Combined SNP analysis and whole genome sequencing to discover immunodeficiency ge

描述（由申请人提供）：原发性免疫缺陷病（PID）是一组影响免疫系统发育和/或功能的遗传性疾病。PID的研究有助于破译控制免疫功能的细胞和分子过程。识别PID的遗传缺陷可能具有预后和治疗意义。因为大多数PID是作为常染色体隐性遗传性状遗传的，所以针对大的近亲家庭的遗传研究成功地鉴定了PID患者的新基因缺陷，这些患者的基因缺陷在遗传上仍然不确定，就像在几种疾病中已经发生的那样。我们与中东的PID中心建立了一个研究网络，收集了26个无血缘关系的家庭。在每种情况下，表型要么是完全新的，要么是以前描述过的，但已知的致病基因在序列和表达上是完整的。这项研究的目的是测试单核苷酸多态性微阵列（SNP）分析和全基因组测序（WGS）相结合的能力，以确定导致PID的新基因。我们的具体目标是我。确定新PID表型II的分子和细胞基础。通过已知的表型和未知的基因型来鉴定PID的分子和细胞基础，我们预计SNP分析、WGS和尖端生物信息学的结合将为发现新的PID基因提供快速且具有成本效益的方法。这将为该技术在PID研究中的广泛应用铺平道路，并将产生关于PID发病机制的假设，这些假设可以在患者和动物模型中进行测试。所获得的结果将适用于具有相似表型的散发性PID病例，并将提高我们对人类免疫系统的理解。 公共卫生相关性：原发性免疫缺陷病（PID）是一组异质性免疫系统遗传性疾病。识别PID的遗传缺陷可能具有预后和治疗意义。PID在具有高血缘比例的地区的人群中更常见，并且对来自这些地区的家庭的研究已经导致鉴定出几种PID引起基因。我们与中东的PID中心建立了一个研究网络，收集了26个遗传原因不明的无关血缘家庭。我们建议使用最先进的遗传分析工具，以确定新的基因，导致PID。我们预计，从拟议的研究中获得的知识将提供一种快速和成本效益的方法来发现新的PID基因，并将提高我们诊断西方国家PID患者的能力，在西方国家，他们经常作为孤立的病例出现。所获得的结果也将增强我们对人类免疫系统的理解。

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.