Improving Strategies to Determine Pathogenicity of Variants of Uncertain Significance

项目总结/摘要 该申请提出了一个为期四年的指导研究和培训经验，旨在推动 候选人作为基因组医学领导者的职业生涯。该候选人获得了分子生物学的MD/PhD 和人类遗传学，并在儿科委员会认证。他的长期职业目标是成为一名 独立资助的物理学家，科学家在一个主要的学术中心，并推进研究工作， 整合翻译基因组学和创新策略以确定错义变异体致病性 目前被归类为不确定意义的变体（VUS）。拟议的工作利用技能， 在之前的培训和研究中开发的，并将构成成功的R 01提案的基础。职业 发展计划包括生物医学信息学的里程碑式培训（包括授予 硕士学位）、统计学以及功能基因组学实验的设计和实施。的 候选人将接受道德和负责任的研究行为，沟通技巧，补助金 通过参加核心课程、讲习班、研讨会、实验室 会议，以及地方，国家和国际演讲。为拟议的 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。的 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，迈克尔省，克里斯蒂娜Gurnett博士， 和大卫莱德贝特，每个人都带来了独特的专业知识和承诺，候选人的成功。额外 师友关系咨询委员会的成员包括候选人的长期导师F。S.科尔 还有约翰·康斯坦蒂诺和神经纤维瘤病专家大卫·古特曼博士。华盛顿大学 医学（WUSM）提供了一个特殊的研究和培训环境，包括来自 麦克唐纳基因组研究所和信息学研究所。这位候选人得到了 儿科系，在培养医生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，以确定错义变体的致病性 目前被归类为不确定意义的变体（VUS），和2）外显子组测序和连锁 来自超过90，000人的电子健康记录数据用于临床验证。研究充分的NF 1肿瘤 抑制基因将作为发展变异解释最佳实践的模型。这项工作将 直接影响NF 1相关疾病患者的评估和护理，并将作为 为一系列疾病建立类似的模型。候选人，他的导师，部门和WUSM 致力于使他成为一名独立的医生科学家和基因组医学的领导者。

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.