Genome-first approach to treatable genetic conditions in adults

基因组优先方法治疗成人遗传性疾病

• 批准号: 10572236
• 负责人: Nina Beth Gold
• 金额: $ 21.23万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-02 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10572236
• 关键词: Acceleration; Adult; Affect; Area; Award; Biochemical Pathway; Caring; Clinical; Code; Data; Development; Development Plans; Diagnosis; Diagnostic; Diet; Disease; Electronic Health Record; Face; Foundations; Frequencies; Future; Genes; Genetic Diseases; Genetic Risk; Genome; Genomic medicine; Genomics; Genotype; Guidelines; Health; Heart Diseases; Hematopoietic Stem Cell Transplantation; Hospitals; Immunologic Deficiency Syndromes; Individual; Infant; Inherited; International; Laboratory Study; Life Style; Marfan Syndrome; Medical; Medical History; Medicine; Mendelian disorder; Mentors; Metabolic; Metabolic Diseases; Neonatal Screening; Noonan Syndrome; Outcome; Participant; Pathogenicity; Penetrance; Persons; Pharmaceutical Preparations; Phenotype; Physicians; Population; Prevalence; Preventive; Preventive screening; Program Development; Public Health; Recommendation; Recontacts; Research; Risk; Scientist; Severity of illness; Surveys; Symptoms; Syndrome; System; Testing; Time; Training; Variant; Visit; Work; adjudication; behavioral outcome; biobank; cancer predisposition; career; career development; design; economic outcome; exome sequencing; experience; follow-up; gene therapy; genetic variant; genome sequencing; genomic data; improved; outcome prediction; population based; programs; rare genetic disorder; risk stratification; risk variant; screening; screening panel; skills

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.

项目总结/摘要： 该提案详细介绍了一项为期五年的研究职业发展计划，重点是确定 基于医院的生物库中的个体，其基因组变异与未诊断的可治疗的遗传病相关， 紊乱拟议的研究建立在我以前的研究和临床经验的基础上，需要 掌握与识别有单基因疾病风险的个体相关的新技能， 人口。我组建了一个国际知名的导师团队，他们的专业领域涵盖 基因组学研究和医学的几个领域。我的导师包括罗伯特绿色博士，他是一位 医学，行为和经济成果与实施基因组医学;博士。 Heidi雷姆，变异治疗和基因-疾病关系专家; Pradeep Natarajan博士， 计算和整合基因组学专家。通过建议的研究和培训，我将开发 跨学科的技能，使我能够过渡到独立作为一个物理学家，科学家。 尽管单基因遗传性疾病在个别情况下很少见，但估计它们总共影响1.5-6.2% 全球人口。大多数患有遗传疾病的人在发展后都会接受医疗护理。 在漫长而昂贵的诊断之旅后接受诊断。的数量 随着可治疗的遗传疾病的增加，早期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”，提供了一个机会， 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，目前对有遗传风险的个体的发病率和健康结果知之甚少 变种人。在这个项目中，我建议：1）确定个人的患病率 一系列可治疗的单基因疾病的风险变异， 生物样本库（MGBB）和英国生物库（UKB），2）MGBB中具有基因型的再接触个体 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中的代谢谱是否可用于预测个体中的结果 与IMD子集的风险变量。这项工作是朝着确定最佳使用 基因组第一医学，最终加速获得基因组风险分层，适当的后续行动， 正交试验和照顾患有罕见遗传疾病的人。