Nonsyndromic Craniosynostosis: Phenotype/Genotype Study

非综合征性颅缝早闭：表型/基因型研究

• 批准号: 8923236
• 负责人: Simeon A Boyadjiev Boyd
• 金额: $ 69.52万
• 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 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8923236
• 关键词: Accounting; Affect; Animals; BMP2 gene; Biological; Biological Assay; Blood; Candidate Disease Gene; Case-Control Studies; Cells; Centers for Disease Control and Prevention (U.S.); Characteristics; Chromosomes, Human, Pair 20; Chromosomes, Human, Pair 7; Classification; Clinical; Clinical Data; Collaborations; Collection; Congenital Abnormality; Craniosynostosis; Data; Defect; Developmental Delay Disorders; Dizygotic Twins; Educational workshop; Environmental Exposure; Environmental Risk Factor; Epidemiology; Epigenetic Process; Etiology; Family; Family Study; Female; Fibroblast Growth Factor Receptors; Funding; Gene Expression; Genes; Genetic; Genetic Predisposition to Disease; Genotype; Health; Individual; Infant; International; Investigation; Joint structure of suture of skull; Leadership; Left; Live Birth; Molecular; Molecular Genetics; Mothers; Newborn Infant; Not Hispanic or Latino; Parents; Participant; Phenotype; Physical Examination; Positioning Attribute; Pregnancy; Prevention; Prevention strategy; Preventive Intervention; Primary Prevention; Recommendation; Recurrence; Reporting; Research; Research Infrastructure; Residual state; Resources; Risk; Role; Sampling; Scientist; Site; Skeletal Development; Specimen; Spottings; Surgical sutures; Syndrome; System; Tobacco; United States; United States National Institutes of Health; Variant; Work; Zebrafish; base; blastomere structure; case control; cell motility; cell transformation; cranium; disorder prevention; gene discovery; genetic risk factor; genetic variant; genome wide association study; insight; interest; male; mouse model; population based; premature; risk variant; scaffold

DESCRIPTION (provided by applicant): Craniosynostosis (CS), the premature fusion of one or more cranial sutures, is a common defect occurring in 1 in 2,500 live births. About 85% of infants with CS present as nonsyndromic (i.e., without unrelated, major birth defects or developmental delay). Nonsyndromic CS (NCS) is a heterogeneous condition with presumed multifactorial etiology; however, after nearly one-half century of study, its causes remain largely unknown. As such, primary prevention strategies for this defect are limited. Through our International Craniosynostosis Consortium (ICC), we have advanced understanding of the genetic etiology for the most common CS subtype, sagittal NCS (sNCS). Specifically, with our previous funding (R01 DE016866), we successfully conducted the first genome-wide association study for sNCS and identified robust associations to loci near BMP2 (rs1884302; P=1.1x10-39; OR=4.38) and within BBS9 (rs10262453; P=5.6x10-20; OR=0.24), both biologically plausible genes with a role in skeletal development. Building on our work, we propose to use a scaffold approach, moving from this "discovery" to "confirmation" through sequencing and functional assays; putative causative variants identified will be further characterized using zebrafish and mouse models. We hypothesize that identified variants contribute to the risk of sNCS by altering gene expression. Using the ICC infrastructure, we also propose to investigate metopic NCS (mNCS). Both sNCS and mNCS affect the midline sutures of the skull, are more likely to occur among non-Hispanic whites, and show a male excess. Given these similarities, we hypothesize that sNCS and mNCS may share common causative variants, and propose an array-based family study of mNCS case-parent trios and replication with an independent case-control sample; sequencing and functional assays of candidate genes and loci will be conducted together with those for sNCS. Subsequently, we propose to move from "confirmation" to "interaction" with environmental exposures, the apex of our scaffold approach. We will investigate environmental exposures and gene-environmental interaction effects associated with each subtype using maternal reports of pregnancy exposures obtained from the ICC and maternal reports and biological specimens obtained from the National Birth Defects Prevention Study (NBDPS). The NBDPS is the largest case-control study of birth defects in the United States. It uses population- based surveillance and systematic case review and classification to enumerate infants with one of over 30 major defects, including NCS. The NBDPS provides a rich resource to investigate environmental exposures and gene-environmental interaction effects. In summary, we propose comprehensive clinical, epidemiological, and molecular characterization of sNCS and mNCS through the collaborative efforts of clinicians and scientists with demonstrated expertise and long-standing interests in NCS. Given our accomplishments and substantial resources of the ICC and NBDPS, we are well-positioned to successfully complete the proposed research and contribute critical insights into the multifactorial etiology of sNCS and mNCS.

描述（由申请人提供）：一个或多个颅骨缝合线的过早融合颅突（CS）是一个常见的缺陷，发生在2,500分之1中。 CS婴儿中约有85％的婴儿（即，没有无关的，主要的先天缺陷或发育迟缓）。非合成CS（NCS）是一种异质性疾病，具有多因素病因。但是，经过将近一个半世纪的研究，其原因仍然很大程度上仍然 未知。因此，该缺陷的主要预防策略是有限的。通过我们的国际颅突式伴侣联盟（ICC），我们对最常见的CS亚型Sagittal NCS（SNC）的遗传病因有了深入的了解。具体而言，在我们以前的资金（R01 DE016866）的情况下，我们成功地进行了首次进行SNC基因组的关联研究，并确定了与BMP2附近的基因座（RS1884302; P = 1.1x10-39; OR = 4.38; OR = 4.38），并在BBS9（RS102222453; PRS1022453; p = 5.6x; p = 1.1x10-39; or = 4.38; p = 1.1x10-39; or = 4.38; p = 5.6x; p = 5.6x; p = 5.6X;合理的基因在骨骼发育中起作用。在我们的工作的基础上，我们建议采用脚手架方法，从这种“发现”转变为“确认”，通过测序和功能测定；假定的因果变体将使用斑马鱼和小鼠模型进一步表征。我们假设确定的变体通过改变基因表达有助于SNC的风险。使用ICC基础架构，我们还建议研究Metopic NCS（MNC）。 SNC和MNC都会影响头骨的中线缝合线，在非西班牙裔白人中更有可能发生，并显示出雄性过剩。鉴于这些相似性，我们假设SNC和MNC可能具有共同的病因变体，并提出了基于阵列的跨国公司病例三重奏的家庭研究，并使用独立的病例对照样本进行了复制；候选基因和基因座的测序和功能测定将与SNC一起进行。随后，我们建议从“确认”转变为与环境暴露的“相互作用”，即我们的脚手架方法的顶点。我们将使用从ICC获得的妊娠暴露以及从国家预防预防研究（NBDPS）获得的母体报告和生物标本获得的母体报告，研究与每种亚型相关的环境暴露和基因 - 环境相互作用效应。 NBDP是美国先天缺陷的最大病例对照研究。它使用基于人群的监视和系统的案例审查和分类来列举30多个主要缺陷之一，包括NC。 NBDP提供了丰富的资源来研究环境暴露和基因环境相互作用的影响。总而言之，我们通过临床医生和科学家的合作努力，在NCS中表现出了专业知识和长期的利益，我们提出了SNC和MNC的全面临床，流行病学和分子表征。鉴于我们在ICC和NBDP中的成就和大量资源，我们有充分的态度可以成功完成所提出的研究，并为SNC和MNC的多因素病因提供了重要的见解。