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

专家对早发性视网膜变性基因的临床显着变异进行管理

• 批准号: 10655529
• 负责人: JACQUE LYNNE DUNCAN
• 金额: $ 34.56万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10655529
• 关键词: Academia; Address; Advanced Development; Amblyopia; Authorization documentation; Benign; Bioinformatics; Blindness; Candidate Disease Gene; Caring; Certification; Cessation of life; Characteristics; Child; Childhood; Classification; ClinVar; Clinical; Clinical Trials; Data; Deposition; Development; Diagnosis; Diagnostic; Disease; Eligibility Determination; FDA approved; Funding Opportunities; Future; Gene Targeting; Genes; Genetic; Genetic Counseling; Genome; Goals; Grant; Guidelines; Hereditary Disease; Industry; Inherited; International; Knowledge; Leadership; Leber' s amaurosis; Medical; Mendelian disorder; Modification; Mutation; Pathogenicity; Patient Care; Patients; Phenotype; Photoreceptors; Process; Protocols documentation; RPE65 protein; Research; Resources; Retina; Retinal Degeneration; Retinal Diseases; Specific qualifier value; Test Result; United States National Institutes of Health; Variant; Work; authority; autosome; clinical care; clinical diagnosis; clinically actionable; clinically relevant; clinically significant; data submission; early onset; experience; gene replacement therapy; gene therapy; genetic testing; genetic variant; genome resource; improved; infancy; molecular pathology; personalized care; pilot test; preclinical study; prevent; public database; response; tool; treatment trial; working group

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.

项目摘要/摘要 该建议的目的是策划与遗传有关的基因中的临床相关变体 单基因疾病常染色体隐性左旋先天性症（LCA）/早期视网膜 从婴儿期或童年开始引起终身失明的退化（EORD）。超过30个基因 已经确定了与这些表型相关的，并批准了第一个基因替代疗法 对于与RPE65变体相关的LCA/EORD，目前正在进行临床试验以治疗疾病 由其他3个基因（AIPL1，GUCY2D和CEP290）引起。尽管有这些进步，但仍然具有挑战性 根据当前对LCA/Eord-的变异知识进行准确的临床诊断和决策。 相关基因。一个主要限制是缺乏针对基因疾病优化的统一分类标准 可以准确且一致地解释变体的临床相关性。到 解决这个问题，我们组装了一个由国际集团组成的变体策划专家小组（VCEP） LCA/Eord遗传学和临床护理方面具有深入知识的专家。此外，我们建立了 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CDWG，以提供建议和指导。与此 领导团队，我们建议策划与LCA/Eord表型相关的基因变体 可以使用基因疗法，或正在进行临床或晚期临床前研究。拟议的项目 涉及2个特定目的：1。通过4个步骤完成LCA/Eord VCEP的批准过程 （组装一组专家，用于LCA/EORD变体策划，用于分类的规则规范 使用疾病特定特征特征，LCA/Eord基因的变体，指定的试点测试规则 对于LCA/EORD相关基因中的变体的策划，并将规则和试验结果提交给 克林根序列变体解释工作组供批准）和2。选定的变体策划 LCA/EORD基因通过实施指定的规则和提交Clinvar。所有步骤将进行 在克林根CDWG监督委员会的批准下，利用一套变体策划工具和 Clingen开发的协议。拟议的项目将导致变异解释的发展 与针对其他疾病制定并针对LCA/Eord基因优化的规则和谐的标准，以及 通过FDA指定的专家级别变体生成LCA/EORD基因变体的全面资源 Clinvar公共数据库中的分类。此信息将推动对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规定的规则将推动针对其他IRD的规则制定，并 其他遗传性疾病。