Individual genomic analyses to discover the molecular basis and mechanisms contributing to adult-onset disease

个体基因组分析以发现导致成人发病的疾病的分子基础和机制

• 批准号: 10089222
• 负责人: Jennifer Ellen Posey
• 金额: $ 16.62万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10089222
• 关键词: 18 year old; Active Learning; Address; Adult; Advisory Committees; Affect; Agreement; Alleles; American; Atherosclerosis Risk in Communities; BMPR2 gene; Bioinformatics; Blood; Candidate Disease Gene; Cardiopulmonary; Chad; Childhood; Clinical; Clinical Data; Collection; Complex; Computing Methodologies; Constitutional; Copy Number Polymorphism; DNA; Data; Data Set; Development; Development Plans; Diagnosis; Diagnostic; Disease; Doctor of Medicine; Doctor of Philosophy; Educational workshop; Enrollment; Ensure; Environment; Environmental Exposure; Ethics; Etiology; Evaluation; Event; Exclusion Criteria; Familial disease; Family; Family history of; Family member; Foundations; Functional disorder; Funding; Gene Frequency; Genes; Genetic; Genetic Diseases; Genetic Predisposition to Disease; Genetic Variation; Genomic medicine; Genomics; Goals; Grant; Heterogeneity; Human; Individual; Inherited; Institution; Internal Medicine; International; Internist; Journals; K-Series Research Career Programs; Knowledge; Laboratories; Laboratory Research; Lead; Leadership; Malignant Childhood Neoplasm; Maps; Measurement; Medical Genetics; Medicine; Mendelian disorder; Mentors; Mentorship; Minor; Modeling; Molecular; Molecular Diagnosis; Molecular Medicine; Mosaicism; Mutation; Nature; Nucleotides; Onset of illness; Parents; Pathogenicity; Patient Recruitments; Patients; Phenotype; Physicians; Play; Population; Positioning Attribute; Postural Orthostatic Tachycardia Syndrome; Publications; Pulmonary artery structure; Recording of previous events; Recurrence; Reporting; Research; Research Personnel; Research Training; Resources; Risk; Role; SNP array; Saliva; Sampling; Scientist; Study models; Syndrome; Technology; Tilt-Table Test; Time; Training; Variant; Vocational Guidance; Writing; base; bioinformatics tool; career; career development; clinical investigation; clinical practice; clinically relevant; cohort; de novo mutation; design; exome; exome sequencing; experience; gene discovery; genetic architecture; genetic epidemiology; genetic information; genetic linkage analysis; genetic pedigree; genetic testing; genome analysis; genome-wide; genomic data; genomic variation; human disease; inclusion criteria; individualized medicine; insertion/deletion mutation; interest; laboratory experience; medical specialties; meetings; novel; patient population; patient subsets; personalized medicine; precision medicine; pressure; proband; pulmonary arterial hypertension; recruit; research and development; research clinical testing; research study; skills; success; trait; tumor

