Whole Exome Sequencing Uncovers Key Genetic Variants in Congenital Tooth Agenesis: An Integrative Omics Approach

Abstract

This study investigates the genetic underpinnings of congenital tooth agenesis (CTA) using a multi-omics approach, integrating whole exome sequencing (WES)and RNA expression analysis. WES was used to analyze the genetic basis of CTA in six affected individuals one with syndromic and five with non-syndromic CTA alongside three healthy and two internal controls. We identified both known and novel variants in candidate genes (EDA, WNT10A, PAX9, TSPEAR) and assessed the functional impacts of novel variants (WNT10A (A135S), and compound heterozygous TSPEAR (L219P, I419Lfs*150) using RT-PCR, while bioinformatics tools were applied to both known and novel variants. RT-PCR indicated disrupted EDA and WNT10A signaling in novel candidate genes WNT10A and TSPEAR. Computational analysis showed deleterious effects for six variants, with gene ontology, protein disorder, localization, and post-translational modifications suggesting significant functional changes. Molecular dynamics simulations predicted that these variants could impact protein stability and function. Additionally, WES analysis revealed 21 genes consistently present in all patients (MAF [≤]20%), including novel variants in OR4F21 (K310R, F44L) and LCORL (L1734P). Two variants, OR4F21 (K310R) and MRTFB (A135A), appeared in all cases. Furthermore, 391 genes were shared among three patients, 204 among four, and 98 among five. Integrating multi-omic data from the GEO database identified 18 upregulated and 15 downregulated genes, with variants linked to systemic conditions such as autism, Alzheimers, congenital heart disease (CHD), ALS (amyotrophic lateral sclerosis) and cancer. Our findings provide insights into CTAs molecular mechanisms, identifying potential biomarkers and therapeutic targets. Further validation could improve diagnosis and treatment strategies for CTA. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=155 SRC="FIGDIR/small/24317461v1_ufig1.gif" ALT="Figure 1"> View larger version (93K): org.highwire.dtl.DTLVardef@718fe2org.highwire.dtl.DTLVardef@19d70ecorg.highwire.dtl.DTLVardef@1609ceforg.highwire.dtl.DTLVardef@1df3dc7_HPS_FORMAT_FIGEXP M_FIG C_FIG