The Genetic Landscape of Human Tooth Agensis

项目总结 这个项目的目标是发现人类牙齿发育不全(TA)的候选因果遗传变异，TA是一种常见的 影响全球约2亿人的头面部出生缺陷，并强加给人们显著的审美、功能、 受影响个人的心理社会和经济负担。尽管研究取得了进展，但已知TA的突变 基因在所有病例中所占比例不到50%，这表明仍有其他原因基因有待发现。 对TA的全基因组研究很少，此外，对已识别的变异体的解释一直具有挑战性 由于缺乏将基因发现与功能基因组方法相结合的研究。这使情况变得复杂 我们对TA基因型-表型相关性的理解，进一步限制了我们提高诊断和 牙齿替换疗法。在这项提案中，我们将识别和功能表征潜在的基因 家族性和散发性TA的变异，以提高我们对参与TA的生物学途径的理解 条件。为了实现我们的目标，我们将：(1)对450名来自我们的 具有良好特征的TA家族和病例对照队列，并应用稳健的生物信息学分析整合 公开可用的数据以确定推定的因果变量，(2)使用泛函来表征优先排序的变量 体外基因组方法，以及(3)应用Phewas方法(表型全组关联研究)来确定 通过将TA基因变异与额外的健康结果联系起来，TA基因具有更广泛的临床意义 通过大型DNA数据库(BioVu Biobank)捕获。这项研究结合了全基因组的发现和 生物实验，并利用现有资源(DNA样本、遗传和表型数据 BioVu，在体外建立的模型)在多管齐下的框架内识别新的TA基因/途径。 因此，本研究不仅在方法上是创新的，而且在能力上也克服了 传统的TA候选基因研究。我们有令人兴奋的已公布和未公布的数据来支持这些 建议的研究将极大地提高我们对TA和TA的分子机制的理解 为开展以患者为中心的诊断和未来转化性研究提供科学依据 关于牙齿替换疗法。最后，这项研究直接涉及NIDCR对以下方面特别感兴趣的通知 支持发现牙科、口腔和颅面部疾病和状况的遗传变异

PROJECT SUMMARY The goal of this project is to discover candidate causal genetic variants for human tooth agenesis (TA), a common craniofacial birth defect that affects ~200 million humans worldwide and imposes significant esthetic, functional, psychosocial, and financial burdens for affected individuals. Despite research progress, mutations in known TA genes account for less than 50% of all cases, suggesting that additional causal genes remain to be found. Genome-wide studies of TA are scarce and, in addition, interpretation of identified variants has been challenging due to the paucity of studies combining gene discovery with functional genomic approaches. This complicates our understanding of TA genotype-phenotype correlations and further limits our ability to improve diagnostic and tooth replacement therapies. In this proposal, we will identify and functionally characterize the underlying genetic variations in familial and sporadic TA to improve our understanding of the biological pathways involved in the condition. To achieve our goal, we will: (1) perform whole exome sequencing (WES) of 450 individuals from our well-characterized TA families and case-control cohort, and apply robust bioinformatic analysis integrating publicly available data to identify putative causal variants, (2) characterize prioritized variants using functional genomic approaches in vitro, and (3) apply a PheWAS approach (phenome-wide association study) to determine the broader clinical significance of TA genes by linking TA genetic variants with additional health outcomes captured through a large DNA databank (BioVu Biobank). This study combines genome-wide discovery with biological experimentation, and leverages existing resources (DNA samples, genetic and phenotypic data from BioVu, established in vitro model) within a multi-pronged framework to identify novel TA genes/pathways. Therefore, this study is not only innovative in its approach, but in its capacity to overcome the limitations of traditional TA candidate gene studies. We have exciting published and unpublished data in support of these proposed studies that will greatly enhance our understanding of the molecular mechanisms underlying TA and provide the scientific basis for the development of patient-centered diagnostic and future translational research on tooth replacement therapies. Finally, this study directly addresses the NIDCR's notice of special interest in “Supporting Discovery Of Genetic Variants Underlying Dental, Oral and Craniofacial Diseases and Conditions”.