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.

项目概要线粒体疾病是一种常见的遗传性疾病，发病率为 1/5000，可影响每个人器官系统，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、慢性进行性外部眼肌麻痹（CPEO）和肌张力低下。最常导致儿童期发病的线粒体疾病来自核基因组的突变；然而，大多数病例仍然没有进行分子诊断并且没有有效的治疗方法，因此强调迫切需要确定驱动这些疾病的遗传畸变失调。我们提出了一种结合全基因组测序的个性化功能基因组学方法，细胞中的转录组学、代谢组学和线粒体功能分析，以鉴定经过验证的新型药物线粒体疾病基因和变异。我们将利用多组学策略来识别致病基因并阐明病理机制：1.对患者进行全基因组测序并结合转录组学和代谢组学 2. 基于细胞的基因和通路的功能研究患者。通过我们的国际合作者网络，我们收集了患有临床症状的患者确诊为原发性线粒体脑病，但未进行分子诊断。对于以下患者已经进行了 WES/WGS，但没有分子诊断，我们将重新解释这些数据并利用我们的解释超出 ABMGG 诊断指南的能力。此外，我们还同时努力确定通过贝勒遗传学诊断实验室临床外显子组数据库的数据挖掘得出疾病基因其中已知对线粒体功能至关重要但尚未被证明的基因分析患者的致病突变。基因因果关系将通过一系列的决定基于细胞的线粒体功能分析疾病模型实验，包括基因策略敲低、高通量诱变敲入和 cDNA 互补研究。我们将利用这个用于测试我们测序工作中确定的具有不确定意义的变体的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信息。这项工作将生成细胞线粒体功能和功能的系统分析的前所未有的资源证实了致病性分子缺陷。这些致病基因和变异的阐明将立即提高疑似线粒体疾病儿童的分子诊断潜力。此外，通过鉴定原发性线粒体脑病的致病基因，我们将增强科学界专注于神经系统和神经退行性疾病，这些疾病具有更复杂的病因学，通过提供基因和途径进一步研究这些全球性的发病机制健康问题。