PROJECT SUMMARY The proposal describes a five-year mentored laboratory training experience designed to lead to an independent academic career in genomic medicine. The applicant holds M.D. and Ph.D. degrees, and is certified by the American Board of Internal Medicine and American Board of Medical Genetics and Genomics. The applicant seeks to become a human geneticist and to make significant contributions to the field of personalized medicine within the adult patient population. The applicant’s long-term goal is to practice as a physician scientist with an independently funded laboratory at an academic institution. The proposed research builds upon skills developed during the applicant’s prior research and training. The applicant has built a career development and research plan that will form a foundation for her transition to an independent position. The first 2 years of the career development award will focus on formal coursework, patient recruitment, and phenotyping. The final 3 years of the career development award will focus on implementation of skills attained and analysis of genomic data. Discoveries during this time will form the foundation of an R01 proposal. The career development plan includes training designed to broaden the applicant’s scientific skillset, including coursework in statistical genetics, bioinformatics, and genetic epidemiology, as well as training that will prepare her in leadership, mentorship, grant writing, and the ethical implications of genomic research. Implementation of these skills within her research plan will enable experiential learning. Seminars, grant- writing workshops, journal clubs, laboratory and research meetings, and presentations at national and international meetings will provide additional opportunities to develop and strengthen skills. The mentor, Dr. James R. Lupski, is a leader in the field of genomic medicine, with >500 publications to date and a superb record of training physician scientists. The proposed advisory committee includes Dr. Suzanne Leal, Dr. David Wheeler, Dr. Sharon Plon, and Dr. Chad Shaw, all experts in their relative fields who will provide scientific and career guidance and oversee development of the proposed skillsets. The mentor and advisory committee will meet regularly with the applicant to ensure that scientific and career development goals are being met, and to offer their individual expertise relevant to the proposed research. The research environment provides an outstanding intellectual environment, and state-of-the-art genomic sequencing and analysis technology will be available to the applicant. The institution and the department are fully committed to the applicant’s success. The proposed research seeks to identify the genetic architecture underlying adult-onset disease. The applicant proposes that the molecular contribution to adult disease is not fully understood, and that a significant proportion of adult-onset disease is caused by germline or de novo mutational events and unrecognized by conventional clinical evaluation. Postural orthostatic tachycardia syndrome (POTS) and BMPR2-negative pulmonary artery hypertension (PAH) will be used as models for study of adult-onset disease. A subset of patients with PAH and POTS have multiple affected family members providing support for a genetic etiology for their disease. A combination of linkage analysis and whole exome sequencing will be used to identify novel disease genes in these families. This research will identify novel disease genes for PAH and POTS and will also provide the applicant an opportunity to utilize new skills in statistical genetics as part of the analytic approach. Many individuals with PAH or POTS do not have affected relatives, and are thus thought to be ‘sporadic’ cases. Typically in these sporadic cases, single gene disorders are not thought to underlie the patient’s disease. However, recent studies have demonstrated that new mutations (‘de novo’) can contribute to disease in adult patients with apparently sporadic disease. The applicant seeks to determine the role of such new mutations in PAH and POTS patients who have no affected relatives. The proposed research will involve analysis of whole exome sequencing data from patients and their unaffected parents to identify new mutations not present in either parent. This analysis will utilize computational methods developed in the mentor’s lab, and will provide the applicant an opportunity to the bioinformatic skills gained during formal training early in the career development award. This research will inform the field’s approach to the evaluation of patients with sporadic disease across all specialties and will inform the understanding of the nature of the genetic contribution to adult-onset disease. The proposed research will occur in an environment dedicated to the career development of the applicant to become an independent physician scientist and leader in the field of genomic medicine.

项目概要 该提案描述了为期五年的指导实验室培训经验，旨在引导 申请人拥有基因组医学领域的独立学术生涯。 经美国内科医学委员会和美国医学遗传学和基因组学委员会认证。 申请人寻求成为一名人类遗传学家并为该领域做出重大贡献 申请人的长期目标是在成年患者群体中进行个性化医疗。 在学术机构拥有独立资助的实验室的医师科学家所提议的研究。 以申请人之前的研究和培训中培养的技能为基础。申请人已经建立了自己的职业生涯。 开发和研究计划将为她过渡到独立职位奠定基础。 职业发展奖的前两年将重点关注正式课程、患者招募和 职业发展奖的最后三年将重点关注所获得的实施技能。 在此期间的发现将构成 R01 提案的基础。 职业发展计划包括旨在扩大申请人科学技能的培训， 包括统计遗传学、生物信息学和遗传流行病学的课程，以及培训 将为她提供领导力、指导、资助写作以及基因组研究的伦理影响方面的准备。 在她的研究计划中实施这些技能将使体验式学习成为可能。 写作研讨会、期刊俱乐部、实验室和研究会议以及在国家和地区的演讲 国际会议将提供额外的机会来发展和加强技能。 James R. Lupski 是基因组医学领域的领导者，迄今为止已发表超过 500 篇论文，并拥有出色的研究成果 拟议的咨询委员会包括 Suzanne Leal 博士、David 博士。 惠勒 (Wheeler)、莎伦·普隆 (Sharon Plon) 博士和查德·肖 (Chad Shaw) 博士都是各自相关领域的专家，他们将提供科学和 导师和咨询委员会将提供职业指导并监督拟议技能的发展。 定期与申请人会面，以确保实现科学和职业发展目标，并 提供与拟议研究相关的个人专业知识 研究环境提供了一个机会。 卓越的智力环境和最先进的基因组测序与分析技术 该机构和部门完全致力于申请人的成功。 拟议的研究旨在确定成人发病疾病的遗传结构。 申请人提出，对成人疾病的分子贡献尚未完全了解，并且显着 成人发病的疾病的比例是由种系或从头突变事件引起的，并且未被识别 常规临床评估：体位性心动过速综合征 (POTS) 和 BMPR2 阴性。 肺动脉高压（PAH）将用作研究成人发病疾病的模型。 PAH 和 POTS 患者有多个受影响的家庭成员，为 PAH 和 POTS 的遗传病因提供支持 他们的疾病将结合连锁分析和全外显子组测序来鉴定。 这项研究将鉴定出 PAH 和 POTS 的新疾病基因，并将 还为申请人提供了利用统计遗传学新技能作为分析的一部分的机会 方法。 许多患有 PAH 或 POTS 的人没有受影响的亲属，因此被认为是 “散发”病例 通常，在这些散发病例中，单基因疾病不被认为是该疾病的基础。 然而，最近的研究表明，新的突变（“从头”）可能有助于改善患者的疾病。 申请人试图确定这种作用对于患有明显散发性疾病的成年患者的作用。 拟议的研究将涉及没有受影响亲属的 PAH 和 POTS 患者的新突变。 分析患者及其未受影响父母的全外显子组测序数据，以识别新突变 该分析将利用导师实验室开发的计算方法， 并将为申请人提供在早期正式培训期间获得的生物信息技能的机会 职业发展奖。 这项研究将为该领域评估散发性疾病患者的方法提供信息 所有专业，并将有助于了解遗传对成人发病疾病的影响的本质。 拟议的研究将在致力于申请人职业发展的环境中进行 成为一名独立的医师科学家和基因组医学领域的领导者。

