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

摘要 过去十年来，智力和发育障碍（IDD）的临床进展， 影响了美国六分之一的人其特点是前所未有的进步， 了解IDD遗传易感性的性质和复杂性。罕见的拷贝数和 现在已知序列变异占人群归因风险的主要份额， IDD，并且在超过30%的接受临床基因组测序的个体中被确定。 致病性变体的临床鉴定产生了重要的转化机会， 加速发现和改善临床治疗，但这些机会受到以下因素的限制： 我们对如何估计给定遗传物质的致病性的理解存在严重差距， 个别患者的异常。本次U 01临床与医学合作创新奖 转化科学奖（CTSA）计划解决了这一主要障碍，利用 基因组信息现在通常在临床环境中获得， 由美国健康保险公司提供补贴。确保临床获得的IDD测序数据 患者与神经行为变异的标准化信息进行系统整合 和临床过程（这是目前不常见的）站在加速理解的 遗传变异与疾病的关系该计划的目的是建立 临床卫生系统中碘缺乏病患者可行的神经行为表征标准 通过CTSA网络，整合表型和临床基因组表征， 患者直接促进IDD基因和变异治疗国家议程的进展， 并建立一个动态的、最先进的IDD患者登记系统，作为NCAT中心的延伸 数据到健康（CD 2 H）倡议。该登记将被设计为共同登记表型， 基因型和脑成像、EEG、实验室生物标志物的电子健康记录数据，以及 临床课程，目的是详细说明风险，弹性和干预的细微差别 反应，并阐明IDD常见和罕见的致病机制。一旦 CTSA-IDD登记处将成为一个自我维持的开放科学平台， IDD的转化进展，为受影响的患者提供了重要的新机会， 由合格的科学家和临床医生确定个别罕见的IDD状况， 根据遗传或表型特征进行分组，并参与重点发现工作， 临床试验和/或针对其病症的个性化干预创新。

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.