Whole exome sequencing uncovers key genetic variants in congenital tooth agenesis: an integrative omics approach.

PURPOSE: This study investigates the genetic basis of congenital tooth agenesis (CTA) using an omics approach. Whole exome sequencing (WES) identified novel variants, which were further analyzed in combination with RNA expression data to uncover genes associated with CTA, molecular mechanisms, and systemic disease links.

METHODS

WES was performed on 11 samples (6 CTA patients and 5 controls) to identify pathogenic variants. Integrative approaches, including gene expression profiling, protein interaction mapping, pathway enrichment, in silico functional assessments and molecular dynamics (MD) simulations, linked genetic findings to functional outcomes. qRT-PCR was used to evaluate signaling pathway alterations, and Sanger sequencing validated key variants.

RESULTS

4 Known and 2 novel variants were identified in candidate genes such as EDA, WNT10A, PAX9, and TSPEAR. Novel variants in WNT10A p.(Ala135Ser) and TSPEAR p.(Leu219Pro), p.(Ile419Leu fs*150) showed functional disruption in signaling pathways. Computational analyses predicted deleterious effects on protein stability for six variants. WES identified 21 genes with variants consistently present in all patients (MAF ≤ 20%), including novel variants in OR4F21 and LCORL. Notably, OR4F21 p.(Lys310Arg) and MRTFB p.(Ala135=) were detected in all affected individuals. Integrated omics analysis revealed 18 upregulated and 15 downregulated genes associated with developmental and systemic pathways.

CONCLUSIONS

Our findings highlight the genetic heterogeneity of congenital tooth agenesis and demonstrate the utility of integrating whole exome sequencing with multi-omics analyses to better understand the molecular basis of tooth development and identify potential genetic contributors to CTA.