Objectives: To identify rare variants contributing to human tooth agenesis.
Methods: Nine individuals presenting with tooth agenesis from 3 unrelated families were subjected to whole exome sequencing and bioinformatics analyses to identify causal variants contributing to tooth agenesis. Exome capture was performed using the Agilent SureSelect 50MB Target Enrichment System. Captured libraries were then subjected to paired-end sequencing on an Illumina HiSeq 2000 sequencing platform. Variants were filtered using information available on mutation/biological databases to prioritize candidate genes. Variants were then prioritized based on predicted functional impact and biological or functional information about the respective gene in a biological pathway or interactions with genes or proteins that are known to cause a similar phenotype. Variants were validated using direct sequencing.
Results: Whole exome sequencing identified thousands of coding variants in each individual sequenced. After discrete filtering and prioritization the number of variants was reduced to a minimum number of high priority candidates. Novel and potentially damaging variants were found in APC, FGFR1, LTBP2, PDGFRL, PMS2, and WNT10A genes among the 3 study families.
Conclusions: Our results provide new evidence for a role of LTBP2, PDGFRL, and PMS2 genes in human tooth agenesis, while supporting previous findings for APC, FGFR1 and WNT10A genes as likely candidate genes. Future studies should include assessing other tooth agenesis families for the variants identified as well as functional studies to investigate the biological effects of each variant.