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

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