mortality risk in patients with febrile seizure phenotype independent of SCN1A gene (aim 3)? We plan to address questions by evaluating clinical profiles and outcome data as well as exome based and copy number variants in 62 known SUDEP genes in two patient cohorts (a) in over 300 carriers of pathogenic variants in the SCN1A gene referred for whole exome clinical sequencing to the Baylor Genetic Diagnostic Laboratory (BG) (aims 1 and 2) and b) in 172 probands and 68 familial controls of the FEBrile STATus epilepticus study (FEBSTAT) cohort. The goal of this pilot project is to develop critically needed bioinformatic tools for genomic SUDEP risk stratification. The results will have an immediate impact on SUDEP risk stratification in patients with epilepsy due to SCN1A gene pathogenic variation, and they will inform future bioinformatics and statistical design when analyzing SUDEP risk in patients with the clinically very common febrile seizure phenotype as well as when evaluating causality in existing collections of SUDEP cases.