Genetic analysis of a Chinese family with non-syndromic tooth agenesis may reveal a potential multi-locus etiology

Abstract

Tooth agenesis (TA), one of the most common craniofacial developmental anomalies, is characterized by the congenital absence of one or more teeth. While numerous genes have been implicated in non-syndromic tooth agenesis (NSTA), its genetic architecture often remains complex. In this study, we investigated the genetic basis of NSTA in a two-generation Chinese family utilizing whole-exome sequencing (WES) complemented by Sanger sequencing. Our analysis revealed a complex segregation pattern of multiple variants. After systematic filtering based on pathogenicity predictions and minor allele frequency (MAF), we identified eight potential contributory variants. These include homozygous missense variants in EDAR (c.1109 T > C), GHR (c.1630A > C), and COL17A1 (c.629C > T), a heterozygous missense variant in CEP152 (c.161C > T), and DSP (c.5213G > A) and three rare heterozygous missense variants in CCDC154 (c.925C > T), FRAS1 (c.9628G > A), and NBAS (c.5095G > A). Notably, the variants in GHR, CCDC154, FRAS1, and NBAS represent potential novel candidate genes for NSTA, thereby expanding the variant spectrum associated with this condition. The co-segregation of these multi-locus variants suggests that inheritance might be complex, perhaps involving oligogenic mechanisms. This points to the possibility of intricate genetic interactions in tooth development, offering new clues about the molecular basis of familial NSTA.