Expert curation of clinically significant variants in genes for early onset retinal degeneration

项目概要/摘要 该提案的目标是策划与遗传相关的基因的临床相关变异 单基因疾病 常染色体隐性遗传 Leber 先天性黑蒙 (LCA)/早发性视网膜 从婴儿期或儿童期开始导致终身失明的变性 (eoRD)。超过30个基因 与这些表型相关的基因已被鉴定，第一个基因替代疗法已获得批准 用于与 RPE65 变异相关的 LCA/eoRD，目前正在进行治疗疾病的临床试验 由其他 3 个基因（AIPL1、GUCY2D 和 CEP290）引起。尽管取得了这些进步，但仍然具有挑战性 根据 LCA/eoRD 变异的当前知识做出准确的临床诊断和决策 相关基因。主要限制是缺乏针对基因疾病优化的统一分类标准 能够准确、一致地解释变异的临床相关性的特定特征。至 为了解决这个问题，我们组建了一个由国际小组组成的变体管理专家小组（VCEP） 由在 LCA/eoRD 遗传学和临床护理方面拥有深入知识的专家组成。此外，我们还建立了 与临床领域工作组 (CDWG) 监督委员会和 NIH 赞助的临床基因组资源 (ClinGen) 的眼科 CDWG 提供建议和指导。有了这个 领导团队，我们建议策划与 LCA/eoRD 表型相关的基因变异，其中 基因疗法已经可用，或者临床或高级临床前研究正在进行中。拟议项目 涉及 2 个具体目标： 1. 通过 4 个步骤完成 LCA/eoRD VCEP 的审批流程 （组建了 LCA/eoRD 变异管理专家组，分类规则规范 使用疾病基因特定特征的 LCA/eoRD 基因变异，指定试点测试规则 用于管理 LCA/eoRD 相关基因的变异，并将规则和试点结果提交给 ClinGen 序列变异解释工作组批准），以及 2. 选定的变异的管理 LCA/eoRD 基因通过执行指定的规则并提交给 ClinVar。所有步骤都将被执行 经 ClinGen CDWG 监督委员会批准，使用一套变体管理工具，并且 由 ClinGen 开发的协议。拟议的项目将导致变异解释的发展 与为其他疾病制定的规则相一致并针对 LCA/eoRD 基因进行优化的标准，以及 使用 FDA 指定的专家级变体生成 LCA/eoRD 基因变体的综合资源 ClinVar 公共数据库中的分类。这些信息将推进 LCA/eoRD 的研究 能够准确、一致、高质量地解释基因检测结果，并改善患者护理。 此外，LCA/eoRD VCEP 指定的规则将推动其他 IRD 和 其他遗传性疾病。

PROJECT SUMMARY/ABSTRACT The goal of this proposal is to curate clinically relevant variants in genes associated with the inherited monogenic diseases autosomal recessive Leber congenital amaurosis (LCA)/early-onset Retinal Degeneration (eoRD) that cause lifelong blindness beginning in infancy or childhood. More than 30 genes associated with these phenotypes have been identified and the first gene replacement therapy was approved for LCA/eoRD associated with RPE65 variants, while clinical trials are currently underway to treat disease caused by 3 other genes (AIPL1, GUCY2D, and CEP290). Despite these advances, it is still challenging to make accurate clinical diagnoses and decisions based on current knowledge of variants in LCA/eoRD- associated genes. A major limitation is the lack of uniform classification criteria optimized for gene-disease specific features that enable accurate and consistent interpretation of the clinical relevance of variants. To address this, we have assembled a variant curation expert panel (VCEP) comprised of an international group of experts with in-depth knowledge in LCA/eoRD genetics and clinical care. Further, we established collaborative relationships with the clinical domain working group (CDWG) oversight committee and the Ocular CDWG of the NIH-sponsored Clinical Genome Resource (ClinGen) for advice and guidance. With this leadership team, we propose to curate variants in genes associated with LCA/eoRD phenotypes for which gene therapies are available, or clinical or advanced pre-clinical studies are underway. The proposed project involves 2 Specific Aims: 1. Complete the approval process for the LCA/eoRD VCEP through 4 steps (assembling a group of experts for LCA/eoRD variant curation, rule specification for the classification of variants in LCA/eoRD genes using disease-gene specific characteristic features, pilot testing rules specified for the curation of variants in LCA/eoRD associated genes, and submitting the rules and pilot results to the ClinGen Sequence Variant Interpretation Working Group for approval), and 2. Curation of variants in selected LCA/eoRD genes by implementing the specified rules and submission to ClinVar. All steps will be carried out with the approval of the ClinGen CDWG oversight committee utilizing a suite of variant curation tools and protocols developed by ClinGen. The proposed project will lead to the development of variant interpretation criteria that are in harmony with rules established for other diseases and optimized for LCA/eoRD genes, and generate a comprehensive resource of LCA/eoRD gene variants with FDA-designated expert level variant classifications in the ClinVar public database. This information will advance research on LCA/eoRD and enable accurate, consistent, high quality interpretation of genetic test results, and improve patient care. Further, the rules specified by the LCA/eoRD VCEP will advance development of rules for other IRDs and other hereditary diseases.