Genome-first approach to treatable genetic conditions in adults

项目摘要/摘要： 这项建议详细说明了一项为期五年的研究职业发展计划，重点是确定 医院生物库中具有与无法诊断的可治疗遗传相关的基因组变异的个体 精神错乱。这项拟议的研究建立在我之前的研究和临床经验的基础上，需要 掌握与识别单基因疾病高危个体相关的新技能 人口。我已经组建了一支享誉国际的导师团队，他们的专业领域涵盖了 基因组学研究和医学的几个领域。我的导师包括罗伯特·格林博士，他是一位 与实施基因组医学相关的医疗、行为和经济后果； 海蒂·雷姆，变异管理和基因-疾病关系方面的专家；普拉迪普·纳塔拉扬博士，一位 在计算和综合基因组学方面的专家。通过建议的研究和培训，我将发展 跨学科的技能，使我能够过渡到作为一名内科科学家的独立。 尽管单基因遗传病是个别罕见的，但据估计，它们总共影响1.5-6.2% 占全球人口的比例。大多数有遗传疾病的人在发育后都会接受医疗护理 在漫长而昂贵的诊断过程之后，接受诊断。作为数量的 随着可治疗遗传疾病的增多，及早识别高危个体的需要变得更加迫切。 基于群体的基因组测序，也被称为“基因组优先方法”，提供了一种机会 通过在症状出现之前对个人进行遗传性疾病筛查，改善公共卫生结果。 然而，目前对具有遗传风险的个体的外显性和健康后果知之甚少。 来自未经选择的群体的变异。在这个项目中，我建议：1)确定患有 一系列可治疗的单基因疾病的风险变异在以医院为基础的布赖格姆综合医院 生物库(MGBB)和英国生物库(UKB)，2)重新联系MGBB中具有基因型的个人 与可治疗的遗传性代谢紊乱(IMD)相关，以确定与疾病相关的变量 表达，以及3)确定UKB中的代谢特征是否可以用于预测个体的结果 具有IMD子集的风险变异体。这项工作代表着朝着确定最佳使用 基因组优先医学，最终加速获得基因组风险分层，适当的后续行动， 正交试验，关爱罕见遗传病患者。

PROJECT SUMMARY/ABSTRACT: This proposal details a five-year research career development program focused on the identification of individuals in a hospital-based biobank with genomic variants associated with undiagnosed treatable genetic disorders. The proposed research, which builds upon my prior research and clinical experience, requires mastery of new skills related to the identification of individuals at risk for monogenic disorders in unselected populations. I have assembled an internationally-renowned team of mentors, whose areas of expertise span several domains of genomics research and medicine. My mentors include Dr. Robert Green, an expert in the medical, behavioral, and economic outcomes associated with the implementation of genomic medicine; Dr. Heidi Rehm, an expert in variant curation and gene-disease relationships; and Dr. Pradeep Natarajan, an expert in computational and integrative genomics. Through the proposed research and training, I will develop interdisciplinary skills that will enable me to transition to independence as a physician-scientist. Although monogenic genetic disorders are individually rare, they are estimated to collectively affect 1.5–6.2% of the global population. Most individuals with genetic conditions present to medical care after the development of symptoms and receive diagnoses following lengthy and expensive diagnostic odysseys. As the number of treatable genetic conditions grows, the need to identify at-risk individuals early has become more urgent. Population-based genomic sequencing, also known as a “genome-first approach,” provides an opportunity to improve public health outcomes by screening individuals for genetic disorders prior to the onset of symptoms. At this time, however, little is known about the penetrance and health outcomes of individuals with genetic risk variants from unselected populations. In this project, I propose to: 1) identify the prevalence of individuals with risk variants for a range of treatable monogenic conditions in both the hospital-based Mass General Brigham Biobank (MGBB) and U.K. Biobank (UKB), 2) recontact individuals in the MGBB who have genotypes associated with treatable inherited metabolic disorders (IMDs) to identify variables associated with disease expression, and 3) determine if metabolic profiling in the UKB can be used to predict outcomes in individuals with risk variants for a subset of IMDs. This work represents a step toward determining the best uses of genome-first medicine, eventually accelerating access to genomic risk-stratification, appropriate follow-up, orthogonal testing, and care for people with rare genetic disorders.