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.

项目总结/文摘