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

• 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
• 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

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）是一种常见的畸形，每10，000例活产中约有4例发生，其中缝合处 过早闭合，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 出血和再结合。即使手术成功，儿童也会经历发育和 学习障碍或视力问题。最常见的是，CS表现为孤立的非综合征型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%。 国家安全委员会的案件。冠状神经干细胞（cNSC）的病因还不清楚，尽管已发表的文献 表明这是一种多因素的疾病大约5-14%的冠状面颅缝早闭患者有一个阳性的 家族史，在>25%的cNSC病例中确定了特定的遗传病因-在所有cNSC病例中比例最大。 任何NSC病例，表明在这种出生缺陷发病机制中有很强的遗传成分。NSC的原因 其表型异质性在很大程度上仍然未知。在第一个也是唯一一个全基因组关联研究中， 在NSC中，我们的研究小组确定了两个区域，BMP 2下游和BBS 9内，与NSC的4-5倍相关。 增加矢状面NSC的风险。虽然BMP 2和BBS 9都是在骨骼发育中起作用的基因，但只有 BMP 2位点在冠状面病例中具有边缘显著性，提示每条骨缝的骨结合 代表了由不同基因引起的不同疾病。因此，我们将与多个 建立迄今为止最大的cNSC病例集，以确定生物学途径 有助于形成共同的cNSC形式。我们假设，遗传变异解释了一个显着的一部分， cNSC风险。我们的具体目标是：1）检测与cNSC相关的新功能变体。我们将执行 对50例最严重疾病表现的病例进行全外显子组测序，并将这些数据全部插补 2）对数百万个普通和低水平的个体进行首次全基因组筛查; 频率变异使用约850个没有已知突变的trios来识别过度传播给儿童的遗传基因座 3）进行验证研究，以使用cNSC的独立队列复制最佳遗传信号; ~850例cNSC病例和对照，以及4）进行成像研究，以检查相关的形态学模式 与遗传风险负担和功能研究，以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将告知人类CS的形态学分析。与cNSC相关的有希望的变体将是 将其纳入网络分析，并使用项目III中的功能测定进行验证。鉴定 易感基因将是理解cNSC生物学机制的第一步， 提出了新产后治疗方法，除了手术之外，还可以提供更好的结果并防止再感染， 狭窄