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

NSR-GENE（新生儿癫痫登记，新生儿后癫痫遗传学）

• 批准号: 10580043
• 负责人: Hannah Cranley Glass
• 金额: $ 66.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580043
• 关键词: Accounting; Acute; Address; Adult; Age; Ambulatory Care Facilities; Benchmarking; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Caring; Child; Clinical; Clinical Data; Code; Collaborations; Copy Number Polymorphism; Coronary Arteriosclerosis; Counseling; DNA; Data; Diagnosis; Electroencephalography; Enrollment; Epilepsy; Epileptogenesis; Family; Foundations; Funding; Genes; Genetic; Genetic Predisposition to Disease; Genetic Risk; Glass; Goals; Health; Hemorrhage; Homeostasis; Incidence; Inflammation; Inflammatory; Infrastructure; Inherited; Intervention Studies; Intervention Trial; Investigation; Knowledge; Life; Link; Magnetic Resonance Imaging; Measures; Microarray Analysis; Mission; Modeling; National Institute of Neurological Disorders and Stroke; Neonatal; Nervous System; Neurology; Neuronal Plasticity; Neurosciences Research; Observational Study; Parents; Pathogenicity; Pathway interactions; Phenotype; Play; Post-Traumatic Epilepsy; Process; Provider; Public Health; Registries; Research; Research Design; Research Personnel; Research Priority; Risk; Risk Factors; Risk Reduction; Role; Sampling; Seizures; Single Nucleotide Polymorphism; Site; Stroke; Study models; Targeted Research; Technology; Test Result; Testing; Training; Traumatic Brain Injury; United States National Institutes of Health; Untranslated RNA; Variant; acquired epilepsy; classification algorithm; clinical care; clinical risk; clinically relevant; cohort; design; disability; excitotoxicity; exome sequencing; follow-up; genetic registry; genetic risk factor; genetic testing; high risk; high risk population; improved; innovation; intervention program; method development; neonatal seizure; neonate; nervous system disorder; neurotransmitter transport; novel; novel strategies; offspring; patient population; predictive modeling; prevent; preventable epilepsy; recruit; risk prediction; therapy design

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.

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）与高度的高风险有关 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， 遗传因素如何改变急性症状新生儿癫痫发作后癫痫的风险知之甚少。 拟议的“新生儿癫痫发作注册表 - 癫痫的遗传学（NSR-GENE）”将测试中心 假设患有肿瘤后癫痫的儿童更有可能在 癫痫基因和关键炎症性神经递质中的单核苷酸多态性的富集 与不发展的儿童相比，运输和稳态以及神经营养基因途径 五岁之前无端癫痫发作，可以将其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注册中心的基础设施，我们对此我们 招募> 300名急性症状新生儿癫痫发作的儿童（NCT02789176，NCT04337697）。这 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，脑电图和MRI指标以及通过遗传测试结果提供的 我们将建立强大的模型，以预测癫痫病的风险和阐明癫痫发生的机制。 我们将通过追求以下特定目的来检验我们的假设：目标1：确定是否存在 患有病原体编码SNV和富基因CNV的发病率增加了患有儿童的癫痫基因 与没有随后的癫痫病相比，急性挑衅的新生儿癫痫发作和神经后癫痫。 AIM 2：确定与癫痫之前先验连接的非编码SNP的事件增加是否为 与神经后癫痫后的风险有关； AIM 3制定预测规则以根据 神经后癫痫的风险。 该创新的提案将维护美国中心的现有多中心队列 用于诊断和调查新生儿癫痫发作的最先进技术，并针对研究优先事项 父母和临床医生。这项精心设计的研究将为关键提供新颖的临床相关答案 在这个高度脆弱的患者人群中有关癫痫的问题。结果将告知随后的设计 干预研究和计划旨在减少早期癫痫发作后癫痫的风险。