Personalized Functional Genomics for Mitochondrial Encephalopathy Gene Discovery

线粒体脑病基因发现的个性化功能基因组学

基本信息

批准号：
10582623
负责人：
Penelope E Bonnen
金额：
$ 65.92万
依托单位：
BAYLOR COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-20 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10582623
关键词：
Affect Area Ataxia Automobile Driving Bioinformatics Biological Biological Assay Biological Markers Cell model Cells Child Childhood Chronic Chronic progressive external ophthalmoplegia Clinical Communities Complement Complementary DNA Complex Consensus Coupled DNA DNA sequencing Data Data Analyses Data Security Data Set Databases Defect Development Diagnosis Diagnostic Disease Disease model Electron Transport Encephalopathies Etiology Evaluation Exhibits Experimental Models Functional disorder Genes Genetic Genome Genomic approach Guidelines Huntington Disease Incidence Individual Inherited International Knock-in Laboratories Lentivirus Vector Measures Membrane Potentials Mitochondria Mitochondrial DNA Mitochondrial Diseases Molecular Molecular Diagnosis Multiomic Data Muscle hypotonia Mutagenesis Mutation Nerve Degeneration Neurodegenerative Disorders Neurologic Nuclear Ontology Parkinson Disease Pathogenesis Pathogenicity Pathology Pathway interactions Patients Phenotype Public Domains RNA Reactive Oxygen Species Resources Seizures Series Software Validation Study Subject System Technology Testing Therapeutic Validation Variant Visualization Work analysis pipeline analytical method analytical tool biobank body system clinical phenotype computational reasoning data integration data mining disease-causing mutation effective therapy empowerment exome experience functional genomics gene discovery genetic variant genome sequencing genome-wide global health heterogenous data human disease improved innovation insight knock-down knowledge base metabolome metabolomics mitochondrial dysfunction mitochondrial membrane molecular diagnostics multiple omics nervous system disorder neuromuscular novel transcriptome sequencing transcriptomics variant of unknown significance virulence gene whole genome

项目摘要

Project Summary Mitochondrial disease is a commonly occurring inherited condition, incidence 1/5000, which can affect every organ system and thus exhibits a broad range of clinical phenotypes. The most common are neurological and neuromuscular dysfunction that manifest as neurodegeneration, seizures, ataxia, chronic progressive external opthalmoplegia (CPEO), and hypotonia. Childhood-onset mitochondrial disease most often results from mutations in the nuclear genome; however, the majority of cases remain without a molecular diagnosis and no effective treatments thus underscoring the critical need to identify the genetic aberrations driving these disorders. We propose a personalized functional genomics approach combining genome-wide sequencing, transcriptomics, metabolomics and mitochondrial functional profiling in cells to identify validated novel mitochondrial disease genes and variants. We will leverage a multi-omic strategy for identifying the pathogenic genes and elucidating pathomechanisms: 1. Genome-wide sequencing of patients coupled with transcriptomics and metabolomics 2. Cell-based functional studies of genes and pathways identified in patients. Through our international network of collaborators we have collected patients with clinically confirmed primary mitochondrial encephalopathy who do not have a molecular diagnosis. For patients who have already had WES/WGS but no molecular diagnosis we will re-interpret these data and leverage our ability to interpret beyond ABMGG guidelines for diagnosis. Additionally, we have a parallel effort to identify disease genes through datamining the clinical exome database at Baylor Genetics diagnostic laboratory wherein genes that are known to be essential for mitochondrial function but are not yet demonstrated as disease causing are analyzed for mutations in patients. Gene causality will be determined through a series of cell-based disease modeling experiments of mitochondrial functional profiling that include strategies of gene knock down, high-throughput mutagenesis knock-in, and cDNA complementation studies. We will utilize this technology to test the functionality of variants of uncertain significance identified in our sequencing efforts as well as those obtained through collaborators, diagnostic laboratories, and the public domain. This work will generate an unprecedented resource of systematic profiling of cellular mitochondrial function and functionally- confirmed pathogenic molecular defects. The elucidation of these pathogenic genes and variants will immediately improve the molecular diagnostic potential for children with suspected mitochondrial disease. Moreover, by identifying the pathogenic genes for primary mitochondrial encephalopathy we will empower the scientific community focused on neurological and neurodegenerative disorders, which have a more complex etiology, by delivering genes and pathways for further study of the pathogenetic mechanisms of these global health problems.

项目摘要线粒体疾病是一种常见的遗传病，发病率为1/5000，可能会影响每一个器官系统，因此表现出广泛的临床表型。最常见的是神经系统和神经肌肉功能障碍表现为神经变性，癫痫发作，共济失调，慢性进行性外毛虫外科（CPEO）和低调。儿童期性线粒体疾病最常见来自核基因组的突变；但是，大多数病例仍没有分子诊断因此，没有有效的治疗方法强调确定驱动这些遗传畸变的迫切需要疾病。我们提出了一种个性化功能基因组学方法，结合了全基因组测序，细胞中的转录组学，代谢组学和线粒体功能分析，以识别经过验证的新型新型线粒体疾病基因和变体。我们将利用一种多功能策略来识别致病基因和阐明病理机制：1。患者的全基因组测序转录组学和代谢组学2。基于细胞的基因和途径的功能研究患者。通过我们的国际合作者网络，我们收集了临床上的患者确认没有分子诊断的原发性线粒体脑病。适用于患者已经有WES/WGS，但是没有分子诊断，我们将重新解释这些数据并利用我们的能够解释ABMGG诊断指南的能力。此外，我们还努力识别疾病基因通过在贝勒遗传学诊断实验室的临床外显子组数据库中进行疾病基因其中所知对于线粒体功能至关重要但尚未证明为必不可少的基因分析引起的疾病的患者突变。基因因果关系将通过一系列线粒体功能分析的基于细胞的疾病建模实验，包括基因策略拆卸，高通量诱变敲入和cDNA互补研究。我们将利用这个测试在我们的测序工作中确定不确定意义的变体功能的技术以及通过合作者，诊断实验室和公共领域获得的。这项工作将生成一个前所未有的细胞线粒体功能系统分析的资源，并在功能上 - 确认的致病分子缺陷。这些致病基因和变体的阐明将立即改善可疑线粒体疾病儿童的分子诊断潜力。此外，通过确定原发性线粒体脑病的致病基因，我们将增强能力科学界关注神经和神经退行性疾病，这些疾病的复杂性更复杂病因，通过传递基因和途径，以进一步研究这些全局的致病机制健康问题。