Cleft Lip Genetics: A Multicenter International Consorti

唇裂伴或不伴腭裂(CL/P)是常见的出生缺陷。以往的研究表明，CL/P是一种复杂的性状，是遗传和环境因素共同作用的结果。这种复杂性限制了研究，以至于只在一个独特的家族中发现了疾病突变。也不太可能确定所有的疾病部位。这个项目的总体目标是通过将新的多阶段连锁和连锁不平衡(LD)策略应用于受影响的亲属对和扩大的家系来识别与非综合征CL/P相关的疾病基因。这种尚未应用于CL/P的多阶段方法非常强大，因为不需要关于所涉及的遗传或生物过程的先验知识。有待检验的假设：非综合征性CL/P是由一个或多个基因座的遗传变异引起的。为了验证这一假设，具有多个受影响成员以及母亲/父亲和受影响儿童三人组的CL/P家庭将从各种临床中心招募，其中包括：俄亥俄州哥伦布；哥伦比亚南卡罗来纳州麦德林；华盛顿州西雅图；匹兹堡；芬兰；以及较小的中心，包括克利夫兰(Nat Robin博士)、旧金山(Ed Lammer博士)和圣地亚哥(Marilyn Jones博士)。多重家系将作为初步评估候选基因的基础，利用连锁和连锁不平衡的遗传工具拒绝(排除)或提供支持(即连锁)假说的证据来检验上述假说。还将进行10厘米宽的基因组筛查，以寻找更多的基因座。阳性基因座将通过多点、多基因座和TDT/关联分析的组合使用更密集的标记进行进一步评估。哥伦比亚和芬兰人口的遗传导致了独特的人口结构，这有利于寻找复杂特征的疾病基因。将这些群体与美国近交系群体进行比较，将提供有关导致CL/P的遗传多样性的重要信息。最初的能力(将足以识别中等或重大风险的基因座(相对风险大于2.0)，在项目期间，能力将增加到能够识别次要基因座(相对风险大于1.5)。它将通过多中心项目，如这个项目，其中已经建立了全球合作，以应用免费遗传策略的组合，将确定CL/P的疾病基因座。最终，这将进一步加深对正常和异常颅面发育的理解，从而可以开发和实施预防CL/P的治疗方法。

Cleft lip with or without cleft palate (CL/P) is a common birth defect. Previous studies have indicated that CL/P is a complex trait that is caused by a combination of genetic and environmental factors. This complexity has limited studies, such that disease mutations have only been identified in one unique family. It is also unlikely that all disease loci have been identified. The overall objective of this project is to identify disease genes involved in nonsyndromic CL/P by applying new multistaged linkage and linkage disequilibrium (LD) strategies to affected relative pairs and extended pedigrees. This multistage approach, which has not yet been applied to CL/P, is very powerful in that no prior knowledge about the involved genetic or biological processes is needed. Hypotheses to be tested: Nonsyndromic CL/P is caused by Genetic Variants at one or more loci. To test this hypothesis, CL/P families with both multiple affected members and mother/father and affected child trios will be recruited from a variety of clinical centers including: Columbus, OH; Medellin, Colombia SA; Seattle, WA; Pittsburgh; and Finland as well as smaller centers including Cleveland (Dr. Nat Robin); San Francisco (Dr. Ed Lammer) and San Diego (Dr. Marilyn Jones). The multiplex families will be the basis for initially evaluating candidate genes to test the above hypothesis using the genetic tools of linkage and linkage disequilibrium to reject (exclude) or provide evidence for support (i.e. linkage) the hypotheses. A 10 cM genome-wide screen will also be performed to find additional loci. Positive loci will be further evaluated by a combination of multipoint, multi-locus and TDT/association analyses using more densely spaced markers. The heritage of the Colombia and Finland populations have led to unique population structures that are advantageous for finding disease genes for complex traits. Comparison of these populations to the outbred US population will provide important information regarding the genetic diversity leading to CL/P. The power initially (will be sufficient to identify loci of moderate or major risk (relative risks greater than 2.0) and during the project, power will increase to be able to identify minor loci (relative risks greater than 1.5). It will be through multi- center projects such as this one, in which worldwide collaborations have been established to apply a combination of complimentary genetic strategies, that disease loci for CL/P will be identified. Ultimately, this will further the understanding of normal and abnormal craniofacial development, such that therapies to prevent CL/P can be developed and implemented.