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

项目摘要/摘要 这项提议的目标是在与遗传性疾病相关的基因中筛选临床上相关的变异。 单基因疾病常染色体隐性遗传性Leber先天性黑色素/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)。30多个基因 与这些表型相关的基因已被确定，并批准了第一种基因替代疗法 与RPE65变种相关的LCA/eoRD，而目前正在进行治疗疾病的临床试验 由另外3个基因(AIPL1、GUCY2D和CEP290)引起。尽管取得了这些进展，但要做到这一点仍然具有挑战性 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。一个主要的限制是缺乏针对基因疾病优化的统一分类标准。 能够准确和一致地解释变异的临床相关性的特定特征。至 为了解决这一问题，我们组建了一个由一个国际小组组成的不同策展专家小组(VCEP 在LCA/eoRD遗传学和临床护理方面拥有深入知识的专家。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寻求建议和指导。有了这个 领导团队，我们建议对与LCA/eoRD表型相关的基因变异进行整理 基因疗法已经可用，或者正在进行临床或高级临床前研究。拟议中的项目 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 (召集一组LCA/eoRD变种管理专家，分类规则规范 使用疾病基因特定特征的LCA/eoRD基因的变种，规定了先导测试规则 用于筛选LCA/eoRD相关基因的变异，并将规则和试验结果提交给 Clingen序列变体解释工作组批准)，以及2.选定的 LCA/eoRD基因通过执行指定的规则并提交给ClinVar。所有步骤都将执行 经Clingen CDWG监督委员会批准，使用一套不同的管理工具和 由Clingen开发的协议。拟议的项目将导致变式口译的发展。 符合为其他疾病制定的规则并针对LCA/eoRD基因进行优化的标准；以及 利用FDA指定的专家级变体生成全面的LCA/eoRD基因变体资源 ClinVar公共数据库中的分类。这些信息将促进LCA/EORD和 实现对基因检测结果的准确、一致、高质量的解释，并改善患者护理。 此外，LCA/eoRD VCEP规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.