Genetic Studies of Clubfoot (ITEV)

描述（由申请人提供）：内翻足或特发性马蹄内翻（ITEV）是五种最常见的出生缺陷之一，每年影响美国约4,000名新生儿。虽然这些儿童的骨科护理得到了改善，但长期问题仍然存在，医疗保健费用也很高。研究表明ITEV是一种复杂的疾病，分离分析和家族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，即母亲在怀孕期间吸烟，与此有关。我们假设少数基因占ITEV的很大一部分，并且这些基因可以在特定的人群中被识别出来。现在的挑战是确定基因位点，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良好的人口和方法来检测有关联和没有关联的联系。为了实现这些目标，我们已经确定并描述了多重ITEV家族和单一ITEV三重奏，其中包括两个大型ITEV家族，这是现有最大的ITEV种群之一。我们将对我们的ITEV数据集进行高密度SNP基因组扫描，以确定可能包含ITEV基因的染色体区域，并随后对这些区域和候选基因进行询问。我们拥有独特的itv人口和开展这项研究的方法。研究阶段为：1)继续确定多重家庭和不同种族的父母子女三人组；2)高密度SNP全基因组扫描；3)收集验证性（单一三人组和病例对照）数据集以测试新发现的基因。这项研究的结果将为鉴定导致ITEV表型的基因提供必要的数据。高风险基因型的鉴定可以导致在选定人群中制定预防方案，并可能提出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.