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: 10408645
• 负责人: JACQUE LYNNE DUNCAN
• 金额: $ 36.11万
• 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/10408645
• 关键词: Academia; Address; Advanced Development; Amblyopia; Benign; Bioinformatics; Blindness; Candidate Disease Gene; Caring; Cessation of life; Characteristics; Child; Childhood; Classification; ClinVar; Clinical; Clinical Trials; Data; Deposition; Development; Diagnosis; Diagnostic; Disease; 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; Problem Solving; 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; base; clinical care; clinical diagnosis; clinically actionable; clinically relevant; clinically significant; 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.

项目总结/摘要 该提案的目标是策划与遗传性疾病相关的基因中的临床相关变异， 单基因疾病常染色体隐性Leber先天性黑蒙（LCA）/早发性视网膜 退化（eoRD）导致从婴儿或儿童开始的终身失明。超过30个基因 与这些表型相关的基因已经被鉴定，并且第一个基因替代疗法被批准。 对于与RPE 65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CEP 290）引起。尽管取得了这些进展， 根据LCA/eoRD变异的现有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统一的分类标准优化基因疾病 能够准确和一致地解释变体临床相关性的特定特征。到 为了解决这个问题，我们已经组建了一个由国际小组组成的变体策展专家小组（VCEP） 在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）的眼部CDWG，以获得建议和指导。与此 领导团队，我们建议策划与LCA/eoRD表型相关的基因变异， 基因疗法是可用的，或者临床或高级临床前研究正在进行中。拟建项目 有两个具体目标：1。通过4个步骤完成LCA/eoRD VCEP的批准流程 （召集一个专家组进行LCA/eoRD变体管理， LCA/eoRD基因变异，使用疾病基因特异性特征，规定了试点测试规则 用于管理LCA/eoRD相关基因的变体，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.在选定的国家中治疗变异体 LCA/eoRD基因，并提交给ClinVar。所有步骤都将执行 经ClinGen CDWG监督委员会批准，使用一套变体管理工具， ClinGen开发的方案。拟议的项目将导致发展不同的解释 与为其他疾病建立的规则相协调并针对LCA/eoRD基因进行优化的标准，以及 生成LCA/eoRD基因变异的综合资源，其中包含FDA指定的专家级变异 ClinVar公共数据库中的分类。这些信息将推动LCA/eoRD的研究， 能够准确、一致、高质量地解读基因检测结果，并改善患者护理。 此外，LCA/eoRD VCEP规定的规则将促进其他IRD规则的制定， 其他遗传性疾病。