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.

项目总结 该提案描述了一项为期五年的有指导的实验室培训经验，旨在 独立从事基因组医学的学术工作。申请人拥有医学博士和博士学位，并且是 由美国内科委员会和美国医学遗传学和基因组委员会认证。 申请者寻求成为一名人类遗传学家，并对人类遗传学家领域做出重大贡献 成人患者群体中的个性化药物。申请者的长期目标是作为一名 在学术机构拥有独立资助的实验室的内科科学家。拟议的研究 建立在申请者之前的研究和培训过程中发展起来的技能。申请者已经建立了自己的事业 将为她过渡到独立职位奠定基础的发展和研究计划。这个 职业发展奖的头两年将重点放在正式课程工作、患者招聘和 表型鉴定。职业发展奖的最后三年将侧重于所获得的技能的实施 以及基因组数据的分析。这段时间内的发现将构成R01提案的基础。 职业发展计划包括旨在扩大申请者科学技能的培训， 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 将使她在领导力、指导、拨款撰写和基因组研究的伦理影响方面做好准备。 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。研讨会、补助金- 写作研讨会、期刊俱乐部、实验室和研究会议，以及在国家和 国际会议将提供更多发展和加强技能的机会。这位导师，Dr。 James R.Lupski是基因组医学领域的领导者，到目前为止已发表了500种出版物， 培养内科科学家的记录。拟议的咨询委员会包括Suzanne Leal博士、David博士 惠勒、莎伦·普隆博士和查德·肖博士，他们都是相关领域的专家，他们将提供科学和 职业指导和监督拟议技能的发展。导师和咨询委员会将 定期与申请者会面，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 卓越的智力环境和最先进的基因组测序和分析技术将是 可供申请人使用。该机构和部门将全力支持申请者取得成功。 这项拟议的研究试图确定成人发病疾病背后的遗传结构。这个 申请人提出，分子对成人疾病的贡献还没有完全被理解，而且一个重要的 成人发病疾病的比例是由生殖系或从头开始的突变事件引起的，并且没有被 常规临床评价。体位直立性心动过速综合征(POTS)与BMPR2阴性 肺动脉高压(PAH)将被用作成人发病研究的模型。的子集 患有PAH和POTS的患者有多个受影响的家庭成员，为其遗传病因提供支持 他们的病。将使用连锁分析和整个外显子组测序相结合的方法来鉴定新的 这些家族中的疾病基因。这项研究将确定PAH和POTS的新疾病基因，并将 也为申请者提供了利用统计遗传学的新技能作为分析的一部分 接近。 许多患有PAH或POTS的人没有受影响的亲属，因此被认为是 “零星”病例。通常，在这些零星病例中，单基因疾病不被认为是导致 病人的疾病。然而，最近的研究表明，新的突变(从头开始)可以起到作用 在成年患者中有明显的散发性疾病。申请者试图确定这种角色 没有受影响亲属的PAH和POTS患者的新突变。拟议的研究将涉及 分析患者及其未患病父母的全部外显子组测序数据以确定新的突变 双亲中都不存在的。这项分析将利用导师实验室开发的计算方法， 并将为申请者提供在早期正式培训期间获得的生物信息学技能的机会 职业发展奖。 这项研究将为实地评估散发性疾病患者的方法提供信息 所有专科，并将有助于了解成人发病的遗传因素的性质。 建议的研究将在一个致力于申请者职业发展的环境中进行 成为基因组医学领域的独立内科医生、科学家和领导者。

项目成果

Retrospective analysis of a clinical exome sequencing cohort reveals the mutational spectrum and identifies candidate disease-associated loci for BAFopathies.

• DOI: 10.1016/j.gim.2021.09.017
• 发表时间: 2022-03
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Chen CA;Lattier J;Zhu W;Rosenfeld J;Wang L;Scott TM;Du H;Patel V;Dang A;Magoulas P;Streff H;Sebastian J;Svihovec S;Curry K;Delgado MR;Hanchard NA;Lalani S;Marom R;Madan-Khetarpal S;Saenz M;Dai H;Meng L;Xia F;Bi W;Liu P;Posey JE;Scott DA;Lupski JR;Eng CM;Xiao R;Yuan B
• 通讯作者: Yuan B

Clinical presentation and evolution of Xia-Gibbs syndrome due to p.Gly375ArgfsTer3 variant in a patient from DR Congo (Central Africa).

• DOI: 10.1002/ajmg.a.62049
• 发表时间: 2021-03
• 期刊: American journal of medical genetics. Part A

Congenital diaphragmatic hernia as a prominent feature of a SPECC1L-related syndrome.

• DOI: 10.1002/ajmg.a.61878
• 发表时间: 2020-12
• 期刊: American journal of medical genetics. Part A
• 作者: Wild KT;Gordon T;Bhoj EJ;Du H;Jhangiani SN;Posey JE;Lupski JR;Scott DA;Zackai EH
• 通讯作者: Zackai EH

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

• DOI: 10.1038/s41436-020-0897-z
• 发表时间: 2020-11
• 期刊: Genetics in medicine : official journal of the American College of Medical Genetics
• 作者: Gambin T;Liu Q;Karolak JA;Grochowski CM;Xie NG;Wu LR;Yan YH;Cao Y;Coban Akdemir ZH;Wilson TA;Jhangiani SN;Chen E;Eng CM;Muzny D;Posey JE;Yang Y;Zhang DY;Shaw C;Liu P;Lupski JR;Stankiewicz P
• 通讯作者: Stankiewicz P

PhenoDB, GeneMatcher and VariantMatcher, tools for analysis and sharing of sequence data.

• DOI: 10.1186/s13023-021-01916-z
• 发表时间: 2021-08-18
• 期刊: Orphanet journal of rare diseases
• 影响因子: 3.7
• 作者: Wohler E;Martin R;Griffith S;Rodrigues EDS;Antonescu C;Posey JE;Coban-Akdemir Z;Jhangiani SN;Doheny KF;Lupski JR;Valle D;Hamosh A;Sobreira N
• 通讯作者: Sobreira N