Exome sequencing in the skeletal dysplasias

骨骼发育不良的外显子组测序

基本信息

批准号：
8503380
负责人：
DANIEL H COHN
金额：
$ 34.87万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-03-01 至 2018-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8503380
关键词：
Acrodysostosis Biochemical Biological Biology Calcium Chromosome Mapping Clinical Complex Data Developmental Delay Disorders Diagnostic Disease Dissection Dysplasia Environment Etiology Exons Family Fracture Frequencies Genes Genetic Genetic Counseling Genetic screening method Genomics Goals Homeostasis Human Inheritance Patterns Inherited International Jeune syndrome Maps Methods Molecular Molecular Genetics Multiple Epiphyseal Dysplasias Mutation Outcome Pathogenesis Pathway interactions Patients Perinatal Phenotype Prenatal Diagnosis Pseudoachondroplastic spondyloepiphyseal dysplasia syndrome Registries Resources Role Sampling Sequence Analysis Skeletal Development Skeleton Spondyloepiphyseal Dysplasia Testing Therapeutic Validation Work base exome exome sequencing gene function genome sequencing improved innovation insight novel public health relevance research study skeletal skeletal disorder skeletal dysplasia skeletogenesis

项目摘要

DESCRIPTION (provided by applicant): We are in the midst of a revolution in our ability to understand the molecular basis of the skeletal dysplasias. Innovations in genome sequence analysis have provided the opportunity to identify the mutations associated with the 100+ clinically distinct skeletal dysplasias for which an associated gene has yet to be found. The clinical resources of the International Skeletal Dysplasia Registry, the largest worldwide registry of cases from skeletal dysplasia patients, are ideally suited for such studies, having both the depth and breadth of disorders that can be solved using a genomic approach. Each of the disorders to be studied will provide new insights into the complex biology of the skeleton, and will do so in a clinical context. Importantly, genomic approaches will allow us to define the genetic basis of disorders in which traditional genetic approaches are impossible, such as phenotypes produced by new dominant mutations. In Specific Aim 1, we will study dominant disorders including acrodysostosis, SMD corner fracture type and forms of multiple epiphyseal dysplasia in which the known genes have been excluded. In Specific Aim 2, recessively inherited phenotypes will be studied including asphyxiating thoracic dystrophy (ATD or Jeune syndrome), opsismodysplasia, a perinatal lethal phenotype with the spondylodysplastic group of disorders, and recessive forms of pseudoachondroplasia and spondyloepiphyseal dysplasia. The genes associated with all of these phenotypes will be defined by exome sequencing. Functional validation will identify the biochemical mechanisms associated with these disorders and begin to explore pathogenesis. The results will reveal new molecular mechanisms for the skeletal dysplasias and define the normal functions of the genes we identify.

描述（由申请人提供）：我们正处于理解骨骼发育不良分子基础能力的一场革命之中。基因组序列分析的创新为识别与 100 多种临床上不同的骨骼发育不良相关的突变提供了机会，而这些突变的相关基因尚未被发现。国际骨骼发育不良登记处（全球最大的登记处）的临床资源来自骨骼发育不良患者的病例非常适合此类研究，具有可以使用基因组方法解决的疾病的深度和广度。每种待研究的疾病都将为骨骼的复杂生物学提供新的见解，并将在临床背景下进行。重要的是，基因组方法将使我们能够定义传统遗传方法无法实现的疾病的遗传基础，例如新的显性突变产生的表型。在具体目标 1 中，我们将研究显性疾病，包括肢端骨质增生、SMD 角骨折类型和已知基因已被排除的多发性骨骺发育不良的形式。在具体目标 2 中，将研究隐性遗传表型，包括窒息性胸椎营养不良（ATD 或 Jeune 综合征）、视性发育不良、脊柱发育不良类疾病的围产期致命表型，以及隐性形式的假性软骨发育不全和脊柱骨骺发育不良。与所有这些表型相关的基因将通过外显子组测序来定义。功能验证将确定与这些疾病相关的生化机制并开始探索发病机制。结果将揭示骨骼发育不良的新分子机制，并确定我们识别的基因的正常功能。