Cleft Lip Genetics: A Multicenter International Consortium

唇裂遗传学：多中心国际联盟

• 批准号: 6788169
• 负责人: Andrew C Lidral
• 金额: $ 10.17万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-07 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6788169
• 关键词: Colombia; Scandinavian country; United States; cleft lip; cleft palate; clinical research; disease /disorder etiology; family genetics; gene mutation; genetic markers; genetic screening; genome; genotype; high throughput technology; human subject; linkage disequilibriums; linkage mapping; patient oriented research

DESCRIPTION (provided by applicant): The focus of my research career is to identify the causes of craniofaciai anomalies, which will provide the foundation to develop strategies and therapies to prevent this common group of birth defects. The specific goals of this award are to 1) provide intensive research time in order to accomplish the goals of the research plan; 2) immerse myself in the literature to stay abreast of new discoveries and technologies such that they can be rapidly integrated into this project when warranted; and 3) broaden my expertise in human genetics as well as molecular and developmental biology to allow me to develop a set of life long skills as my career progresses from disease gene identification and molecular characterization, to the development and study of animal models to finally the development and implementation of prevention therapies. 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 multistage 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. Hypothesis to be tested: Nonsyndromic CLIP 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. The 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. 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 wilt 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.

描述（由申请人提供）：我的研究生涯的重点是确定颅面异常的原因，这将为制定预防这一常见出生缺陷的策略和疗法奠定基础。该奖项的具体目标是1）提供密集的研究时间以实现研究计划的目标； 2）沉浸在文献中，以了解新的发现和技术，以便在需要时能够将它们快速集成到该项目中； 3) 拓宽我在人类遗传学以及分子和发育生物学方面的专业知识，使我能够在职业生涯从疾病基因识别和分子表征，到动物模型的开发和研究，最后到预防疗法的开发和实施的过程中，培养一套终生技能。 唇裂伴或不伴腭裂（CL/P）是一种常见的出生缺陷。先前的研究表明，CL/P是一个复杂的性状，是由遗传和环境因素共同引起的。这种复杂性限制了研究，因此仅在一个独特的家族中发现了疾病突变。也不可能确定所有疾病位点。该项目的总体目标是通过对受影响的亲属对和扩展谱系应用新的多级连锁和连锁不平衡（LD）策略来识别与非综合征性 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 CLIP 是由一个或多个基因座的遗传变异引起的。 为了检验这一假设，将从多个临床中心招募具有多名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。这些家族将成为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 全基因组筛选以寻找其他基因座。将使用更密集的标记物，通过多点、多位点和 TDT/关联分析的组合来进一步评估阳性位点。 CL/P 的疾病基因座将通过诸如此类的多中心项目来确定，其中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颅面发育，从而可以开发和实施预防 CL/P 的疗法。