Nonsyndromic Craniosynostosis: Phenotype/Genotype Study

描述(申请人提供)：颅缝融合(CS)，一条或多条颅缝的过早融合，是一种常见的缺陷，每2,500名活产儿中就有1人发生。大约85%患有CS的婴儿表现为非综合征(即没有无关的、重大出生缺陷或发育迟缓)。非综合征性CS(NCS)是一种具有多因素病因的异质性疾病；然而，经过近半个世纪的研究，其病因在很大程度上仍然存在 未知。因此，针对这一缺陷的初级预防策略是有限的。通过我们的国际颅骨融合联合会(ICC)，我们对最常见的CS亚型矢状面NCS(SNCS)的遗传病因有了更深入的了解。具体地说，利用我们之前的资金(R01 DE016866)，我们成功地进行了第一个SNC全基因组关联研究，并确定了与BMP2(rs1884302；P=1.1x10-39；OR=4.38)和BBS9(rs10262453；P=5.6x10-20；OR=0.24)附近的基因座之间的强大关联，这两个基因在生物学上都可能在骨骼发育中发挥作用。在我们工作的基础上，我们建议使用脚手架方法，通过测序和功能分析从这一“发现”转移到“确认”；将使用斑马鱼和小鼠模型进一步表征已确定的假定致病变异。我们假设，已识别的变异通过改变基因表达而增加了SNCS的风险。利用ICC的基础设施，我们还建议研究元主题NC(MNC)。SNC和MNC都会影响颅骨的中线缝合，更可能发生在非西班牙裔白人中，并显示出男性过多。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，并建议使用独立的病例对照样本对MNCs病例-亲本三联体和复制进行基于阵列的家系研究；候选基因和基因座的测序和功能分析将与SNC的测序和功能分析一起进行。随后，我们建议从“确认”转移到与环境暴露的“互动”，这是我们脚手架方法的顶峰。我们将使用从ICC获得的孕妇暴露报告和从国家出生缺陷预防研究(NBDPS)获得的孕产妇报告和生物标本来调查与每个亚型相关的环境暴露和基因-环境交互影响。NBDPS是美国最大的出生缺陷病例对照研究。它使用以人口为基础的监测和系统的病例审查和分类来列举有30多种主要缺陷之一的婴儿，包括非传染性疾病。NBDPS为研究环境暴露和基因-环境相互作用效应提供了丰富的资源。总之，我们建议通过临床医生和对NCS具有专业知识和长期兴趣的科学家的合作努力，对SNCs和MNCs进行全面的临床、流行病学和分子表征。鉴于我们在ICC和NBDPS的成就和大量资源，我们处于有利地位，能够成功完成拟议的研究，并为SNC和MNC的多因素病因提供重要的见解。

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.