Cleft Lip Genetics: A Multicenter International Consorti

唇裂伴或不伴腭裂（CL/P）是常见的先天性缺陷。以往的研究表明，CL/P是一种遗传和环境因素共同作用的复杂性状。这种复杂性限制了研究，例如疾病突变只在一个独特的家族中被发现。也不太可能确定所有的疾病位点。本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）策略对受影响的亲属对和扩展家系，确定与非综合征性CL/P相关的疾病基因。这种多阶段方法尚未应用于CL/P，但它非常强大，因为不需要事先了解所涉及的遗传或生物过程。有待检验的假设：非综合征性CL/P是由一个或多个位点的遗传变异引起的。为了验证这一假设，将从不同的临床中心招募有多个患病成员以及母亲/父亲和患病儿童三人组的CL/P家庭，包括：俄亥俄州哥伦布市；哥伦比亚南部麦德林；西雅图,华盛顿州;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（埃德·拉默博士）和圣地亚哥（玛丽莲·琼斯博士）。多重家族将成为初步评估候选基因以检验上述假设的基础，使用连锁和连锁不平衡的遗传工具来拒绝（排除）或提供支持（即连锁）假设的证据。还将进行10 cM全基因组筛选以寻找其他位点。阳性位点将通过多点、多位点和使用更密集间隔标记的TDT/关联分析的组合进一步评估。哥伦比亚和芬兰人口的遗传导致了独特的人口结构，有利于寻找复杂性状的疾病基因。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。最初的权力将足以识别中度或主要风险位点（相对风险大于2.0），并且在项目期间，权力将增加以能够识别次要位点（相对风险大于1.5）。通过像这样的多中心项目，已经建立了全球合作，以应用互补遗传策略的组合，将确定CL/P的疾病位点。最终，这将进一步了解正常和异常颅面发育，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.