Precision Genomic Medicine in The Plain Communities and its Impact on The Plain and General Population

平原社区的精准基因组医学及其对平原和普通人群的影响

• 批准号: 10200113
• 负责人: Lina Ghaloul-Gonzalez
• 金额: $ 18.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10200113
• 关键词: Americas; Amish; Apoptosis; Ataxia; Binding Proteins; Bioinformatics; Cardiac Myocytes; Cardiomyopathies; Caring; Cell Line; Cells; Chronic Childhood Arthritis; Chronic diarrhea; Clinical; Communities; Community Outreach; Computer software; Consent; Cytoskeleton; Development; Development Plans; Diagnosis; Dilatation - action; Dilated Cardiomyopathy; Disease; Educational Materials; Embryonic Heart; Emigrations; Etiology; Extended Family; Family; Founder Generation; Gene Expression; Gene Mutation; General Population; Genes; Genetic; Genetic Diseases; Genetic Drift; Genetic Risk; Genetic study; Genomics; Geography; Goals; Health; Healthcare; Hereditary Disease; Home; Human; Immunologic Deficiency Syndromes; In Vitro; Inbreeding; Individual; Institutes; Intestines; Knockout Mice; Knowledge; Learning; Link; Marriage; Medical; Mennonite; Mentors; Metabolic; Microtubule Bundle; Microtubules; Mitochondria; Mitochondrial Diseases; Movement; Mutation; North America; Nuclear Family; Parents; Pathogenicity; Pathway Analysis; Patient-Focused Outcomes; Patients; Pediatric Hospitals; Pennsylvania; Phenotype; Population; Population Genetics; Positioning Attribute; Prevalence; Rattus; Reporting; Research; Risk; Running; Siblings; Sociology; Syndrome; Technology; Testing; Training; Translational Research; Variant; Work; adenylate kinase; base; bioinformatics tool; burden of illness; career; career development; cost; cost effective; crosslink; exome sequencing; genetic analysis; genetic disorder diagnosis; genetic makeup; genetic testing; genetic variant; health care availability; improved; medically underserved population; mitochondrial DNA mutation; mitochondrial dysfunction; mutant; neonatal mice; novel; outreach clinics; overexpression; patient population; personalized medicine; population health; precision genomic medicine; programs; protein protein interaction; rare genetic disorder; recruit; research clinical testing; skills; tool; translational genomics; translational research program; ubiquitin-protein ligase

Abstract The Plain populations (Amish and Mennonites) originated from founder populations with subsequent genetic bottlenecks and genetic drift; leading to a loss of diversity and an altered genetic disease burden. The Western PA Plain people are among the least genetically characterized Plain communities in the US. This application proposes to use Whole Exome Sequencing (WES) to identify novel genetic disorders in this population. Due to the Plain Populations loss of population genomic complexity, inbreeding, and sociologic isolation, many of the genetic disorders are inherited in autosomal recessive fashion due to homozygous mutations. This genetic makeup as well as the large families will facilitate WES analysis to find candidate variants that can potentially be pathogenic causes of diseases. A multitude of genetic diseases are characterized in the Plain population, and this proposed study will identify additional diseases, enabling a community-centric personalized medicine approach to care based on individual genetic risk. In addition, knowledge of genetic disorders originally developed through study of the Plain Populations, can subsequently be applied in the general population. The central hypothesis is that the Amish and Mennonite communities will allow the identification of novel genetic disorders/pathogenic variants of relevance to the Plain communities, and ultimately the general population. The following aims are proposed: (1) Identification of novel genetic disorders/ disease-causing variants in the Plain communities. The hypothesis is that genetics studies of the Western PA Plain people using WES will allow for continued characterization of novel genetic disorders/pathogenic variants that are relevant to both the Plain and general populations. (2) Performing functional studies for a novel genetic disorder causing dilated cardiomyopathy (DCM). The hypothesis is that the MTCL1 variant (c.82C>G;p.His28Asp) is pathogenic and MTCL1 gene mutations are novel cause of DCM. The candidate is firmly committed to a career in translational genomics research and its implications on the Plain and General populations. She has already worked within the Plain communities, proving her ability to connect with and perform research within these culturally distinct groups. These connections, and her research focus on translational research using WES as a diagnosis tool with functional studies when needed, have already led to the discovery of several mitochondrial disorders and an AK2 gene mutation as a cause of an immunodeficiency with a novel phenotype in the Amish. The primary sponsor is a world recognized expert in the field of Genetics with an outstanding track record of training and with a great working relationship with the candidate. The candidate has developed a comprehensive career development plan to improve her bioinformatics and WES analysis skills, and will learn to perform functional studies related to cardiomyopathy.

抽象的 普通人群（阿米什人和门诺人）起源于创始人人群，随后遗传 瓶颈和遗传漂移；导致多样性丧失和遗传疾病负担改变。西方 PA普通人是美国遗传特征最少的普通社区之一。此应用程序 建议使用整个外显子组测序（WES）鉴定该人群中的新遗传疾病。由于 人口基因组复杂性，近交和社会学隔离的普通人群丧失，许多人的丧失 由于纯合突变，遗传疾病以常染色体隐性方式遗传。这个遗传 化妆以及大家庭将促进WES分析，以找到可能是可能是的候选变异者 疾病的致病原因。在普通人群中表征了多种遗传疾病，并且 这项拟议的研究将确定其他疾病，使以社区为中心的个性化医学 基于个人遗传风险的护理方法。此外，对遗传疾病的了解最初是 通过对普通人群的研究开发，随后可以应用于一般人群中。这 中心假设是阿米什人和门诺派社区将允许鉴定新的遗传 与普通社区及其一般人群相关的疾病/致病变异。这 提出了以下目的：（1）鉴定普通的新型遗传疾病/引起疾病的变体 社区。假设是，使用WES对西部PA普通人的遗传学研究将允许 与普通和平原相关的新型遗传疾病/致病变异的持续表征 一般人群。 （2）对新型遗传疾病进行功能研究，导致扩张 心肌病（DCM）。假设是MTCL1变体（c.82c> g; p.his28asp）是致病性的，并且 MTCL1基因突变是DCM的新原因。候选人坚定地致力于转化职业 基因组学研究及其对普通和普通人群的影响。她已经在里面工作了 平原社区，证明了她在这些文化上与众不同的研究能力 组。这些联系以及她的研究重点是使用WES作为诊断工具的转化研究 在需要时进行功能研究，已经导致发现了几种线粒体疾病， AK2基因突变是Amish中具有新表型的免疫缺陷的原因。主要 赞助商是遗传学领域的全球知名专家，并具有出色的培训记录，并与 与候选人建立了良好的工作关系。候选人发展了全面的职业 开发计划以提高她的生物信息学和WES分析技能，并将学会执行功能 与心肌病有关的研究。