Candidate Gene Analysis/Nonsyndromic Craniosynostosis

颅缝闭合症，即一个或多个颅缝的过早闭合，在2000个活产儿中约有1例发生。超过85%的颅缝闭锁病例被认为是非综合征性的，即与其他先天性异常或已知的导致颅缝闭锁综合征的基因突变无关。鉴定导致非综合征性颅缝闭合的基因将有助于更好地理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领域。单核苷酸多态性（SNPs）是最常见的遗传标记类型，其使用已成为检测遗传连锁和疾病关联的主要工具。新的基因分型技术使我们能够快速和高度敏感地对候选基因内或附近的大量snp进行基因分型。我们建议对根据生物学功能、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。我们的研究小组已经确定了候选基因，对snp进行了表征，并已经成功地对48个颅缝紧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多个具有良好特征的颅缝闭锁家族的一组DNA样本。SNP基因型将允许在候选基因位点上比较等位基因频率、连锁不平衡模式和单倍型。本研究的具体目的是：1)对大量DNA样本进行SNP基因型分析，发现位于50个颅缝闭合候选基因内或附近的750-1000个SNP；2)进行基于病例-亲本三人组的等位基因和单倍型传播不平衡测试（tdt），以检测标记位点与非综合征性颅缝闭合之间存在关联；3)利用条件逻辑回归分析检验基因-基因相互作用。这一新发现将为非综合征性颅缝闭锁的诊断和治疗提供更好的策略。

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.