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: 10657596
• 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/10657596
• 关键词: Amish; Apoptosis; Ataxia; Binding Proteins; Bioinformatics; Cardiac Myocytes; Cardiomyopathies; Caring; Cell Line; Cells; Chronic Childhood Arthritis; Chronic diarrhea; Clinical; Communities; 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; Heterozygote; Home; Human; Immunologic Deficiency Syndromes; In Vitro; Inbreeding; Individual; 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; Persons; Phenotype; Population; Population Genetics; Population Study; Positioning Attribute; Prevalence; Rattus; Reporting; Research; Risk; Running; Siblings; Sociology; Syndrome; Technology; Testing; Training; Translational Research; Variant; Work; adenylate kinase; autosome; 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.

摘要 平原人口（阿米什人和门诺派）起源于创始人人口，随后的遗传 瓶颈和遗传漂变;导致多样性的丧失和遗传疾病负担的改变。西部 PA平原人是美国遗传特征最少的平原社区之一。本申请 建议使用全外显子组测序（WES）来鉴定该人群中的新型遗传疾病。由于 平原种群由于种群基因组复杂性的丧失、近亲繁殖和社会隔离， 遗传性疾病由于纯合突变而以常染色体隐性方式遗传。这种遗传 组成以及大家族将有助于WES分析，以找到可能被 疾病的致病原因。许多遗传性疾病的特点是在平原人口， 这项拟议中的研究将确定其他疾病，从而实现以社区为中心的个性化医疗 基于个体遗传风险的护理方法。此外，遗传疾病的知识最初 通过对平原人群的研究而开发的，随后可以应用于一般人群。的 中心假设是，阿米什人和门诺派社区将允许识别新的遗传 与平原社区相关的疾病/致病性变体，并最终与普通人群相关。的 提出了以下目标：（1）在平原地区鉴定新的遗传性疾病/致病变体 社区.假设是，使用WES的西PA平原人的遗传学研究将允许 继续表征与普通和 一般人群。(2)对一种新的遗传性疾病进行功能研究， 心肌病（DCM）。假设MTCL 1变体（c.82C>G;p.His28Asp）是致病性的， MTCL 1基因突变是DCM的新病因。候选人坚定地致力于翻译事业 基因组学研究及其对平原和普通人群的影响。她已经在 平原社区，证明她有能力与这些文化上不同的社区建立联系并进行研究。 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， 一种AK 2基因突变，是阿米什人中具有新表型的免疫缺陷的原因。主 赞助商是世界公认的遗传学领域的专家，具有出色的培训记录， 与候选人保持良好的工作关系。候选人已经发展了全面的职业生涯 发展计划，以提高她的生物信息学和WES分析技能，并将学习执行功能 与心肌病有关的研究。

项目成果

Clinical case report of intractable paroxysmal sympathetic hyperactivity in TANGO2 deficiency disorder.

• DOI: 10.1002/ajmg.a.63633
• 发表时间: 2024-04
• 期刊: American journal of medical genetics. Part A
• 作者: Kaitlin Morrison;Hitoshi Koshiya;R. Safier;Amanda Brown;Carol May;J. Vockley;Lina Ghaloul-Gonzalez

Under-referral of Plain community members for genetic services despite being qualified for genetic evaluation.

尽管有资格获得遗传评估，但普通社区成员的转诊率是基因服务。

• DOI: 10.1002/jgc4.1395
• 发表时间: 2021-08
• 期刊: Journal of genetic counseling
• 影响因子: 1.9
• 作者: Ehrenberg S;Walsh Vockley C;Nelson E;Baker J;Arcieri M;Lindenberger J;Ghaloul-Gonzalez L
• 通讯作者: Ghaloul-Gonzalez L

Novel GUCY2C variant causing familial diarrhea in a Mennonite kindred and a potential therapeutic approach.

• DOI: 10.1002/ajmg.a.62207
• 发表时间: 2021-07
• 期刊: American journal of medical genetics. Part A
• 作者: Wolfe RM;Mohsen AW;Walsh Vockley C;Bertrand CA;Nicholls RD;Heiman P;Seibold LM;Vockley J;Ghaloul-Gonzalez L
• 通讯作者: Ghaloul-Gonzalez L

Natural history of propionic acidemia in the Amish population.

• DOI: 10.1016/j.ymgmr.2022.100936
• 发表时间: 2022-12
• 期刊: MOLECULAR GENETICS AND METABOLISM REPORTS
• 影响因子: 1.9
• 作者: Ehrenberg, Sarah;Vockley, Catherine Walsh;Heiman, Paige;Ammous, Zineb;Wenger, Olivia;Vockley, Jerry;Ghaloul-Gonzalez, Lina
• 通讯作者: Ghaloul-Gonzalez, Lina

ITCH deficiency clinical phenotype expansion and mitochondrial dysfunction.

• DOI: 10.1016/j.ymgmr.2022.100932
• 发表时间: 2022-12
• 期刊: MOLECULAR GENETICS AND METABOLISM REPORTS
• 影响因子: 1.9
• 作者: Wolfe, Rachel;Heiman, Paige;D'Annibale, Olivia;Karunanidhi, Anuradha;Powers, Alyssa;Mcguire, Marianne;Seminotti, Bianca;Dobrowolski, Steven F.;Reyes-Mugica, Miguel;Torok, Kathryn S.;Mohsen, Al-Walid;Vockley, Jerry;Ghaloul-Gonzalez, Lina
• 通讯作者: Ghaloul-Gonzalez, Lina