Integrative Curation of Clinically Relevant Variants in X-Linked Inherited Retinal Disease Genes

摘要 遗传性视网膜疾病（IRD）是早发性失明的主要原因，严重影响数百万人的视力。 患者鉴于IRD的临床和遗传异质性，靶向基因治疗正在成为主要的治疗方法。 目前正在进行的许多临床试验是治疗这种疾病的有效方法。效益最大化 在这些新兴的治疗方法中，分子诊断是第一个关键步骤。 在与ClinGen眼科临床领域工作组委员会协调时，我们建议建立一个 新的变异管理专家小组（VCEP）将专注于开发疾病和基因规范， 策划专家评估七个X连锁IRD基因的变体，包括RPGR，CHM，RS1，RP2， OFD1、NDP和CACNA1F。总的来说，这些基因的突变占IRD患者的15%。我们有 确定了一个由世界各地的杰出科学家组成的小组，他们将致力于这项工作，拥有各种专业知识： 执业眼科医生、临床诊断实验室主任和世界领先的研究人员 研究X连锁IRD基因在临床和研究领域的功能。这些专家带来 这一努力的补充知识和资源，包括功能性实验室测定，以评估 患者变异的影响，基于基因治疗的临床试验，以及患者样本的收集， 测序变异和详细的临床病史。 与专门的生物信息学，策展和行政支持一起，X连锁IRD变体策展 专家组建议将FDA批准的ClinGen基础设施工具和流程与 我们建议收集、整理和提供给事务委员会的支援资源，以制订规则规格 用于X连锁IRD基因治疗。通过我们的小组和协调的策展志愿者团队，我们将策展和 熟练地评估这些基因的变异。这一努力的成果将是双重的。第一，规范， 可以应用于评估七个基因中的新变体，并且可以适用于其他X连锁IRD基因。 第二，七个X连锁IRD基因中的策划变体，在2011年获得三星级（专家小组评估）评级， ClinVar数据库，将改善对新发患者变异的评估，并使治疗 基因疗法

Abstract Inherited retinal diseases (IRD) are a major cause of early-onset blindness, profoundly affecting millions of patients. Given the clinical and genetic heterogeneity of IRD, targeted gene therapy is emerging as the main effective approach for treating the disease with many clinical trials currently underway. To maximize the benefit of these emerging therapies to patients, molecular diagnosis is the first critical step. In coordinating with the ClinGen Ocular Clinical Domain Working Group committee, we propose to establish a new variant curation expert panel (VCEP) that will focus on developing disease and gene specifications and curating expert assessment of variants in the seven X-linked IRD genes, including RPGR, CHM, RS1, RP2, OFD1, NDP, and CACNA1F. Collectively, mutations in these genes account for 15% of IRD patients. We have identified a distinguished panel of scientists across the world who will commit to this effort with diverse expertise: practicing ophthalmologic physicians, clinical diagnostic laboratory directors, and world-leading researchers studying the function of the X-linked IRD genes in the clinical and research domains. These experts bring complementary knowledge and resources to this effort including functional laboratory assays to assess the impact of patient variants, clinical trials for gene-based treatments, and collections of patient samples with sequenced variants and a detailed clinical history. Together with dedicated bioinformatics, curatorial, and administrative support, the X-linked IRD Variant Curation Panel proposed will deploy the FDA approved ClinGen infrastructure tools and processes in combination with the supportive resources we propose to collect, organize and provide to the panel to develop rule specifications for X-linked IRD gene curation. With our panel and team of coordinated curation volunteers, we will curate and expertly assess the variants in these genes. The products of this effort will be two-fold. First, specifications that can be applied to assess new variants in the seven genes and can be adapted for other X-linked IRD genes. And second, curated variants in the seven X-linked IRD genes with three-star (expert panel assessed) ratings in the ClinVar databasethat will improve the assessment of de novo patient variants and enable treatments with gene-based therapies.