Unraveling the mechanisms of prenatal-onset disorders affecting the skeleton

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DESCRIPTION (provided by applicant): The skeletal dysplasias (SDs) are a heterogeneous group of genetic disorders associated with abnormalities in the skeleton that lead to long-term physical disabilities in survivors and lethal skeletal abnormalities in some cases. Over the last 30 years, we have collected material on more than 18,000 skeletal dysplasia cases, more than half presenting to various degrees in the prenatal period. This project is aimed at defining the ultrasound, clinical, histologic, molecular, and pathophysiologic features of novel or poorly delineated prenatal onset skeletal disorders. The goals of this project are to define and solve the molecular basis of these disorders, thereby increasing our knowledge of skeletal development and biology and improving our understanding of the mechanisms and developmental course of prenatal onset skeletal dysplasias. We will achieve these goals through the following Specific Aims: 1. Define and characterize novel skeletal dysplasias. Using the large number of previously ascertained cases, we have determined that approximately 10% of prenatal onset skeletal dysplasias cannot be assigned a specific diagnosis. We will take advantage of this unique resource of unclassified cases by defining novel prenatal onset skeletal disorders. We will first concentrate on phenotyping and classifying poorly defined, yet frequently encountered, disorders with the findings of bent bones and multiple vertebral segmentation defects. 2. Identify the underlying genetic basis of novel skeletal dysplasias. This Aim will capitalize on the availability of DNA for the disorders defined in Aim 1 and will use exome sequencing as the primary approach to identifying their genetic basis. The exome sequencing data will be filtered based on the pattern of inheritance, loci identified by homozygosity mapping in selected cases of recessive disorders with parental consanguinity, and gene expression in the target tissues, growth plate cartilage and perichondrium/periosteum. For the perichondrium/periosteum, our preliminary data on bent bone disorders have identified an important yet unappreciated role for the effects of genes expressed in perichondrium/periosteum on skeletal development. It is thus our expectation that many of the bent bone disorders that we will characterize, define and solve will result from genes with high expression in this region of the developing skeleton. Identifying the molecular defect in these understudied disorders, will be complemented by experiments aimed at determining their pathogenetic mechanisms, and will provide molecular, histologic and clinical structures within which to understand and classify this diverse group of disorders. The expected outcomes of the proposed work will improve our understanding of currently poorly delineated prenatal onset skeletal disorders. Of medical importance to the general population, discovering the genes and pathways in these prenatal onset genetic skeletal dysplasias will identify previously unknown mechanisms and pathways involved in normal growth, bone and cartilage homeostasis and the development of arthritis and osteoporosis, thus providing essential data for developing rational clinical care and treatment paradigms.