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）

基本信息

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
项目类别：
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

项目摘要

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.

项目概要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。尽管临床危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癫痫的风险知之甚少。拟议的“新生儿癫痫登记——癫痫遗传学（NSR-GENE）”研究将测试中央假设患有新生儿后癫痫的儿童更有可能携带致病性变异癫痫基因，以及关键炎症、神经递质内单核苷酸多态性的富集与未发育的儿童相比，运输和体内平衡以及神经营养基因途径五岁前无缘无故的癫痫发作，这些可以添加到传统的临床危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处的基础设施，我们招募了超过 300 名患有急性症状新生儿癫痫的儿童（NCT02789176、NCT04337697）。将邀请独特的儿童群体及其父母参与非侵入性基因检测。可通过登记处获得新生儿临床、脑电图和 MRI 测量，以及基因检测结果，我们将建立强大的模型来预测癫痫风险并阐明癫痫发生机制。我们将通过追求以下具体目标来检验我们的假设：目标 1：确定是否存在患有癫痫病的儿童中癫痫基因中致病性编码 SNV 和富含基因的 CNV 的发生率增加与随后没有癫痫发作的患者相比，急性诱发的新生儿癫痫发作和新生儿后癫痫；目标 2：确定与癫痫先验相关的非编码 SNP 的发病率增加是否与癫痫相关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。这项创新提案将维持从美国中心招募的现有多中心队列，这些中心雇用用于诊断和调查新生儿癫痫的最先进技术，并针对研究重点这项精心设计的研究将为关键问题提供新颖的、临床相关的答案。关于这一高度脆弱的患者群体的癫痫问题的结果将为后续设计提供信息。旨在降低生命早期癫痫发作后癫痫风险的干预研究和计划。