Project II: Genomic Approaches to Coronal Nonsyndromic Craniosynostosis

颅脑融合(CS)是一种常见的畸形，发生在每10,000名活产儿中约4名，其中缝线 过早关闭，会长期影响大脑和头骨的正常发育。患有CS的婴儿通常 需要广泛的外科治疗，可能会经历许多围手术期并发症，包括 出血和再联会。即使手术成功，儿童也可以经历发育和 学习障碍或视力问题。大多数情况下，CS表现为孤立的非综合征CS(NSC)。单边 或双侧冠状缝融合是第二常见的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)的病因尚不清楚，尽管已发表的文献 这表明这是一个多因素的条件。约5%-14%的冠状融合患者有阳性反应 家族病史，在25%的CNSC病例中发现了特定的遗传病因--这是 任何NSC病例，表明在这种出生缺陷的发病机制中有很强的遗传成分。NSC产生的原因 它的表型异质性在很大程度上仍不清楚。在第一次也是唯一一次全基因组关联研究中 在NSC中，我们的研究小组确定了BMP2下游和BBS9内的两个区域，与4-5个折叠相关 矢状位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，但只有 BMP2基因座在冠状病例中接近显著，提示每条缝合线的融合 代表了一种由不同组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病例集合的地点，以确定生物途径 为常见形式的CNSC作出贡献。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)发现与CNSC相关的新的功能变体。我们将表演 50例具有最严重疾病表现的外显子全基因组测序 未测序的个体；2)对数百万普通和低基因进行首次全基因组筛查 使用~850个无已知突变的三联体的频率变异来识别过度传播给儿童的遗传基因座 与CNSC合作；3)执行验证研究，以使用独立的 约850例CNSC病例和对照，以及4)进行成像研究以检查与 用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殊参数 项目I将对人类CS进行形态计量分析。与CNSC相关的有前景的变体将是 纳入网络分析，并在项目III中使用功能分析进行验证。 易感基因将是了解CNSC生物学机制的第一步，这可能 建议新的产后治疗方法，除了手术外，还可以提供更好的结果，防止复发 狭窄。

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.