关键词: 先天缺牙, 全外显子组测序, LENG9

Abstract:

Objective To investigate mutations in a family lineage with congenital absence of lower incisors, identify mutation sites and explore the effects of mutations on protein structure and function to provide new insights into the mechanisms underlying the development of congenital absence of lower incisors. Methods Whole-exome sequencing and Sanger sequencing were used to screen the possible causative genes in this family lineage. The validated genes were analyzed for functional prediction and amino acid conservation at the mutation sites. The three-dimensional structure of the protein was predicted by AlphaFold and PyMOL. Candidate gene expression was analyzed using mouse genome informatics and the spatiotemporal transcriptome atlas. Single-cell RNA sequencing data were used to analyze downstream pathways potentially regulated by the LENG9 gene. Results A family pedigree with congenital absence of lower incisors was identified during clinical practice. A phenotype of congenitally missing lower incisors was present in the proband and the proband’s younger brother. The proband had distal molar relationship and distal canine relationship on both sides, mild crowding of upper anterior teeth, scattered spaces in the mandible, and deep overbite as well as deep overjet, whereas the proband’s parents did not have a missing tooth phenotype. Through whole-exome sequencing, a mutation(c.392C>T: p.Arg131His) was identified in exon 1 of the LENG9 gene, and the arginine at position 131 was highly conserved among various species. Bioinformatics analyses showed that LENG9 was expressed in the jaws and teeth. GO and KEGG pathway annotation analyses indicated that LENG9 may play a role in the pathogenesis of congenital tooth agenesis by regulating oxidative phosphorylation-related pathways. Conclusion In this study, we report a family lineage with congenital absence of lower incisors and a de novo mutation in LENG9 (c. 392C>T: p. Arg131His), and the findings suggest that the mutation LENG9 may be the causative gene responsible for the congenital absence of lower incisors in this family lineage with congenital tooth agenesis.

Key words: congenital tooth agenesis, whole-exome sequencing, LENG9