New York Regional Inborn Errors of Immunity Resource Initiative League (NY-ROYAL)

项目摘要 先天性免疫缺陷（IEI）是一种免疫系统疾病，单独罕见，但总体罕见 影响1/10，000人。遗传学诊断是及时进行遗传咨询和临床诊断的基础。 在乎这种治疗可能涉及骨髓移植、基因治疗或精确的药物治疗， 可以治愈的疾病基因组测序在质量和价格方面的最新进展导致了一个 发现IEIs的致病基因的速度加快，目前已有400多个基因成为IEIs的基础。然而，大约3 四分之一的IEI测序产生400多个基因之一的未知重要性变体（VUS）， 需要发现新的原因。这导致了诊断和治疗的延误，特别是因为大多数人 这些VUS不能使用临床可用的测定法来验证。随着测序板越来越多地被使用 由于有保险，基因数据的生产速度超过了个人的解释能力， 了该提案的主要目的是建立一个区域资源，使案件审查正规化 处理，匹配提供者及其携带VUS的患者与能够有针对性地 功能评价和/或生物信息学评估，从而导致VUS重新分类、诊断和 治疗它还将为研究企业注入具有临床意义的生物学问题。我们建议 通过建立1）患者转诊平台和数据库来简化纽约地区的这一流程， 提供者将能够输入去识别的患者临床信息以及相关的遗传数据（IEI 基因面板，WES和WGS测序），2）多学科审查过程，提交的数据将 由IEI基因发现和功能验证最前沿的专家评审小组进行评估， 定期由一个合作伙伴处理相关的VUS，以进行3）功能表征 专家小组随后是4）结果报告，VUS重新分类及其纳入国家临床相关 遗传变异数据库这个多学科诊断纽约区域免疫学资源是关键， 支持新的IEI相关遗传变体的发现和功能表征。这个资源 将服务于未来更广泛应用的基因组学、人工智能/机器学习、快速 功能评估和精准医疗。

Project Summary Inborn errors of immunity (IEI) are disorders of the immune system which are individually rare but collectively affect 1 in 10,000 individuals. Definitive genetic diagnosis is of essence for timely genetic counseling and clinical care. Such care may involve bone marrow transplantation, gene therapy or precision pharmacotherapeutics, all of which can be curative. The recent advancement of genome sequencing in quality and price has led to an increased rate of discovery of what are now over 400 causal genes underlying IEIs. However, about three quarters of IEI sequencing yields either variants of unknown significance (VUSs) in one of the 400+ genes or require discovery of novel causes. This leads to delays in diagnosis and treatment, especially since most of these VUSs cannot be validated using clinically available assays. As sequencing panels are increasingly utilized and being covered by insurance, the rate of genetic data production outpaces indiividuals’ capacity to interpret it. The primary purpose of this proposal is to build a regional resource which would formalize case review process, match providers and their patients carrying VUSs with research laboratories capable of targeted functional evaluation and/or bioinformatic assessment, thereby leading to VUS reclassification, diagnosis and treatment. It also will infuse research enterprises with clinically significant biological questions. We propose to streamline this process in the NY region by building a 1) patient referral platform and database where providers will be able to input deidentified patient clinical information alongside the associated genetic data (IEI gene panels, WES, and WGS sequencing), 2) a multidisciplinary review process where submitted data will be evaluated by an expert review panel at the forefront of IEI gene discovery and functional validation on a regular basis who will work to disposition relevant VUSs for 3) functional characterization by a collaborating expert team followed by 4) result reporting, VUS reclassification and its inclusion in the national clinically relevant genetic variation database. This multidisciplinary diagnostic NY regional immunology resource is key to supporting the discovery and functional characterization of novel IEI associated genetic variants. This resource will serve future, more broadly applied integration of genomics, artificial intelligence/machine learning, rapid functional assessment and precision medicine.