Whole genome sequencing analysis of nonsyndromic craniosynostosis

派：西蒙·博伊德。国防部 项目摘要 颅脑融合症(CS)是一种主要的结构性出生缺陷，其特征是一个或多个 头颅缝合影响大约2500名活产儿中的1名。大多数CS病例表现为非综合征(NCS)， 孤立性出生缺陷按涉及的缝线(S)分类。NCS被认为是一个异类 NCS的多因素疾病和初级预防策略有限。NCS的病因主要是 未知；然而，基因组技术产生的发现已经开始缩小这一知识差距。 利用我国国际颅脑融合协会标本资源和国家出生缺陷 预防研究，我们成功地进行了前两项全基因组关联研究(GWAS)S的矢状面 NCS(SNCS)和MNC(MNC)，执行候选基因座的下一代测序(NGS SNC和MNC，并完成了240多个病例-亲本三联体，多重， 和/或患有NCS的多代家庭。这些努力使我们能够确定与基因座之间的强大关联 在BMP2、BBS9附近和BMP7内，以及涉及骨骼的生物合理基因中的罕见变体 发展。加布里埃拉·米勒儿童第一儿科研究基金X01 HL140535-01的支持 我们已经完成了321例亲本三联体的全基因组测序 具有各种类型NC的多个家庭。此外，来自其中31个家庭的样本目前在 长时间阅读WGS的过程。我们假设WGS的分析及其与我们现有基因组的整合 数据将确定新的遗传因素，而不是那些已确定的与GWAs有关的因素，这些因素有助于 NCS。在这项应用中，我们建议通过实施一个 目标1中WGS的综合基因组分析。在目标2中，我们将全面询问遗传 NCS的架构，通过协调和识别NCS的所有可能的因果候选基因和基因座 分析我们从受影响家庭的GWAS、WGS、WES和NGS积累的现有基因组数据。在……里面 目标3我们将对可能的致病变异进行初步表征，并为将来确定它们的优先顺序 分子研究。我们现有的基因组数据代表了最大的NCS数据集合之一，它是 研究NCS遗传病因的无与伦比的资源。我们的方法将为以下方面奠定基础 基因组数据的综合集成，以确定候选基因和基因座并追踪动物 未来网络控制系统的模型。鉴于我们过去的成就，经验丰富的跨学科研究团队，以及 大量资源，我们准备好实现这项建议的目标，并提供关键的见解 NCS的病因学。

PI: Simeon Boyd. MD Project Abstract Craniosynostosis (CS) is a major structural birth defect characterized by the premature fusion of one or more cranial sutures that affects about 1 in 2,500 live births. Most CS cases present as nonsyndromic (NCS), an isolated birth defect classified according to the suture(s) involved. NCS is considered a heterogeneous multifactorial disease and primary prevention strategies for NCS are limited. The etiology of NCS is largely unknown; however, findings generated by genomic technologies have begun to narrow this knowledge gap. Using the specimen resources of our International Craniosynostosis Consortium and the National Birth Defects Prevention Study, we successfully conducted the first two genome-wide association studies (GWAS)s for sagittal NCS (sNCS) and metopic NCS (mNCS), performed next generation sequencing (NGS) of candidate loci for sNCS and mNCS, and completed whole exome sequencing (WES) of more than 240 case-parent trios, multiplex, and/or multigenerational families with NCS. These efforts have allowed us to identify robust associations to loci near BMP2, BBS9, and within BMP7, as well as rare variants in biologic plausible genes involved in skeletal development. With the support of grant X01 HL140535-01 from the Gabriella Miller Kids First Pediatric Research Program we have already completed the whole genome sequencing (WGS) of 321 case-parent trios and multiplex families with various types of NCS. In addition, samples from 31 of those families are currently in process of long-read WGS. We hypothesize that the analysis of WGS and its integration with our extant genomic data will identify novel genetic factors beyond those identified with GWAS’s that contribute to the etiology of NCS. In this application, we propose to elucidate the genetic factors that contribute to NCS by implementing an integrative genomic analysis of WGS in Aim 1. In Aim 2 we will comprehensively interrogate the genetic architecture of NCS to identify all possible causal candidate genes and loci for NCS by harmonizing and analyzing our existing genomic data accumulated from GWASs, WGS, WES, and NGS of affected families. In Aim 3 we will perform initial characterization of likely causative variants and will prioritize them for future molecular studies. Our extant genomic data represents one of the largest NCS data collections compiled and is an unparalleled resource for studying the genetic etiology of NCS. Our approach will lay the foundation for comprehensive integration of genomic data in order to identify candidate genes and loci and to pursue animal models of NCS in the future. Given our past accomplishments, experienced interdisciplinary research team, and substantial resources, we are well poised to achieve the aims of this proposal and provide critical insights into the etiology of NCS.