Cleft Lip Genetics: A Multicenter International Consorti

唇裂伴或不伴腭裂（CL/P）是一种常见的出生缺陷。 以往的研究表明，CL/P是一个复杂的性状，是由遗传和环境因素的组合。 这种复杂性限制了研究，例如仅在一个独特的家族中发现了疾病突变。 也不可能确定所有的疾病位点。 该项目的总体目标是通过应用新的多阶段连锁和连锁不平衡（LD）策略来确定涉及非综合征型CL/P的疾病基因。 这种多阶段方法尚未应用于CL/P，但非常强大，因为不需要有关所涉及的遗传或生物过程的先验知识。待检验的假设：非综合征性CL/P由一个或多个基因座的遗传变异引起。为了检验这一假设，将从多个临床中心招募有多名受影响成员和母亲/父亲和受影响儿童三人组的CL/P家庭，这些临床中心包括：哥伦布，OH;麦德林，哥伦比亚SA;西雅图，WA;匹兹堡和芬兰以及较小的中心，包括克利夫兰（Nat Robin博士）;旧金山弗朗西斯科（艾德拉默博士）和圣地亚哥（Marilyn Jones博士）。 多重家族将是初步评估候选基因的基础，以使用连锁和连锁不平衡的遗传工具来检验上述假设，以拒绝（排除）或提供支持（即连锁）假设的证据。 还将进行10 cM全基因组筛选以发现其他基因座。 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间隔的标记物进行进一步评价。哥伦比亚和芬兰种群的遗传导致了独特的种群结构，有利于寻找复杂性状的疾病基因。 这些人群与远交美国人群的比较将提供有关导致CL/P的遗传多样性的重要信息。最初的功效将足以识别中度或重大风险的基因座（相对风险大于2.0），在项目期间，功效将增加，以能够识别次要基因座（相对风险大于1.5）。 将通过多中心项目（如本项目）确定CL/P的疾病位点，在该项目中，已建立了全球合作，以应用互补遗传策略的组合。 最终，这将进一步了解正常和异常的颅面发育，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.