Candidate Gene Analysis/Nonsyndromic Craniosynostosis

颅缝早闭，一个或多个颅缝过早闭合，发生率约为1/2000活产。 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引起颅缝早闭综合征的基因突变无关。鉴定非综合征型颅缝早闭症的基因将使我们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途径。单核苷酸多态性（SNPs）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。新的基因分型技术，我们可以快速和高灵敏度的基因分型的一个大的SNPs组或附近的候选基因。我们建议对一组根据其生物学功能、表达模式或观察到的表型选择的候选基因进行遗传关联和连锁分析。我们的研究小组已经确定了候选基因，表征了SNPs，并已经成功地对48个颅缝早闭家族进行了基因分型。已经建立了与几个候选基因的关联。我们实验室验证的一组SNP将应用于来自200多个特征良好的颅缝早闭症家族的一组DNA样本。SNP基因型将允许在候选基因座处比较等位基因频率、连锁不平衡模式和单倍型。本研究的具体目标是：1）对大量DNA样本进行SNP基因型分析，寻找位于50个颅缝早闭候选基因内或附近的750-1000个SNP; 2）进行基于病例父母三人组的等位基因和单倍型传递不平衡测试（TDT），以测试标记基因座与非综合征性颅缝早闭之间存在连锁的关联;（3）采用条件Logistic回归分析检验基因间的相互作用。这一新的信息将导致更好的诊断和管理的非综合征性颅缝早闭的策略。

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.