Combined SNP analysis and whole genome sequencing to discover immunodeficiency ge

结合SNP分析和全基因组测序发现免疫缺陷基因

基本信息

批准号：
8091834
负责人：
RAIF SALIM GEHA
金额：
$ 8.7万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-19 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8091834
关键词：
Affect Animal Model Area Autoimmunity B-Lymphocytes Bacteria Bioinformatics Candidate Disease Gene Cells Childhood Chromosomes, Human, Pair 3 Collaborations Consanguinity Country DNA DNA Viruses Defect Development Diagnosis Disease Eosinophilia Etiology Exons Family Family Study Family member Generations Genes Genetic Genetic Polymorphism Genome Genomics Genotype Goals Hereditary Disease Human IgE Immune system Immunologic Deficiency Syndromes Infection Inherited Knowledge Microarray Analysis Middle East Molecular Mutation Neutropenia Pathogenesis Pathway interactions Patients Pediatric Hospitals Phenotype Population Process RNA Splicing Recurrence Research Single Nucleotide Polymorphism Site Syndrome Technology Testing Therapeutic Thrombocytopenia autosomal recessive trait base cost cost effective disease phenotype exome experience gene discovery genetic analysis genetic pedigree genome sequencing immune function improved mRNA Expression member novel prognostic programs tool

项目摘要

DESCRIPTION (provided by applicant): Primary Immunodeficiency diseases (PIDs) are a heterogeneous group of genetic disorders of that affect the development and/or function of the immune system. The study of PID has helped decipher the cellular and molecular processes that govern immune function. Identification of the genetic defect in PIDs may have prognostic and therapeutic implications. Because most PIDs are inherited as autosomal recessive traits, genetic studies targeted to large consanguineous families are successful in identifying novel gene defects in patients with PIDs that are still genetically undefined, as has been already the case in several disorders. We have established a research network with PID centers in the Middle East and have collected 26 unrelated consanguineous families. In each case, the phenotype is either entirely novel or has been previously described but the known disease-causing gene(s) are intact in sequence and expression. The goal of the proposed research is to test the power of combining Single Nucleotide Polymorphism microarray (SNP) analysis and whole genome sequencing (WGS) to identify novel genes that cause PIDs. Our specific aims are I. Identify the molecular and cellular bases underlying novel PID phenotypes II. Identify the molecular and cellular bases of PID with known phenotypes, but unknown genotype we anticipate that the combination of SNP analysis, WGS and cutting-edge bioinformatics will provide a rapid and cost effective approach to the discovery of novel PID genes. This will pave the way for widespread application of this technology to the study of PIDs and will generate hypotheses on the pathogenesis of PIDs that can be tested in patients and in animal models. The results obtained will be applicable to sporadic cases of PIDs with similar phenotype and will improve our understanding of the human immune system. PUBLIC HEALTH RELEVANCE: Primary Immunodeficiency diseases (PIDs) are a heterogeneous group of genetic disorders of the immune system. Identification of the genetic defect in PIDs may have prognostic and therapeutic implications. PIDs are more common among populations in areas with a high consanguinity rate, and the study of families from such areas has led to identification of several PID causing genes. We have established a research network with PID centers in the Middle East and have collected 26 unrelated consanguineous families of unknown genetic cause. We propose to use cutting edge genetic analysis tools to identify novel genes that cause PIDs. We anticipate that the knowledge gained from the proposed studies will provide a rapid and cost effective approach to the discovery of novel PID genes and will improve our ability to diagnose patients with PIDs in Western countries, where they often present as isolated cases. The results obtained will also enhance our understanding of the human immune system.

描述（由申请人提供）：原发性免疫缺陷疾病（PID）是一组异质的遗传疾病，影响了免疫系统的发展和/或功能。 PID的研究有助于破译控制免疫功能的细胞和分子过程。 PID中遗传缺陷的鉴定可能具有预后和治疗意义。由于大多数PID遗传为常染色体隐性性状，因此针对大型亲属家族的遗传研究成功地识别了仍然存在基因不确定的PID患者的新基因缺陷，而且在几种疾病中已经是这种情况。我们已经在中东建立了一个研究网络，并收集了26个不相关的亲密家庭。在每种情况下，表型要么是完全新颖的，要么是先前已经描述的，但是已知的引起疾病的基因的序列和表达完整。拟议的研究的目的是测试结合单核苷酸多态性微阵列（SNP）分析和整个基因组测序（WGS）的能力，以鉴定引起PID的新基因。我们的具体目的是I。确定新型PID表型ii的分子和细胞碱基II。通过已知表型确定PID的分子和细胞碱基，但未知基因型我们预计SNP分析，WGS和尖端生物信息学的组合将为发现新型PID基因的发现提供快速有效的方法。这将为这项技术广泛应用于PID的研究铺平道路，并将产生关于可以在患者和动物模型中测试的PID发病机理的假设。获得的结果将适用于具有相似表型的PID的零星病例，并将改善我们对人类免疫系统的理解。公共卫生相关性：原发性免疫缺陷疾病（PID）是免疫系统的一组遗传疾病。 PID中遗传缺陷的鉴定可能具有预后和治疗意义。 PID在血缘高率较高的地区的人群中更为普遍，对这些地区的家庭的研究导致了几种引起基因的PID鉴定。我们已经在中东建立了一个研究网络，并收集了26个无关的遗传原因的亲属家族。我们建议使用尖端遗传分析工具来识别引起PID的新基因。我们预计，从拟议的研究中获得的知识将为发现新型PID基因的发现提供快速且具有成本效益的方法，并将提高我们诊断西方国家中PID患者的能力，在那里他们经常以孤立的病例出现。获得的结果还将增强我们对人类免疫系统的理解。