Whole genome sequencing analysis of nonsyndromic craniosynostosis

非综合征性颅缝早闭的全基因组测序分析

• 批准号: 10490875
• 负责人: Simeon A Boyadjiev Boyd
• 金额: $ 15.96万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490875
• 关键词: Affect; Animal Model; Award; BMP2 gene; BMP7 gene; Bioinformatics; Biological; Candidate Disease Gene; Clinical; Code; Congenital Abnormality; Craniosynostosis; DNA; Data; Data Analyses; Data Collection; Data Files; Early Diagnosis; Enrollment; Etiology; Family; Female; Foundations; Funding; Future; Genes; Genetic; Genetic Epistasis; Genetic Predisposition to Disease; Genetic study; Genomics; Goals; Grant; Health Personnel; In Vitro; Interdisciplinary Study; International; Joint structure of suture of skull; Knowledge; Leadership; Live Birth; Molecular; Mutation; National Institute of Dental and Craniofacial Research; Parents; Pediatric Research; Penetrance; Physicians; Positioning Attribute; Prevention; Prevention strategy; Primary Prevention; Process; Recurrence; Resources; Risk; Role; Sampling; Scientist; Skeletal Development; Specimen; Structural Congenital Anomalies; Surgical sutures; Technology; Testing; Time; Twin Studies; United States National Institutes of Health; Untranslated RNA; Variant; Work; base; case control; causal variant; common treatment; disorder prevention; exome sequencing; experience; genetic architecture; genetic variant; genome sequencing; genome wide association study; genomic data; genomic locus; in vivo; insight; male; next generation sequencing; novel; premature; preventive intervention; programs; rare variant; trait; whole genome

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.

PI：Simeon Boyd。 MD 项目摘要 颅骨突变病（CS）是一个主要的结构性出生缺陷，其特征是一个或多个的过早融合 颅骨缝合线影响2500分之一的活产。大多数CS病例都以非元素（NCS）为单位 根据所涉及的缝合线分类的孤立出生缺陷。 NCS被认为是异质的 NCS的多因素疾病和主要预防策略受到限制。 NCS的病因很大 未知;但是，基因组技术产生的发现已开始缩小这一知识差距。 利用我们国际颅突的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个全基因组关联研究（GWAS）s的矢状 NCS（SNC）和Metopic NC（MNC），对候选基因座进行了下一代测序（NGS） SNC和MNC，并完成了超过240个案例三个以上的多路的整个外显子组测序（WES） 和/或具有NCS的多代家庭。这些努力使我们能够确定与基因座的强大关联 在BMP2，BBS9和BMP7中附近，以及与骨骼合理基因的稀有变体 发展。在Gabriella Miller Kids First Pediatiric Research的Grant X01 HL140535-01的支持下 程序我们已经完成了321个案例三个案例三重奏的整个基因组测序（WGS） 具有多种类型NC的多重家族。此外，目前有31个家庭的样本正在 长阅读WGS的过程。我们假设WGS的分析及其与我们的额外基因组的整合 数据将确定超出与GWA的遗传因素的新遗传因素 NCS。在此应用中，我们建议通过实施一个 AIM 1中WGS的集成基因组分析。在AIM 2中，我们将全面询问通用 NC的建筑通过协调和协调和 分析我们现有的基因组数据，这些数据从受影响家庭的GWASS，WGS，WES和NGS中积累。 AIM 3我们将对可能的因果变体进行初始表征，并将其优先考虑未来 分子研究。我们的额外基因组数据代表了编译最大的NCS数据收集之一，IS 研究NCS的遗传病因的无与伦比的资源。我们的方法将为 基因组数据的全面整合，以识别候选基因和局部并追求动物 未来的NC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，我们有充分的中毒来实现该提案的目标，并为 NCS的病因。