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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/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，重点是确定医院生物库中具有与未确诊的可治疗遗传相关的基因组变异的个体拟议的研究建立在我之前的研究和临床经验的基础上，需要掌握与识别未经选择的单基因疾病风险个体相关的新技能我组建了一支国际知名的导师团队，其专业领域涵盖各个领域。我的导师包括基因组学研究和医学的多个领域的专家罗伯特·格林博士。与基因组医学实施相关的医疗、行为和经济成果； Heidi Rehm，变异管理和基因疾病关系专家；Pradeep Natarajan 博士，通过拟议的研究和培训，我将发展成为计算和综合基因组学方面的专家。跨学科技能将使我能够过渡为独立的医师科学家。尽管单基因遗传病个别罕见，但据估计它们共同影响 1.5-6.2% 全球人口中大多数患有遗传疾病的人在发病后就医。经过漫长而昂贵的诊断过程后，才能了解症状并接受诊断。可治疗的遗传疾病不断增加，尽早识别高危个体的需要变得更加紧迫。基于群体的基因组测序，也称为“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体进行遗传性疾病筛查来改善公共卫生结果。然而，目前对具有遗传风险的个体的外显率和健康结果知之甚少在这个项目中，我建议：1）确定患有这种疾病的个体的患病率。麻省总医院布里格姆总医院的一系列可治疗的单基因疾病的风险变异生物银行 (MGBB) 和英国生物银行 (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 中的代谢谱是否可用于预测个体的结果这项工作代表了确定 IMD 最佳用途的一步。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，正交测试以及对患有罕见遗传疾病的人的护理。