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：
8628740
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/8628740
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 High-Throughput Nucleotide Sequencing 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）：我们正处于一场革命之中，以了解骨骼发育不良的分子基础。基因组序列分析中的创新提供了机会，可以识别与100多个临床上不同的骨骼发育不良相关的突变，尚未找到相关基因。国际骨骼发育不良注册表的临床资源，全球最大的注册表在骨骼发育不良患者的病例中，理想地适合此类研究，具有可以使用基因组方法来解决的疾病的深度和广度。要研究的每种疾病都将提供有关骨骼复杂生物学的新见解，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不可能的传统遗传方法的遗传基础，例如新的主要突变产生的表型。在特定的目标1中，我们将研究包括杂咽，SMD角骨折类型和多种外周性发育不良的形式的显性疾病，其中已被排除在其中。 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.与所有这些表型相关的基因将由外显子组测序定义。功能验证将确定与这些疾病相关的生化机制，并开始探索发病机理。结果将揭示骨骼发育不良的新分子机制，并定义我们识别的基因的正常功能。