The Genetic Landscape of Human Tooth Agensis

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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 We have exciting published and unpublished data in support of these proposed studies that will greatly enhance our understanding of the molecular mechanisms underlying TA and provide the scientific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”.