Core A - Variant prioritization and curation core

项目概要-核心A 离子通道基因变异是严重儿童癫痫最常见的遗传学发现。 然而，由于以下原因，对通道病相关癫痫的遗传背景的了解是不完整的： 变异发现的快速步伐和变异解释的挑战。此外，现有的许多 相关知识尚未广泛获得，包括最近发现的变异、相关临床 表型，变异功能分析的协议，以及整合功能，遗传， 临床数据，以评估致病性和预后。变体优先级和固化核心（核心A）将 修改和部署现有的协作生物信息学和变异体管理平台，以支持使命 我们的中心。核心A将作为正在进行的NIH策展工作的接口，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，我们将对癫痫相关电压门控离子通道基因的变异进行分类。最大化 在项目1-3中进行的体外和体内功能研究的效用，核心A将建立和维持一个 电压门控离子通道基因中已知癫痫相关变异的数据库。我们将组装基因 和表型信息来自不同的来源，包括出版物，基因座特异性数据库，以前 来自诊断实验室（约30，000例患者）和研究（约20，000例受试者）的未公开数据。在 目的2，我们将优先考虑离子通道基因的变异体进行功能评价。离子通道基因变异体 将选择临床重要性和分析有效性最高的研究用于中提出的高通量研究。 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 美国医学遗传学和基因组学学院（ACMG）诊断规则和先进的数据驱动 该算法考虑了突变“热点”、基因家族信息和区域不容忍。基于 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。在Aim中 3，我们将使用功能数据来迭代地改进变体分类和诊断标准。我们将应用 中心的结果，提出改进的变异分类规则，并在ClinGen内工作 联盟开发一种基于基因/变异的早发性癫痫分类法， 国际抗癫痫联盟（ILAE）分类和术语。为确保公众可获取，核心A 成员将扩大与NIH资助的ClinGen联盟和ClinVar的持续合作， 通过将所有分类的离子通道变体和关键支持证据作为专家提交给ClinVar进行存档 面板作为这项工作的一部分，我们将增加现有的ClinVar数据元素，以包括变体的数据字段 使用Project 1开发的本体函数。

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.