项目成果

A comprehensive clinical and genetic study in 127 patients with ID in Kinshasa, DR Congo.

对刚果民主共和国金沙萨 127 名智力障碍患者进行的综合临床和基因研究。

• 发表时间: 2018
• 作者: Lumaka, Aimé;Race, Valerie;Peeters, Hilde;Corveleyn, Anniek;Coban;Jhangiani, Shalini N;Song, Xiaofei;Mubungu, Gerrye;Posey, Jennifer;Lupski, James R;Vermeesch, Joris R;Lukusa, Prosper;Devriendt, Koenraad
• 通讯作者: Devriendt, Koenraad

Clinical characterization of individuals with the distal 1q21.1 microdeletion.

具有远端 1q21.1 微缺失的个体的临床特征。

• 发表时间: 2021
• 作者: Edwards, Stacey D;Schulze, Katharina V;Rosenfeld, Jill A;Westerfield, Lauren E;Gerard, Amanda;Yuan, Bo;Grigorenko, Elena L;Posey, Jennifer E;Bi, Weimin;Liu, Pengfei
• 通讯作者: Liu, Pengfei

Clinical, neuroimaging, and molecular spectrum of TECPR2 ‐ associated hereditary sensory and autonomic neuropathy with intellectual disability

TECPR2 的临床、神经影像学和分子谱 - 与智力障碍相关的遗传性感觉和自主神经病

• DOI: 10.1016/j.ijfoodmicro.2024.110621
• 发表时间: 2024-09-14
• 期刊: International journal of food microbiology
• 影响因子: 5.4
• 作者: Sonja Neuser;Barbara Brechmann;G. Heimer;Ines Brösse;S. Schubert;Lauren O'Grady;M. Zech;Siddharth Srivastava;D. Sweetser;Yasemin Dincer;Volker Mall;Juliane Winkelmann;Christian Behrends;Basil T. Darras;Robert J. Graham;P. Jayakar;Barry Byrne;Bat;Aluma;Y. Haberman;A. Szeinberg;H. Aldhalaan;Mais Hashem;Amal Al Tenaiji;O. Ismayl;Asma E. Al Nuaimi;K. Maher;Shahnaz Ibrahim;F. Khan;H. Houlden;S. Ramakumaran;T. Pagnamenta;J. Posey;J. R. Lupski;Wen;Hann Tan;G. Elghazali;Isabella Herman;Tatiana Muñoz;G. Repetto;Angelika Seitz;M. Krumbiegel;M. Poli;U. Kini;S. Efthymiou;Jens Meiler;R. Maroofian;F. Alkuraya;R. Jamra;B. Popp;Bruria Ben;Zeev;Darius Ebrahimi;Fakhari
• 通讯作者: Fakhari

Detection of mosaic and population-level structural variants with Sniffles2.

使用 Sniffles2 检测镶嵌和群体水平的结构变异。

• 发表时间: 2024-01-02
• 影响因子: 46.9
• 作者: Smolka, Moritz;Paulin, Luis F;Grochowski, Christopher M;Horner, Dominic W;Mahmoud, Medhat;Behera, Sairam;Kalef;Gandhi, Mira;Hong, Karl;Pehlivan, Davut;Scholz, Sonja W;Carvalho, Claudia M B;Proukakis, Christos;Sedlazeck, Fritz J
• 通讯作者: Sedlazeck, Fritz J

Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions.

来自一大群具有不同疑似孟德尔条件的三人组的外显子组中的低水平亲代体细胞嵌合 SNV。

• 发表时间: 2020
• 作者: Gambin, Tomasz;Liu, Qian;Karolak, Justyna A;Grochowski, Christopher M;Xie, Nina G;Wu, Lucia R;Yan, Yan Helen;Cao, Ye;Coban Akdemir, Zeynep H;Wilson, Theresa A;Jhangiani, Shalini N;Chen, Ed;Eng, Christine M;Muzny, Donna;Posey, Jennifer E;Yan
• 通讯作者: Yan