NONSYNDROMIC CRANIOSYNOSTOSIS: PHENOTYPE/GENOTYPE STUDY

描述（由申请人提供）：颅缝闭合，1条或多条颅缝过早融合是一种常见的畸形，每10000例活产婴儿中有3至5例发生。颅缝闭闭通常是孤立的（即非综合征性）异常。非综合征性颅缝闭闭（NSC）是一种多因素的异质性疾病，有遗传因素的证据。在了解单基因综合征性颅缝闭闭的临床和分子方面取得了重大进展。然而，NSC的表型特征和诊断亚组内的变异性是不完整的，NSC的原因仍然未知。在标准化方案下评估的大量矢状面和冠状面NSC患者的临床特征和颅面人体测量特征分析将进一步表征这些表型。临床均质组孤立无综合征矢状颅缝闭塞患者将通过候选基因关联分析来确定致病基因。我们已经招募并鉴定了100个矢状面和39个冠状面NSC家族，我们现有的招募系统将确保在本研究的第4年至少增加250个矢状面和冠状面NSC家族。我们将使用先进的成像技术和定量形态学工具来表征和评估矢状面和冠状面NSC诊断类别内部和之间的3D表型差异。对前47例分离矢状状NSC的亲本三人组进行了基因分型，结果表明与染色体3q上的一个区域和几个已测试的候选基因有关。我们的努力将致力于再现和验证这些关联，并确定这些基因中易患NSC的变异。我们还将继续进行基于snp的基因分型和其他候选基因的关联分析。总之，本申请提出了一项多中心表型和基因型研究，旨在确定NSC的临床、人体计量学和分子特征。我们的目标是积累良好特征的矢状面和冠状面患者群体，确定改善临床护理的领域，并建立一个可供科学界使用的样本库。此外，我们还将确定与矢状面NSC相关的基因。我们积累的资源以及我们将利用的协作和综合方法使我们处于实现这些目标的独特地位。

DESCRIPTION (provided by applicant): Craniosynostosis, the premature fusion of 1 or more cranial sutures is a common malformation occurring in 3 to 5 per 10,000 live births. Most often craniosynostosis occurs as an isolated (i.e. nonsyndromic) anomaly. Nonsyndromic craniosynostosis (NSC) is a heterogeneous condition of multifactorial etiology with evidence of genetic factors. Significant progress has been made in understanding the clinical and molecular aspects of monogenic syndromic craniosynostosis. However, the phenotype characterization of NSC and the variability within diagnostic subgroups is incomplete and the causes of NSC remain unknown. Analysis of the clinical features and the craniofacial anthropometric profiles of a large group of prospectively recruited patients with sagittal and coronal NSC evaluated under a standardized protocol will further characterize these phenotypes. The clinically homogeneous group of patients with isolated nonsyndromic sagittal craniosynostosis will be used to identify causative genes by candidate gene association analysis. We have already enrolled and characterized 100 sagittal and 39 coronal NSC families and our existing recruitment system will ensure at least 250 additional sagittal and coronal NSC families by year 4 of this study. We will use advanced imaging technologies and quantitative morphological tools to characterize and evaluate 3D phenotypic variation within and between the diagnostic categories of sagittal and coronal NSC. The genotyping of the first 47 case-parent trios with isolated sagittal NSC was initiated and the results indicate associations with a region on chromosome 3q and with several of the tested candidate genes. Our efforts will be dedicated to reproducing and validating these associations and to identifying variants within these genes that predispose to NSC. We will also continue SNP-based genotyping and the association analysis of additional candidate genes. In summary, this application proposes a multicenter phenotype and genotype study aimed at determining the clinical, anthropometric, and molecular characteristics of NSC. Our aims are to accrue well-characterized sagittal and coronal patient populations, to identify areas for improved clinical care, and to establish a sample repository available to the scientific community. In addition, we will also identify genes associated with sagittal NSC. The resources that we have amassed and the collaborative and integrated approaches that we will utilize put us in a unique position to accomplish these aims.