NSR-GENE (Neonatal Seizure Registry, GEnetics of post-Neonatal Epilepsy)

项目总结 由脑损伤引起的新生儿癫痫(急性症状性癫痫)与高风险的后遗症有关 新生儿癫痫。尽管临床风险因素可以帮助预测哪些儿童患癫痫的风险最高， 关于遗传因素如何改变急性症状性新生儿癫痫发作后的癫痫风险，人们知之甚少。 拟议的“新生儿癫痫发作登记-癫痫的遗传学(NSR-基因)”研究将测试中央 假设患有新生儿后癫痫的儿童更有可能有致病变异 癫痫基因和关键炎症、神经递质内单核苷酸多态的丰富 与不发育的儿童的运输和内稳态以及神经营养基因通路的比较 在五岁之前无缘无故发作，这些可以被添加到传统的临床风险因素中 预测新生儿癫痫发作后的癫痫。 这项观察性研究利用了九个中心新生儿癫痫登记的基础设施，我们 招募了300名有急性症状性新生儿癫痫发作的儿童(NCT02789176，NCT04337697)。这 独一无二的儿童及其父母将被邀请参加非侵入性基因检测。vbl.使用 通过注册中心提供的新生儿临床、脑电和核磁共振测量，以及基因测试结果， 我们将建立稳健的模型来预测癫痫的风险，并阐明癫痫发生的机制。 我们将通过追求以下具体目标来检验我们的假设：目标1：确定是否存在 致病基因编码SNV和致病基因丰富的CNV在儿童癫痫基因中的发生率增加 与无继发性癫痫的新生儿相比，急性发作的新生儿癫痫和新生儿后癫痫； 目的2：确定与癫痫有先天关联的非编码SNPs的发病率是否增加 与新生儿后癫痫的风险相关；目标3制定预测规则，根据以下因素对新生儿进行分层 新生儿后癫痫的风险。 这一创新计划将保持现有的多中心队列，这些队列来自美国中心，这些中心 用于诊断和调查新生儿癫痫的最新技术，并针对研究优先事项 父母和临床医生的关系。这项精心设计的研究将提供新的、与临床相关的答案 在这一高度脆弱的患者群体中存在有关癫痫的问题。结果将为后续设计提供信息 旨在降低早期癫痫发作后癫痫风险的干预研究和计划。

PROJECT SUMMARY Neonatal seizures due to brain injury (acute symptomatic seizures) are associated with high risk of post- neonatal epilepsy. Although clinical risk factors can help predict which children are at highest risk for epilepsy, little is known about how genetic factors modify the risk for epilepsy after acute symptomatic neonatal seizures. The proposed “Neonatal Seizure Registry – GENetics of Epilepsy (NSR-GENE)” study will test the central hypothesis that children who develop post-neonatal epilepsy are more likely to have pathogenic variants in epilepsy genes, and enrichment in single nucleotide polymorphisms within key inflammatory, neurotransmitter transport and homeostasis, and neurotrophic gene pathways as compared with children who do not develop unprovoked seizures before age five years, and that these can be added to traditional clinical risk factors to predict epilepsy after neonatal seizures. This observational study leverages the infrastructure of the nine center Neonatal Seizure Registry, to which we have recruited >300 children with acute symptomatic neonatal seizures (NCT02789176, NCT04337697). This unique cohort of children and their parents will be invited to participate in non-invasive genetic testing. Using neonatal clinical, EEG, and MRI measures available through the Registry, along with genetic testing results, we will build robust models to predict risk of epilepsy and elucidate mechanisms of epileptogenesis. We will test our hypotheses by pursuing the following specific aims: Aim 1: Determine whether there is an increased incidence of pathogenic coding SNVs and gene rich CNVs within epilepsy genes among children with acute provoked neonatal seizures and post-neonatal epilepsy compared to those without subsequent epilepsy; Aim 2: Determine whether an increased incidence of non-coding SNPs with a priori linkage to epilepsy is associated with the risk of post-neonatal epilepsy; Aim 3 Develop prediction rules to stratify neonates based on risk for post-neonatal epilepsy. This innovative proposal will maintain an existing, multicenter cohort enrolled from US centers that employ state-of-the-art technology for diagnosis and investigation of neonatal seizures, and targets research priorities of parents and clinicians. This carefully designed study will provide novel, clinically relevant answers to key questions about epilepsy in this highly vulnerable patient population. Results will inform the subsequent design of intervention studies and programs designed to reduce the risk of epilepsy after early life seizures.