Unraveling the mechanisms of prenatal-onset disorders affecting the skeleton

描述（由申请人提供）：骨骼发育不良（SD）是一组与骨骼异常相关的遗传性疾病，导致幸存者长期身体残疾，在某些情况下导致致命的骨骼异常。在过去的30年里，我们收集了超过18，000例骨骼发育不良病例的材料，其中一半以上在产前出现不同程度的骨骼发育不良。该项目旨在确定新的或描述不清的产前骨骼疾病的超声、临床、组织学、分子和病理生理学特征。该项目的目标是定义和解决 这些疾病的分子基础，从而增加我们的骨骼发育和生物学知识，提高我们的机制和产前发病骨骼发育不良的发展过程的理解。我们将通过以下具体目标来实现这些目标：1.定义和描述新的骨骼发育不良。使用大量的先前确定的情况下，我们已经确定，大约10%的产前发病骨骼发育不良不能被分配一个特定的诊断。我们将利用这一独特的资源，未分类的情况下，通过定义新的产前发病骨骼疾病。我们将首先集中在表型和分类定义不明确，但经常遇到的，与弯曲的骨和多个椎体分割缺陷的发现疾病。2.确定新的骨骼发育不良的潜在遗传基础。该目标将利用目标1中定义的疾病的DNA的可用性，并将使用外显子组测序作为鉴定其遗传基础的主要方法。外显子组测序数据将基于遗传模式、在具有亲本血缘关系的隐性疾病的选定病例中通过纯合性作图鉴定的基因座以及靶组织、生长板软骨和软骨膜/骨膜中的基因表达进行过滤。对于软骨膜/骨膜，我们关于弯曲骨疾病的初步数据已经确定了软骨膜/骨膜中表达的基因对骨骼发育的影响的重要但未被重视的作用。因此，我们期望，我们将描述、定义和解决的许多弯曲骨疾病将由发育中骨骼这一区域的高表达基因引起。确定这些未充分研究的疾病中的分子缺陷，将通过旨在确定其发病机制的实验进行补充，并将提供分子，组织学和临床结构，以了解和分类这组不同的疾病。这项工作的预期结果将提高我们对目前产前发病骨骼疾病的认识。对一般人群具有医学重要性的是，发现这些产前发病的遗传性骨骼发育不良中的基因和途径将确定涉及正常生长、骨和软骨稳态以及关节炎和骨质疏松症的发展的先前未知的机制和途径，从而为开发合理的临床护理和治疗范例提供必要的数据。

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.