Candidate Gene Analysis/Nonsyndromic Craniosynostosis

候选基因分析/非综合征性颅缝早闭

• 批准号: 7275750
• 负责人: Simeon A Boyadjiev Boyd
• 金额: $ 5.71万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-12 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275750
• 关键词: bone development; clinical research; computed axial tomography; craniosynostosis; developmental disease /disorder; family genetics; gene expression; gene frequency; gene interaction; gene mutation; genetic markers; genetic screening; genetic susceptibility; high throughput technology; human genetic material tag; human subject; linkage disequilibriums; linkage mapping; musculoskeletal disorder diagnosis; nucleic acid sequence; quantitative trait loci; single nucleotide polymorphism; skull

Craniosynostosis, the premature closure of one or more cranial sutures, occurs in approximately 1 in 2000 live births. More than 85% of all craniosynostosis cases are thought to be nonsyndromic, i.e., not associated with other congenital anomalies or with known mutations in the genes causing craniosynostosis syndromes. Identification of genes causing nonsyndromic craniosynostosis will allow better understanding of the complex process of calvarial formation and will open new venues for study of normal and abnormal development of the skull. Single nucleotide polymorphisms (SNPs) are the most common type of genetic markers and their use has become a major tool for the detection of genetic linkage and disease associations. New genotyping technologies that are available to us allow rapid and highly sensitive genotyping of a large set of SNPs in or near candidate genes. We propose to perform genetic association and linkage analysis on a group of candidate genes selected on the basis of their biologic function, expression pattern, or observed phenotype. Our group has identified candidate genes, characterized SNPs and has already successfully genotyped 48 families with craniosynostosis. Associations with several candidate genes have been established. A panel of SNPs validated in our laboratory will be applied on a set of DNA samples from more than 200 well-characterized craniosynostosis families. The SNP genotypes will allow comparison of allele frequencies, linkage disequilibrium patterns, and haplotypes at the candidate gene loci. The specific aims for this study are: 1) to perform SNP genotype analysis of a large set of DNA samples for 750-1000 SNPs located within or near 50 craniosynostosis candidate genes; 2) to perform case-parent trio based allelic and haplotype Transmission Disequilibrium Tests (TDTs) to test for associations in the presence of linkage between marker loci and nonsyndromic craniosynostosis; and 3) to test for gene-gene interaction using conditional logistic regression analysis. This new information will lead to better strategies for diagnosis and management of nonsyndromic craniosynostosis.

颅缝早闭（一根或多根颅缝过早闭合）的发生率约为 2000 名活产儿中的 1 人。 超过 85% 的颅缝早闭病例被认为是非综合征性的，即与其他先天性异常或导致颅缝早闭综合征的基因已知突变无关。鉴定导致非综合征性颅缝早闭的基因将有助于更好地了解颅骨形成的复杂过程，并为研究颅骨的正常和异常发育开辟新的场所。单核苷酸多态性（SNP）是最常见的遗传标记类型，它们的使用已成为检测遗传连锁和疾病关联的主要工具。我们可用的新基因分型技术可以对候选基因内或附近的大量 SNP 进行快速且高度敏感的基因分型。我们建议对根据其生物学功能、表达模式或观察到的表型选择的一组候选基因进行遗传关联和连锁分析。我们的团队已经确定了候选基因，对 SNP 进行了表征，并已成功对 48 个颅缝早闭家族进行了基因分型。与几个候选基因的关联已经建立。我们实验室验证的一组 SNP 将应用于来自 200 多个特征明确的颅缝早闭家族的一组 DNA 样本。 SNP 基因型将允许比较候选基因位点的等位基因频率、连锁不平衡模式和单倍型。本研究的具体目的是： 1) 对大量 DNA 样本进行 SNP 基因型分析，找出位于 50 个颅缝早闭候选基因内或附近的 750-1000 个 SNP； 2) 进行基于病例亲本三重奏的等位基因和单倍型传递不平衡测试（TDT），以测试标记位点与非综合征性颅缝早闭之间存在连锁的关联性； 3) 使用条件逻辑回归分析测试基因-基因相互作用。这些新信息将为非综合征性颅缝早闭的诊断和治疗提供更好的策略。