NONSYNDROMIC CRANIOSYNOSTOSIS: PHENOTYPE/GENOTYPE STUDY

非综合征性颅缝早闭：表型/基因型研究

• 批准号: 7456449
• 负责人: Simeon A Boyadjiev Boyd
• 金额: $ 44.75万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7456449
• 关键词: Affect; Area; Biological; Blood specimen; Candidate Disease Gene; Caring; Categories; Cephalic; Characteristics; Chromosome abnormality; Chromosomes; Classification; Clinical; Clinical assessments; Communities; Computer Analysis; Condition; Congenital Abnormality; Congenital abnormal Synostosis; Craniosynostosis; Cryopreservation; Cutaneous; DNA; Data; Data Set; Development; Diagnostic; Disease; Early Diagnosis; Enrollment; Ensure; Etiology; Evaluation; Exons; FGF2 gene; FGF8 gene; FGFR1 gene; FGFR2 gene; FGFR3 gene; Face; Family; Family member; Fibroblast Growth Factor 2; Fibroblast Growth Factor 8; Fibroblast Growth Factor Receptor 1; Genes; Genetic; Genetic Determinism; Genetic Variation; Genotype; Hot Spot; Imaging technology; Intracranial Hypertension; Joint structure of suture of skull; Live Birth; Logistics; Measurement; Medical; Molecular; Mutation; Mutation Analysis; Natural History; Neurologic; Operative Surgical Procedures; Outcome; Parents; Patient Care; Patients; Phenotype; Population; Positioning Attribute; Prevention; Proteins; Protocols documentation; Recruitment Activity; Recurrence; Registries; Regression Analysis; Reporting; Research; Research Personnel; Resources; Risk; Sample Size; Sampling; Scanning; Source; Specimen; Subgroup; Surface; Susceptibility Gene; Syndrome; System; Testing; Variant; X-Ray Computed Tomography; base; craniofacial; cranium; gene environment interaction; ilium; improved; lymphoblast; malformation; proband; programs; prospective; repository; tool; transmission process

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.

描述（由申请人提供）： 颅缝早闭，即 1 个或多个颅缝的过早融合，是一种常见的畸形，每 10,000 名活产儿中有 3 至 5 名发生。大多数情况下，颅缝早闭是作为一种孤立的（即非综合征性）异常发生的。非综合征性颅缝早闭 (NSC) 是一种多因素病因的异质性疾病，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并不完整，NSC 的原因仍不清楚。对一大群前瞻性招募的矢状面和冠状面 NSC 患者的临床特征和颅面人体测量资料进行分析，并根据标准化方案进行评估，将进一步表征这些表型。临床上同质的孤立性非综合征性矢状颅缝早闭患者组将用于通过候选基因关联分析来识别致病基因。我们已经招募并表征了 100 个矢状和 39 个冠状 NSC 家族，我们现有的招募系统将确保到本研究的第 4 年至少增加 250 个矢状和冠状 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和冠状 NSC 诊断类别内和之间的 3D 表型变异。开始对前 47 个具有分离的矢状 NSC 的病例亲本三人组进行基因分型，结果表明与染色体 3q 上的一个区域以及与几个测试的候选基因相关。我们的努力将致力于重现和验证这些关联，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、人体测量和分子特征。我们的目标是积累特征明确的矢状面和冠状面患者群体，确定需要改进临床护理的领域，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 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。