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

项目摘要 由于脑损伤引起的新生儿癫痫发作（急性症状性癫痫发作）与术后高风险相关。 新生儿癫痫虽然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新生儿急性症状性癫痫发作后的癫痫风险，我们知之甚少。 拟议的“新生儿癫痫登记-癫痫遗传学（NSR-GENE）”研究将测试中央 这一假说认为，儿童谁发展后新生儿癫痫更有可能有致病性变异， 癫痫基因，并在关键炎症，神经递质， 运输和体内平衡，以及神经营养基因途径，与不发育的儿童相比， 5岁之前的无端癫痫发作，这些可以添加到传统的临床风险因素， 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处的基础设施，我们 招募了>300名患有急性症状性新生儿癫痫发作的儿童（NCT 02789176，NCT 04337697）。这 一组独特的儿童及其父母将被邀请参加非侵入性基因检测。使用 新生儿临床、EEG和MRI测量可通过登记处获得，沿着基因检测结果， 我们将建立可靠的模型来预测癫痫的风险和阐明癫痫发生的机制。 我们将通过追求以下具体目标来测试我们的假设：目标1：确定是否存在 癫痫患儿癫痫基因内致病性编码SNV和基因丰富CNV的发生率增加， 急性激发的新生儿癫痫发作和新生儿后癫痫与无继发癫痫的患者相比; 目的2：确定与癫痫有先验联系的非编码SNP的发生率增加是否与癫痫相关。 与新生儿后期癫痫风险相关;目的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。 这项创新提案将维持现有的多中心队列，这些队列从雇用了 用于诊断和调查新生儿癫痫发作的最先进技术，并针对研究重点 家长和临床医生。这项精心设计的研究将提供新的，临床相关的答案， 关于癫痫的问题在这个高度脆弱的患者群体中。结果将为后续设计提供信息 干预研究和项目旨在减少癫痫发作后的风险。

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.