Mapping nonsyndromic cleft lip and palate genetic loci

描述(由申请人提供)：非综合征性唇裂伴或不伴腭裂(NSCLP)是美国每年影响4000名新生儿的五种最常见的出生缺陷之一。NSCLP的病因很复杂。虽然已经确定了一些易感基因，但它们在病因学上只起到了很小的作用。现在的挑战是找出起主要作用的基因。 最近在小鼠身上的一项研究表明，存在主要的NSCLP基因座，并且可以识别它们。为了完成这项任务，重要的是要有一个确定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，我们已经确定并表征了一个多基因非小细胞肺癌家族的大样本。这一独特的非小细胞肺癌家系资源为遗传因素(S)发挥重要作用提供了有力证据。利用这些家系，我们已经确定了四个新的候选染色体区域，并从最近的同胞对分析研究中确认了六个可能包含NSCLP基因座的染色体区域。 在这项持续的工作中，我们将使用我们独特的和大量的多重NSCLP家族来提炼这些新的候选区域，并测试一组与生物相关的候选基因。同时，我们将扩大我们的多重家族，然后进行密集的5 cM全基因组扫描，以优化NSCLP遗传基因座的检测。参数和非参数分析将包括环境和维生素暴露以及母亲的基因信息。最后，所有产生阳性结果的候选NSCLP基因将在我们正在收集的不同种族的单纯型三联体中进行测试。这项研究的结果将为家族性非小细胞肺癌的病因提供洞察力，并可能为孤立的非小细胞肺癌提供新的信息。最后，识别高危基因类型可能导致在选定的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): Nonsyndromic cleft lip with or without cleft palate (NSCLP) is one of the five most common birth defects affecting 4,000 newborns per year in the United States. The etiology of NSCLP is complex. Although a number of susceptibility loci have been identified, they are postulated to play only a small etiologic role. The challenge now is to identify the genes that play a major role. A recent study in the mouse suggests that there are major NSCLP loci and that they can be identified. To accomplish this task, it is important to have a defined population and the methodology to detect linkage with and without association. Towards these goals, we have identified and characterized a large sample of multiplex NSCLP families. This unique resource of NSCLP families provides strong evidence that genetic factor(s) play an important role. Using these families, we have positionally identified four new candidate chromosomal regions and confirmed six chromosomal regions from a recent sib-pair analysis study that may contain NSCLP loci. In this continuing work, we will use our unique and large set of multiplex NSCLP families to refine these new candidate regions and test a set of biologically relevant candidate genes. At the same time, we will expand our multiplex families and then conduct a dense 5 cM genome-wide scan to optimize detection of NSCLP genetic loci. Parametric and nonparametric analyzes will incorporate environmental and vitamin exposures and maternal genotype information. Finally all candidate NSCLP genes yielding positive results will be tested in ethnically diverse simplex trios that we are collecting. The results of this study will provide insights into the causes of familial NSCLP and may yield new information about isolated NSCLP. Finally, identification of high-risk genotypes may lead to the development of prevention programs in selected populations and may suggest gene-based prevention strategies.