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）：颅突变，1个或更多颅骨缝合线的过早融合是每10,000个活产3至5的常见畸形。大多数通常是颅突式发生的，是一种分离的（即非综合症）异常。非合成颅颅突变（NSC）是多因素病因的异质疾病，具有遗传因素的证据。在理解单基因促颅颅神经病的临床和分子方面方面取得了重大进展。但是，NSC的表型表征和诊断子组中的可变性是不完整的，NSC的原因仍然未知。根据标准化协议评估的一大群前瞻性招募的患有矢状招募的患者的临床特征和颅面人体测量谱的分析将进一步表征这些表型。临床上均匀的非副颅骨颅颅神经症患者将通过候选基因关联分析来鉴定致病基因。我们已经招募并表征了100个矢状和39个Coronal NSC家族，我们现有的招聘系统将在本研究的第4年内确保至少250个额外的矢状和冠状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和冠状NSC诊断类别内和之间的3D表型变化。启动了第一个47个具有分离的矢状NSC的案例三重奏的基因分型，结果表明与3Q染色体上的区域以及与几个测试的候选基因的区域相关。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于NSC的变体。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。总而言之，该应用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。我们的目的是累积特色的矢状和冠状动脉群体，以确定改善临床护理的领域，并建立可供科学界可用的样本存储库。此外，我们还将确定与矢状NSC相关的基因。我们积累的资源以及我们将利用的协作和集成的方法使我们处于实现这些目标的独特位置。