CLINICAL, MORPHOLOGIC AND MOLECULAR STUDIES

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Description (provided by applicant): The skeletal dysplasias are a heterogeneous group of over 200 disorders. This project seeks to define the clinical and genetic and pathologic features of these disorders, develop animal models to better understand their pathogenesis, define the molecular defect in three disorders by linkage analysis and perform clinical molecular correlative studies with each of the other projects and other collaborators. During the period of support, we will: 1) definitively classify cases submitted to the International Skeletal Dysplasia Registry (Core A), improve the characterization of previously described skeletal dysplasias, and define novel disorders; 2) improve the methods used for prenatal diagnosis of the skeletal dysplasias; 3) correlate the clinical, radiographic, and morphological features of different skeletal dysplasias with their specific biochemical and molecular defects; 4) in collaboration with subprojects 5, 2, 8, and other workers analyze animal chondrodysplasias for identification of human homologues, validation of experimental models, and insight into the pathophysiology; and 5) localize the disease gene locus using linkage analysis and identify the genetic defect for three skeletal dysplasias where the basic defect is not known, specifically Desbuquois syndrome, autosomal dominant brachyolmia, and linked faciocardiomusculoskeletal syndrome.