Project II: Genomic Approaches to Coronal Nonsyndromic Craniosynostosis

项目二：冠状非综合征性颅缝早闭的基因组学方法

基本信息

批准号：
8803596
负责人：
Inga Peter
金额：
$ 8.87万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8803596
关键词：
Accounting Affect BMP2 gene Bilateral Biological Biological Assay Brain Candidate Disease Gene Case-Control Studies Child Clinical Clinical Data Collaborations Collection Congenital Abnormality Congenital abnormal Synostosis Craniosynostosis Data Defect Developmental Disabilities Diagnostic Disease Drug usage Environmental Risk Factor Etiology Exons Family Frequencies Functional Imaging Gene Mutation Genes Genetic Genetic Predisposition to Disease Genetic Risk Genetic Variation Genome Genomics Goals Growth Hemorrhage Heterogeneity Human Image Individual Infant Intracranial Hypertension Language Delays Learning Disabilities Literature Live Birth Medical Molecular Mus Mutation New York Operative Surgical Procedures Parents Pathogenesis Pathway Analysis Pathway interactions Patients Pattern Perioperative complication Phenotype Predisposition Proteins Publishing Quality Control Recording of previous events Registries Reporting Research Risk Role Severities Signal Transduction Site Skeletal Development Specimen Speech Stenosis Surgical sutures Susceptibility Gene Therapeutic Tobacco Variant Vision X-Ray Computed Tomography base case control cohort coronal suture craniofacial cranium exome sequencing experience genome wide association study genome-wide analysis malformation novel osteoblast differentiation parity postnatal premature prenatal prevent therapeutic target tool validation studies

项目摘要

Craniosynostosis (CS) is a common malformation occurring in ~4 per 10,000 live births in which the sutures close too early, causing long-term problems with normal brain and skull growth. Infants with CS typically require extensive surgical treatment and may experience many perioperative complications, including hemorrhage and re-synostosis. Even with successful surgery, children can experience developmental and learning disabilities or vision problems. Most often, CS appears as isolated nonsyndromic CS (NSC). Unilateral or bilateral fusion of the coronal suture is the second most common form of CS accounting for 20-30% of all NSC cases. The etiology of coronal NSC (cNSC) is not well understood, although the published literature suggests that it is a multifactorial condition. About 5-14% of coronal craniosynostosis patients have a positive family history, with a specific genetic etiology identified in >25% of cNSC cases - the largest proportion among any NSC cases, suggesting a strong genetic component in this birth defect pathogenesis. The causes for NSC and its phenotypic heterogeneity remain largely unknown. In the first and only genome-wide association study of NSC, our group identified two regions, downstream of BMP2 and within BBS9, associated with a 4-5 fold increased risk of sagittal NSC. While both BMP2 and BBS9 are genes with a role in skeletal development, only the BMP2 locus was borderline significant in coronal cases, suggesting that synostosis of each suture represents a different disease caused by different sets of genes. Therefore, we will collaborate with multiple sites to establish the largest collection of cNSC cases to date in order to identify biological pathways contributing to common forms of cNSC. We hypothesize that genetic variation explains a significant portion of cNSC risk. Our specific aims are to: 1) Detect novel functional variants associated with cNSC. We will perform whole exome sequencing of 50 cases with the most severe disease manifestation and impute these data in all un-sequenced individuals; 2) Conduct the first genome-wide screening of several millions common and low frequency variants using ~850 trios with no known mutations to identify genetic loci over-transmitted to children with cNSC; 3) Perform validation studies to replicate the top genetic signals using an independent cohort of ~850 cNSC cases and controls, and 4) Perform imaging studies to examine morphometric patterns associated with the genetic risk burden and functional studies to determine functional consequences of the most promising genetic mutations. Synergy: specific parameters characterizing severity of craniofacial phenotypes in mice in Project I will inform morphometric analyses of human CS. The promising variants associated with cNSC will be incorporated into the network analysis and validated using functional assays in Project III. Identification of susceptibility genes will be the first step toward understanding the biological mechanisms of cNSC that may suggest novel postnatal therapeutics that in addition to surgery can provide a better result and prevent re- stenosis.

颅缝早闭 (CS) 是一种常见畸形，每 10,000 名活产儿中约有 4 名发生这种畸形，其中缝合线关闭得太早，会导致大脑和头骨正常生长的长期问题。患有 CS 的婴儿通常需要广泛的手术治疗，并可能经历许多围手术期并发症，包括出血和再粘连。即使手术成功，儿童仍可能经历发育和学习障碍或视力问题。大多数情况下，CS 表现为孤立性非综合征性 CS (NSC)。单方面冠状缝或双侧融合是第二常见的 CS 形式，占所有 CS 的 20-30% 国家安全委员会案例。冠状 NSC (cNSC) 的病因尚不清楚，尽管已发表的文献表明这是一个多因素的情况。大约 5-14% 的冠状颅缝早闭患者的检测呈阳性家族史，超过 25% 的 cNSC 病例具有特定的遗传病因——其中比例最大任何 NSC 病例，表明这种出生缺陷发病机制中有很强的遗传因素。 NSC 的原因其表型异质性仍然很大程度上未知。第一个也是唯一一个全基因组关联研究在 NSC 中，我们的小组确定了两个区域，即 BMP2 下游和 BBS9 内，与 4-5 倍相关矢状 NSC 的风险增加。虽然 BMP2 和 BBS9 都是在骨骼发育中发挥作用的基因，但只有 BMP2 基因座在冠状病例中具有临界显着性，表明每条缝合线的骨连接代表由不同基因组引起的不同疾病。因此，我们将与多个建立迄今为止最大的 cNSC 病例收集网站，以确定生物学途径为常见形式的 cNSC 做出贡献。我们假设遗传变异解释了很大一部分 cNSC 风险。我们的具体目标是：1）检测与 cNSC 相关的新功能变异。我们将表演对 50 例疾病表现最严重的病例进行全外显子组测序，并将这些数据归咎于所有病例未测序的个体； 2) 对数百万种常见和低等疾病进行首次全基因组筛查使用约 850 个没有已知突变的三重奏的频率变异来识别过度传播给儿童的基因位点与国家安全委员会； 3) 使用独立的队列进行验证研究以复制顶级遗传信号约 850 个 cNSC 病例和对照，以及 4) 进行成像研究以检查相关的形态测量模式通过遗传风险负担和功能研究来确定最有希望的功能后果基因突变。协同作用：表征小鼠颅面表型严重程度的特定参数项目 I 将为人类 CS 的形态测量分析提供信息。与 cNSC 相关的有希望的变体将是纳入网络分析并使用项目 III 中的功能分析进行验证。鉴定易感基因将是了解 cNSC 生物学机制的第一步，这可能是提出新的产后治疗方法，除了手术之外，还可以提供更好的结果并防止再次发生。狭窄。