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 已经改变了我们诊断疑似遗传病患者的能力。随着这些技术的引入， 技术，可以在至少25-30%的疑似肿瘤患者中确定潜在的分子DNA损伤。 基因诊断这些技术还导致发现了数百种新的疾病基因， 已知遗传诊断中的表型扩张。新的疾病基因的不断发现导致了 结构、功能和机制的发现，有助于个性化的管理方法， 疗法然而，高达70%的疑似遗传性疾病患者仍然没有被诊断出来，这可能是因为 它们的致病变体尚未被发现，或者已鉴定变体的临床意义仍然存在 不清楚利用各种基因组修饰技术在果蝇中产生的精确模型 (fly)和小家鼠（小鼠）是重要的工具，有助于解释这些不确定的变异， 临床意义，并且对于测试治疗范例至关重要。我们会利用专业知识， 基础设施，并建立了罕见的孟德尔疾病临床和基因发现之间的合作 程序;苍蝇、老鼠和非人类灵长类动物建模程序;以及数据库基础设施程序 贝勒医学院分子与人类遗传学系（DMHG）， 建立精准医学建模中心（BCPMM）。我们中心的愿景是支持 地方，国家和国际计划和个人研究人员在精密模型的发展 这将结束未确诊的罕见疾病和孟德尔疾病患者的诊断之旅， 用于临床前研究的资源，研究个性化医疗方法对其进行护理。我们将 通过追求以下目标实现这些目标：（1）利用联合国系统内现有的多学科专门知识 设计，生成和识别精确的动物模型，用于回答临床问题的研究 （2）开展示范项目，展示中心模拟未确诊病例的能力 和罕见疾病，并将模式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疾病相关的变异提名， 中心内的模型研究;（4）对精密动物模型的结果进行双向翻译 以及从患者临床研究中整合到临床诊断、临床护理或临床试验中;（5） 实施优化中心疾病建模和组织活动的生物信息学平台。 虽然我们最初的重点将建立在我们的专业知识在未确诊的，罕见的，孟德尔疾病，我们的长期 我们的目标是通过与调查人员和项目建立合作来扩大我们的范围， 多基因和常见病。

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.