The Genetic Landscape of Human Tooth Agensis

项目摘要 该项目的目标是发现人类牙齿发育不全（TA）的候选致病遗传变异， 颅面出生缺陷影响全球约2亿人，并对人类的美学，功能， 对受影响的个人造成心理和经济负担。尽管研究取得了进展，但已知TA中的突变 基因占所有病例的不到50%，这表明其他致病基因仍有待发现。 TA的全基因组研究很少，此外，对已鉴定变体的解释也具有挑战性 这是因为缺乏将基因发现与功能基因组学方法相结合的研究。这使得 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，我们将确定和功能特征的潜在遗传 在家族性和散发性TA的变异，以提高我们的生物学途径参与的理解， 条件为了实现我们的目标，我们将：（1）对我们的450名个体进行全外显子组测序（WES）。 良好表征的TA家族和病例对照队列，并应用稳健的生物信息学分析， 公开可用的数据，以确定推定的因果变异，（2）使用功能性 体外基因组方法，和（3）应用PheWAS方法（全表型关联研究）来确定 通过将TA遗传变异与其他健康结果联系起来，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。这项研究将全基因组发现与 生物实验，并利用现有的资源（DNA样本，遗传和表型数据， BioVu，建立的体外模型），以鉴定新的TA基因/途径。 因此，这项研究不仅在方法上具有创新性，而且在克服 传统的TA候选基因研究。我们有令人兴奋的已发表和未发表的数据支持这些观点。 提出的研究将大大提高我们对TA的分子机制的理解， 为发展以患者为中心的诊断和未来的转化研究提供科学依据 牙齿替换疗法的研究最后，这项研究直接解决了NIDCR的特别关注的通知， “支持发现牙齿，口腔和颅面疾病和条件下的遗传变异”。

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”.