Nonsyndromic Craniosynostosis: Phenotype/Genotype Study

描述（由申请方提供）：颅缝早闭（CS），一条或多条颅缝过早融合，是一种常见缺陷，每2,500例活产婴儿中发生1例。大约85%的CS婴儿表现为非综合征（即，没有不相关的、重大的出生缺陷或发育迟缓）。非综合征性CS（NCS）是一种异质性疾病，其病因可能是多因素的，然而，经过近半个世纪的研究，其病因仍主要是 未知因此，这种缺陷的一级预防策略是有限的。通过我们的国际颅缝早闭联合会（ICC），我们对最常见的CS亚型矢状面NCS（sNCS）的遗传病因有了进一步的了解。特别是，我们之前的资金（R 01 DE 016866），我们成功地进行了sNCS的第一个全基因组关联研究，并鉴定了与BMP 2附近基因座的稳健关联。（rs 1884302; P=1.1x10-39; OR=4.38）和BBS 9内（rs 10262453; P=5.6x10-20; OR=0.24），这两个生物学上合理的基因在骨骼发育中起作用。在我们工作的基础上，我们建议使用支架方法，通过测序和功能测定从这种“发现”转移到“确认”;将使用斑马鱼和小鼠模型进一步表征鉴定的推定致病变体。我们假设，已确定的变异有助于通过改变基因表达的sNCS的风险。使用ICC的基础设施，我们还建议调查metopic NCS（mNCS）。sNCS和mNCS都影响颅骨的中线缝，更有可能发生在非西班牙裔白人中，并显示男性过剩。鉴于这些相似之处，我们假设sNCS和mNCS可能有共同的致病变异，并提出了一个基于阵列的mNCS病例-父母三人组和复制与一个独立的病例对照样本的家庭研究;测序和候选基因和位点的功能测定将与sNCS一起进行。随后，我们建议从“确认”到“互动”与环境暴露，我们的脚手架方法的顶点。我们将使用从ICC获得的妊娠暴露的母体报告和从国家出生缺陷预防研究（NBDPS）获得的母体报告和生物标本，研究与每个亚型相关的环境暴露和基因-环境相互作用效应。NBDPS是美国最大的出生缺陷病例对照研究。它使用基于人群的监测和系统的病例回顾和分类来列举具有30多个主要缺陷之一的婴儿，包括NCS。NBDPS为研究环境暴露和基因-环境交互作用效应提供了丰富的资源。总之，我们提出了全面的临床，流行病学和分子表征的sNCS和mNCS通过临床医生和科学家的合作努力，证明专业知识和长期的利益在NCS。鉴于我们的成就和ICC和NBDPS的大量资源，我们有能力成功完成拟议的研究，并为sNCS和mNCS的多因素病因学提供重要见解。

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.