Exome sequencing in the skeletal dysplasias

描述（由申请人提供）：我们正在进行一场革命，以了解骨骼发育不良的分子基础。基因组序列分析的创新为鉴定与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，这些骨骼发育不良的相关基因尚未找到。 来自骨骼发育不良患者的病例非常适合这种研究，具有可以使用基因组方法解决的疾病的深度和广度。每一种待研究的疾病都将为骨骼的复杂生物学提供新的见解，并将在临床背景下这样做。重要的是，基因组学方法将使我们能够确定传统遗传学方法无法确定的疾病的遗传基础，例如新显性突变产生的表型。在特定目标1中，我们将研究显性疾病，包括肢端骨发育不全，SMD角骨折类型和多种形式的多发性骨骺发育不良，其中已知基因已被排除。在特定目标2中，将研究隐性遗传表型，包括窒息性胸营养不良（ATD或Jeune综合征）、视神经发育不良、脊椎发育不良疾病组的围产期致死表型以及隐性形式的假软骨发育不全和脊椎骨骺发育不良。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，并确定我们鉴定的基因的正常功能。

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.