Enhancing mouse embryo imaging capabilities at the BCM Center for Precision Medicine Models

摘要 介绍临床外显子组测序、全基因组测序、RNA测序和代谢组学 改变了我们诊断疑似遗传病患者的能力。随着这些产品的推出 技术，至少25%-30%的疑似患者可以确定潜在的分子DNA损伤 基因诊断。这些技术还导致了数百种新的疾病基因的发现，并 已知基因诊断中的表型扩展。新疾病基因的不断发现导致了 结构、功能和机制发现，有助于个性化的管理和 心理治疗。然而，高达70%的疑似遗传病患者可能仍未得到诊断，因为 它们的致病变异(S)尚未被发现，或已确定的变异的临床意义仍然存在 不清楚。用不同基因组修饰技术制作的果蝇精确模型 (苍蝇)和小鼠(小鼠)是帮助解释这些不确定的变体的重要工具 具有临床意义，对测试治疗范例至关重要。我们将利用专业知识， 基础设施，以及罕见的孟德尔病临床和基因发现之间建立的合作 程序；飞行、鼠标和非人类灵长类动物建模程序；以及数据库基础设施程序 在贝勒医学院(BCM)分子和人类遗传学(DMHG)系 建立精准医学建模中心(BCPMM)。我们中心的愿景是支持 开发精密模型的地方、国家和国际项目和个人研究人员 这将结束未诊断的、罕见的和孟德尔式疾病患者的诊断之旅，并作为 临床前研究的资源，调查他们护理的个性化药物方法。我们会 通过追求以下目标实现这些目标：(1)利用BCM内现有的多学科专业知识 设计、生成和识别精确的动物模型，用于回答具有影响力的临床问题的研究 关于病人护理；(2)开展示范项目，展示该中心模拟未确诊病例的能力 和罕见疾病，并将模型生物的发现转化为病人护理；(3)参与人类基因组 发现计划、临床医生和研究人员招募与疾病相关的变异提名以确保准确性 中心内的模型研究；(4)对精密动物模型的研究结果进行双向翻译 来自患者的临床研究，以融入临床诊断、临床护理或临床试验；(5) 实施生物信息学平台，以优化中心疾病建模和组织活动。 虽然我们最初的重点是建立在我们在未诊断的、罕见的和孟德尔疾病方面的专业知识上，但我们的长期目标是 目标是通过与调查人员和专注于以下方面的项目建立合作来扩大我们的范围 多基因、常见病。

ABSTRACT The introduction of clinical exome sequencing, whole genome sequencing, RNA sequencing, and metabolomics has transformed our ability to diagnose patients with suspected genetic disease. With the introduction of these technologies, a potential molecular DNA lesion can be identified in at least 25-30% of patients with a suspected genetic diagnosis. These technologies have also led to the discovery of hundreds of new disease genes and to phenotypic expansion within known genetic diagnoses. This continued discovery of new disease genes leads to structure, function and mechanistic discoveries that assist personalized approaches for management and therapy. However, up to 70% of patients with suspected genetic disease remain undiagnosed likely because their disease-causing variant(s) has yet to be discovered or the clinical significance of identified variants remains unclear. Precision models produced using various genome modification techniques in Drosophila melanogaster (fly) and Mus musculus (mouse) are important tools aiding in the interpretation of these variants of uncertain clinical significance and are critical for testing therapeutic paradigms. We will leverage the expertise, infrastructures, and established collaborations between the rare, Mendelian disease clinical and gene discovery programs; fly, mouse, and nonhuman primate animal modeling programs; and database infrastructure programs within the Department of Molecular and Human Genetics (DMHG) at the Baylor College of Medicine (BCM) to establish the BCM Center for Precision Medicine Modeling (BCPMM). The vision of our Center is to support local, national, and international programs and individual researchers in the development of precision models that will end the diagnostic odyssey of patients with undiagnosed, rare, and Mendelian diseases and serve as resources for pre-clinical studies investigating personalized medicine approaches to their care. We will achieve these goals by pursuing the following aims: (1) leverage existing multidisciplinary expertise within BCM to design, generate, and identify precision animal models for studies that answer clinical questions with impact on patient care; (2) conduct demonstration projects that showcase the Center’s capacity to model undiagnosed and rare diseases and to translate model organism findings back to patient care; (3) Engage human genome discovery programs, clinicians, and researchers to recruit disease-associated variant nominations for precision model studies within the Center; (4) Perform bidirectional translation of findings from precision animal models and from patient clinical studies for integration into clinical diagnostics, clinical care, or clinical trials; (5) Implement bioinformatics platforms that optimize Center disease modeling and organizational activities. Although our initial focus will build on our expertise in undiagnosed, rare, and Mendelian diseases, our long-term goal is to broaden our scope by establishing collaborations with investigators and programs focused on multigenic and common disease.