Candidate Gene Analysis/Nonsyndromic Craniosynostosis

颅缝早闭是指一条或多条颅缝过早闭合，约1/2000的活产儿会发生这种情况。超过85%的颅缝早闭病例被认为是非综合征性的，即与其他先天畸形或引起颅缝早闭综合征的已知基因突变无关。识别导致非综合征颅缝闭锁的基因将有助于更好地了解颅骨形成的复杂过程，并将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(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。我们可用的新的基因分型技术可以对候选基因中或附近的大量SNP进行快速和高度敏感的基因分型。我们建议对一组候选基因进行遗传关联和连锁分析，这些候选基因是根据它们的生物学功能、表达模式或观察到的表型而选择的。我们小组已经确定了候选基因，确定了SNPs的特征，并已经成功地对48个颅缝融合症家庭进行了基因分型。已经建立了与几个候选基因的关联。在我们实验室验证的一组SNPs将应用于来自200多个特征良好的颅缝融合症家系的DNA样本。SNP基因型将允许比较候选基因座上的等位基因频率、连锁不平衡模式和单倍型。这项研究的具体目的是：1)对位于50个颅缝融合候选基因内或附近的750-1000个SNP的DNA样本进行SNP基因型分析；2)进行基于病例-父母三重的等位基因和单倍型传递不平衡检验(TDT)，以检验标记基因与非综合征型颅缝融合之间是否存在连锁；以及3)使用条件Logistic回归分析来检验基因-基因的相互作用。这一新信息将为诊断和治疗非综合征型颅缝早闭提供更好的策略。

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.