NONSYNDROMIC CRANIOSYNOSTOSIS: PHENOTYPE/GENOTYPE STUDY

描述(申请人提供)：颅缝融合，一条或多条颅缝的过早融合是一种常见的畸形，发生在每10,000名活产儿中有3到5名。最常见的情况是，颅缝融合是一种孤立的(即非综合征的)异常。非综合征性颅缝早闭(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颅缝早闭的临床和分子方面已取得重大进展。然而，NSC的表型特征和诊断亚组内的变异性是不完整的，NSC的原因仍然不清楚。对一大组预期招募的矢状面和冠状NSC患者的临床特征和颅面部人体测量资料进行分析，将进一步确定这些表型的特征。通过候选基因关联分析，临床同质性的孤立性非综合征矢状位颅缝早闭患者组将被用来识别致病基因。我们已经登记了100个矢状和39个冠状NSC家庭，我们现有的招募系统将确保到本研究的第四年至少额外增加250个矢状和冠状NSC家庭。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神经干细胞诊断类别内和诊断类别之间的3D表型差异。对首批47例分离矢状型NSC的病例-父母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测试的候选基因相关。我们的努力将致力于复制和验证这些关联，并识别这些基因中易患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。综上所述，本申请提出了一项旨在确定NSC的临床、人体测量和分子特征的多中心表型和基因研究。我们的目标是积累具有良好特征的矢状和冠状患者群体，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，我们还将鉴定与矢状面神经干细胞相关的基因。我们已经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.