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.

颅骨突变病（CS）是一种常见的畸形，在每10,000个活产中〜4个缝合线。 过早关闭，导致正常大脑和头骨生长的长期问题。 CS的婴儿通常 需要大量的手术治疗，可能会遇到许多围手术期并发症，包括 出血和重新发挥性。即使进行了成功的手术，儿童也可以体验发展和 学习障碍或视力问题。大多数情况下，CS显示为孤立的非综合症CS（NSC）。单方面 或冠状缝合线的双边融合是CS的第二大最常见形式，占全部的20-30％ NSC案例。尽管已发表的文献 表明这是多因素条件。大约5-14％ 家族史，在> 25％的CNSC病例中鉴定出特定的遗传病因 - 这是最大的比例 任何NSC病例，都表明在这种出生缺陷发病机理中具有强大的遗传成分。 NSC的原因 它的表型异质性在很大程度上仍然未知。在第一个也是唯一的全基因组关联研究中 在NSC中，我们的小组确定了两个区域，即BMP2的下游和BBS9，与4-5倍相关 矢状NSC的风险增加。虽然BMP2和BBS9都是在骨骼发育中起作用的基因，但仅 BMP2基因座在冠状动物的情况下是显着的，这表明每个缝合线的冲突 代表由不同基因集引起的一种不同的疾病。因此，我们将与多个合作 迄今为止，建立最大的CNSC案例集合以识别生物学途径 有助于CNSC的共同形式。我们假设遗传变异解释了很大一部分 CNSC风险。我们的具体目的是：1）检测与CNSC相关的新功能变体。我们将表演 全外显子组测序50例具有最严重疾病表现的病例，并将这些数据算 未序的人； 2）对数百万个常见和低的基因组进行首次筛查 使用〜850三重量的频率变体没有已知突变来识别儿童过度转移的遗传基因座 与CNSC； 3）执行验证研究以使用独立的队列复制顶部遗传信号 〜850 CNSC病例和对照，4）进行成像研究以检查相关的形态计量模式 通过遗传风险负担和功能研究来确定最有前途的功能后果 基因突变。协同作用：特定参数表征小鼠颅面表型严重程度的特定参数 项目我将告知人类CS的形态分析。与CNSC相关的有希望的变体将是 并入网络分析并使用项目III中的功能测定进行验证。识别 易感基因将是理解CNSC生物学机制的第一步 建议新型的产后治疗剂，除了手术外还可以提供更好的结果并防止重新 狭窄。