Core A - Variant prioritization and curation core

核心 A - 变体优先级和管理核心

• 批准号: 10477449
• 负责人: EDWARD C COOPER
• 金额: $ 22.99万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10477449
• 关键词: Algorithms; American; Archives; Bioinformatics; Catalogs; Classification; ClinVar; Clinical; Clinical Data; Clinical Research; Collaborations; Communities; Complement; Data; Data Element; Data Set; Databases; Diagnostic; Ensure; Epilepsy; Evaluation; Funding; Future; Gene Family; Genes; Genetic; Genetic Research; Genomics; Genotype; Hot Spot; Human; In Vitro; International; Ion Channel; Ion Channel Gating; Knowledge; Laboratories; Medical Genetics; Mission; Mutation; Neurons; Ontology; Outcome Assessment; Pathogenicity; Patients; Phenotype; Process; Prognosis; Protocols documentation; Publications; Recommendation; Recurrence; Research; Research Personnel; Resources; Scientist; Secure; Severities; Source; Standardization; Taxonomy; Terminology; Translating; United States National Institutes of Health; Variant; Work; base; childhood epilepsy; clinical phenotype; diagnostic criteria; early onset; genetic variant; improved; in vivo; induced pluripotent stem cell; medical schools; member; mouse model; novel; precision medicine; prospective; recruit; research study; variant of unknown significance; voltage; web portal

PROJECT SUMMARY – CORE A Variants in ion channel genes represent the most common genetic finding in severe pediatric epilepsies. However, knowledge of the genetic landscape of channelopathy-associated epilepsy is incomplete, owing to the rapid pace of variant discovery and the challenges of variant interpretation. Further, much of the existing relevant knowledge is not widely available, including recently identified variants, associated clinical phenotypes, protocols for variant functional analysis, and best practices for integrating functional, genetic, and clinical data to assess pathogenicity and prognosis. The Variant Prioritization and Curation Core (Core A) will modify and deploy an existing collaborative bioinformatics and variant curation platform to support the mission of our Center. Core A will serve as an interface to ongoing NIH curation efforts, including ClinVar and ClinGen, to ensure that functional data generated by the Center are enduring and fully accessible. In Aim 1, we will catalog variants in the epilepsy-associated voltage-gated ion channel genes. To maximize the utility of in vitro and in vivo functional studies performed in Projects 1-3, Core A will establish and maintain a database of known epilepsy-associated variants in voltage-gated ion channel genes. We will assemble genetic and phenotypic information from diverse sources including publications, locus-specific databases, previously undisclosed data from diagnostic laboratories (~30,000 patients) and research studies (~20,000 subjects). In Aim 2, we will prioritize variants in ion channel genes for functional evaluation. Ion channel gene variants of the highest clinical importance and analytical validity will be selected for the high-throughput studies proposed in Project 1. To identify which variants meet this standard, we will apply a range of criteria including established American College of Medical Genetics and Genomics (ACMG) diagnostic rules and an advanced data-driven algorithm that considers mutational ‘hot spots,’ gene family information, and regional intolerance. Based on the applied criteria, we will prioritize 1,000 variants for functional evaluation over the 5-year funding period. In Aim 3, we will use functional data to iteratively refine variant classifications and diagnostic criteria. We will apply results from the Center to propose improved classification rules for variants and work within the ClinGen consortium to develop a gene/variant-based taxonomy of early onset epilepsy that harmonizes with the International League Against Epilepsy (ILAE) classification and terminology. To ensure public access, Core A members will expand their ongoing collaboration with the NIH-funded ClinGen consortium, and the ClinVar archive by submitting all classified ion channel variants and key supporting evidence to ClinVar as an Expert Panel. As part of this effort, we will augment existing ClinVar data elements to include data fields on variant function using an ontology developed by Project 1.

项目摘要 – 核心 A 离子通道基因的变异代表了严重小儿癫痫中最常见的遗传发现。 然而，由于以下原因，对离子通道病相关癫痫的遗传状况的了解并不完整： 变异发现的快速步伐以及变异解释的挑战。 相关知识尚未广泛获得，包括最近发现的变异、相关的临床 表型、变异功能分析方案以及整合功能、遗传和功能的最佳实践 评估致病性和预后的临床数据将用于评估变异优先级和管理核心（核心 A）。 修改和部署现有的协作生物信息学和变异管理平台以支持任务 我们中心的核心 A 将作为 NIH 正在进行的管理工作的接口，包括 ClinVar 和 ClinGen， 确保中心生成的功能数据持久且完全可访问。 在目标 1 中，我们将对癫痫相关的电压门控离子通道基因的变异进行分类，以最大化。 项目 1-3 中进行的体外和体内功能研究的效用，核心 A 将建立并维护 我们将收集电压门控离子通道基因中已知的癫痫相关变异的数据库。 以及来自不同来源的表型信息，包括出版物、位点特异性数据库、以前 来自诊断实验室（约 30,000 名患者）和研究（约 20,000 名受试者）的未公开数据。 目标 2，我们将优先考虑离子通道基因，以进行离子通道基因变体的功能评估。 将选择最高临床重要性和分析有效性的高通量研究 项目 1. 为了确定哪些变体符合此标准，我们将应用一系列标准，包括已建立的标准 美国医学遗传学与基因组学学院 (ACMG) 诊断规则和先进的数据驱动 考虑突变“热点”、基因家族信息和区域不耐受的算法。 根据应用标准，我们将在 5 年资助期内优先考虑 1,000 个变体进行功能评估。 3、我们将使用功能数据迭代完善变异分类和诊断标准。 该中心提出改进的变异分类规则并在 ClinGen 内开展工作 联盟开发一种基于基因/变异的早发性癫痫分类法，该分类法与 国际抗癫痫联盟 (ILAE) 分类和术语 为了确保公众获取，核心 A。 成员将扩大与 NIH 资助的 ClinGen 联盟和 ClinVar 的持续合作 通过向 ClinVar 作为专家提交所有分类的离子通道变体和关键支持证据来存档 作为这项工作的一部分，我们将扩充现有的 ClinVar 数据元素以包含变体的数据字段。 使用项目 1 开发的本体的函数。