Genetic Studies of Clubfoot (ITEV)

描述(申请人提供)：马蹄内翻足或特发性马蹄内翻足(ITEV)是五种最常见的出生缺陷之一，在美国每年影响大约4000名新生儿。虽然这些儿童的整形外科护理有所改善，但长期问题依然存在，医疗保健费用也很高。研究表明，ITEV是一种复杂的疾病，分离分析和家系研究表明遗传因素在ITEV的发展中起着重要的病因学作用。只有一个环境因素与此有关，那就是孕妇在怀孕期间吸烟。我们假设少数基因在ITEV中占相当大的比例，并且这些基因可以在一个确定的人群中被识别。现在的挑战是确定遗传基因，然后确定环境暴露的影响。为了完成这项任务，重要的是要有一个定义明确的群体和检测有关联和无关联的连锁的方法。为了实现这些目标，我们已经确定了多个ITEV家族和包括两个ITEV大家族在内的单一ITEV三联体的特征，这是现有ITEV种群中最大的资源之一。我们将在我们的ITEV数据集上进行高密度SNP基因组扫描，以识别可能包含ITEV基因的染色体区域，并随后询问这些区域和候选基因。我们拥有独特的ITEV人群，并具备开展这项研究的方法。研究阶段是：1)继续确定多基因家庭和不同种族的亲子三元组，2)高密度SNP全基因组扫描，3)收集验证性(单纯三元组和病例对照)数据集，以测试新发现的基因。本研究的结果将为鉴定与ITEV表型有关的基因(S)提供必要的数据。识别高危基因类型可导致在选定人群中制定预防计划，并可能建议基于基因的预防策略。

DESCRIPTION (provided by applicant): Clubfoot or idiopathic talipes equinovarus (ITEV) is one of the five most common birth defects, affecting approximately 4,000 newborns each year in the US. While the orthopedic care of these children has improved, longterm problems persist and the health care costs are significant. Studies suggest that ITEV is a complex disorder with segregation analyses and family studies indicating that genetic factors play an important etiologic role in the development of ITEV. Only one environmental factor, maternal smoking during pregnancy, has been implicated. We postulate that a small number of genes account for a substantial fraction of ITEV and that these genes can be identified in a defined population. The challenge now is to identify the genetic loci and, later, the effect of environmental exposures. To accomplish this task, it is important to have a well-defined population and the methodology to detect linkage with and without association. Towards these goals, we have identified and characterized multiplex ITEV families and simplex ITEV trios including two large ITEV families, a resource which is among the largest ITEV population in existence. We will perform a high-density SNP genome scan on our ITEV dataset to identify chromosomal regions that may harbor ITEV genes with subsequent interrogation of these regions and candidate genes. We are in a position with our unique ITEV population and with the methodology in place to undertake this study. The study phases are: 1) continued ascertainment of multiplex families and ethnically diverse parent child trios, 2) high density SNP genome-wide scan 3) collection of confirmatory (simplex trios and case-control) datasets to test newly identified genes. The results of this study will provide data essential to the identification of the gene(s) contributing to the ITEV phenotype. Identification of high-risk genotypes can lead to the development of prevention programs in selected populations and may suggest gene-based prevention strategies.