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多种临床不同的骨骼发育不良（尚未发现相关基因）相关的突变提供了机会。临床资源的国际骨骼发育不良登记处，世界上最大的登记处

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.