Harnessing Clinical Genomic Characterization to Accelerate Translational Advances for Patients with IDD

摘要 过去十年在智力和发育障碍(IDD)方面的临床进展-- 影响到美国六分之一的人--以前所未有的进步为特征 了解碘缺乏病遗传易感性的性质和复杂性。稀有拷贝数和 现已知，序列变异在人群致病风险中占很大比例。 在接受临床基因组测序的人中，超过30%的人被发现患有IDD。 对致病变种的临床鉴定产生了重大的翻译机会 加速发现和改进临床治疗，但这些机会受到以下因素的限制 我们对如何估计一种特定基因的致病性的理解存在严重差距 个别病人的异常。本次U01临床与临床协同创新奖 翻译科学奖(CTSA)计划解决了这一主要障碍，利用 基因组信息现在通常是在临床环境中获得的，并且基本上 由美国健康保险公司补贴。确保临床获取的碘缺乏病测序数据 患者与神经行为变异的标准化信息系统地集成在一起 而临床病程(这在目前并不常见)将加速对 遗传变异与疾病的关系。这项计划的目标是建立 临床卫生系统中IDD患者可行神经行为特征的标准 通过CTSA网络，整合表型和临床基因组特征 患者直接推动国家IDD基因和变异治疗议程的进展， 并建立一个动态的、最先进的IDD患者登记，作为NCAT中心的扩展 用于数据到健康(CD2H)倡议。这个注册表将被设计为联合注册表型， 关于大脑成像、脑电、实验室生物标记物和 临床课程，目的是明确风险、复原力和干预的细微差别 并阐明碘缺乏病常见和罕见的致病机制。一次 CTSA-IDD注册中心的建立将构成一个自我延续的开放科学平台 通过为受以下疾病影响的患者提供重大的新机会，在IDD方面取得翻译性进展 个别-罕见的IDD疾病将由合格的科学家和临床医生识别，将亚 根据遗传或表型特征进行分组，并参与有重点的发现工作， 临床试验和/或针对其具体情况的个性化干预创新。

Abstract The last decade of clinical progress in intellectual and developmental disabilities (IDD)—which affect one in six individuals in the U.S.—has been characterized by unprecedented advances in understanding the nature and complexity of genetic susceptibility to IDD. Rare copy number and sequence variants are now known to account for a major share of population-attributable risk for IDD, and are being identified in over 30% of individuals who undergo clinical genomic sequencing. Clinical identification of pathogenic variants has generated major translational opportunities to accelerate discovery and improve clinical treatment, but these opportunities are constrained by serious gaps in our understanding of how to estimate the pathogenicity of a given genetic abnormality in an individual patient. This U01 Collaborative Innovation Award of the Clinical and Translational Science Award (CTSA) Program addresses this major roadblock, capitalizing upon the fact that genomic information is now commonly acquired in clinical settings and substantially subsidized by U.S. health insurers. Ensuring that clinically-acquired sequencing data of IDD patients is systematically integrated with standardized information on neurobehavioral variation and clinical course (this is currently uncommon) stands to accelerate understanding of the relationship between genetic variation and disease. The aims of this program are to establish standards for feasible neurobehavioral characterization of IDD patients in clinical health systems across the CTSA Network, to integrate phenotypic and clinical genomic characterization of patients to directly promote progress in the national agenda for IDD gene and variant curation, and to establish a dynamic, state-of-the-art IDD patient registry, as an extension of NCAT’s Center for Data To Health (CD2H) Initiative. This registry will be designed to co-register phenotypic, genotypic, and electronic health record data on brain imaging, EEG, laboratory biomarkers, and clinical course, for the purpose of specifying nuanced profiles of risk, resilience, and intervention response, and to elucidate both common and rare pathogenic mechanisms in IDD. Once established, the CTSA-IDD Registry will constitute a self-perpetuating open science platform for translational advances in IDD, by providing major new opportunity for patients affected by individually-rare IDD conditions to be identified by qualified scientists and clinicians, to be sub grouped according to genetic or phenotypic profile, and to participate in focused discovery efforts, clinical trials, and/or innovations in personalized intervention specific to their conditions.