Improving Strategies to Determine Pathogenicity of Variants of Uncertain Significance

改进确定意义不确定的变异的致病性的策略

• 批准号: 10328487
• 负责人: Dustin M Baldridge
• 金额: $ 15.62万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10328487
• 关键词: Address; Advisory Committees; Biological Assay; Cells; Child; Childhood; ClinVar; Clinic; Clinical; Collection; Communication; Computing Methodologies; DNA; Data; Data Set; Databases; Development Plans; Diagnosis; Diagnostic; Diagnostic tests; Disease; Doctor of Philosophy; Educational Curriculum; Educational workshop; Electronic Health Record; Environment; Epidemiology; Ethics; Evaluation; Family; Funding; Future; Genes; Genetic Diseases; Genome; Genomic medicine; Genomics; Goals; Grant; Health system; Hospitals; Human Genetics; Impairment; Individual; Industry; Informatics; Institutes; Institution; Insurance; International; K-Series Research Career Programs; Knowledge; Laboratories; Lead; Learning; Link; Malignant Neoplasms; Master' s Degree; Measures; Medical; Mentors; Mentorship; Modeling; Modernization; Molecular; Molecular Genetics; Mutagenesis; NF1 gene; NF1 tumor suppressor; Neurodevelopmental Disorder; Neurofibromatoses; Pain; Pathogenicity; Patient Care; Patients; Pediatrics; Persons; Phenotype; Physicians; Population; Province; Recording of previous events; Reporting; Research; Research Subjects; Research Training; Resources; Risk; Scientist; Sensitivity and Specificity; Signal Transduction; Statistical Models; Testing; Time; Training; Translational Research; Tumor Suppressor Genes; Universities; Ursidae Family; Validation; Variant; Washington; Work; Writing; autism spectrum disorder; base; biomedical informatics; career; career development; clinical phenotype; cohort; computerized tools; cost; design; diagnostic tool; exome; exome sequencing; experience; experimental study; falls; functional genomics; genetic variant; improved; in silico; innovation; medical schools; meetings; member; mutation screening; pediatric department; programs; prospective; responsible research conduct; skills; statistics; success; tool; translational genomics; variant of unknown significance

PROJECT SUMMARY / ABSTRACT The application proposes a four-year mentored research and training experience crafted to advance the candidate’s career as a leader in genomic medicine. The candidate earned a combined MD/PhD in Molecular and Human Genetics and is board certified in Pediatrics. His long-term career goal is to become an independently funded physician-scientist at a major academic center and to advance research efforts that integrate translational genomics with innovative strategies to determine pathogenicity of missense variants currently categorized as variants of uncertain significance (VUS). The proposed work leverages skills he developed during prior training and research and will form the basis for a successful R01 proposal. The career development plan includes milestone-based training in biomedical informatics (including the conferring of a Master’s degree), statistics, and the design and implementation of functional genomics experiments. The candidate will receive training in ethical and responsible conduct of research, communication skills, grant writing, and laboratory management via participation in core curricula, workshops, seminars, laboratory meetings, and local, national, and international presentations. The mentoring team for the proposed interdisciplinary project includes expertise in clinical, statistical, computational, and functional genomics. The primary mentor, Dr. Barak Cohen, is an experienced mentor and an expert in experimental and computational approaches for functional genomics evaluations. The co-mentors, Drs. Michael Province, Christina Gurnett, and David Ledbetter, each bring unique expertise and commitment to the candidate’s success. Additional members of the mentorship advisory committee include the long-term mentors of the candidate, Drs. F. S. Cole and John Constantino, and the neurofibromatosis expert, Dr. David Gutmann. Washington University School of Medicine (WUSM) provides an exceptional research and training environment, including resources from the McDonnell Genome Institute and the Institute for Informatics. The candidate has the full support of the Department of Pediatrics, which has a long history of training physician-scientists. The research proposed addresses a central problem in human genetics today, namely variant interpretation. This work will integrate 1) deep mutational scanning and experimental validation to determine pathogenicity of missense variants currently categorized as variants of uncertain significance (VUS), and 2) exome sequencing and linked Electronic Health Record data from >90,000 individuals for clinical validation. The well-studied NF1 tumor suppressor gene will serve as a model for developing best practices for variant interpretation. The work will directly impact the assessment and care of patients with NF1-related diseases and will serve as a template for generating similar models for a range of diseases. The candidate, his mentors, the Department, and WUSM are committed to his becoming an independent physician-scientist and leader in genomic medicine.

项目概要/摘要 该申请提出了为期四年的指导研究和培训经验，旨在推进 候选人作为基因组医学领导者的职业生涯。候选人获得了分子医学博士学位/博士学位 和人类遗传学，并获得儿科委员会认证。他的长期职业目标是成为一名 在主要学术中心独立资助的医师科学家，并推进研究工作 将翻译基因组学与创新策略相结合，以确定错义变异的致病性 目前被归类为意义不确定的变体（VUS）。拟议的工作利用了他的技能 在之前的培训和研究中开发的，并将构成成功的 R01 提案的基础。职业生涯 发展计划包括基于里程碑的生物医学信息学培训（包括授予 硕士学位）、统计学、功能基因组学实验的设计和实施。这 候选人将接受道德和负责任的研究行为、沟通技巧、资助等方面的培训 通过参与核心课程、讲习班、研讨会、实验室来进行写作和实验室管理 会议以及地方、国家和国际演讲。拟议的指导团队 跨学科项目包括临床、统计、计算和功能基因组学方面的专业知识。这 首席导师 Barak Cohen 博士是一位经验丰富的导师，也是实验和计算方面的专家 功能基因组学评估方法。共同导师，博士。迈克尔省，克里斯蒂娜·古内特， 和大卫·莱德贝特 (David Ledbetter) 都为候选人的成功带来了独特的专业知识和承诺。额外的 导师顾问委员会成员包括候选人的长期导师 Drs. F·S·科尔 约翰·康斯坦丁 (John Constantino) 和神经纤维瘤病专家大卫·古特曼 (David Gutmann) 博士。华盛顿大学学院 医学（WUSM）提供了卓越的研究和培训环境，包括来自 麦克唐纳基因组研究所和信息学研究所。该候选人得到了议会的全力支持 儿科在培养医师科学家方面有着悠久的历史。研究提出 解决了当今人类遗传学的一个核心问题，即变异解释。这项工作将整合 1) 深度突变扫描和实验验证以确定错义变异的致病性 目前被归类为意义不确定的变体 (VUS)，以及 2) 外显子组测序和关联 来自超过 90,000 名个人的电子健康记录数据用于临床验证。经过充分研究的 NF1 肿瘤 抑制基因将作为开发变异解释最佳实践的模型。该工作将 直接影响 NF1 相关疾病患者的评估和护理，并将作为 为一系列疾病生成类似的模型。候选人、他的导师、系和 WUSM 致力于让他成为一名独立的医师科学家和基因组医学领域的领导者。