A novel phex gene variant causes non-syndromic tooth agenesis

Objectives For a long time, phosphate regulating endopeptidase X-linked (phex) gene variants have been considered the primary cause of hypophosphatemic rickets. Here, we recruited a pedigree with non-syndromic tooth agenesis (NSTA), where all patients exhibit solely the absence of mandibular central incisors, indicating a highly conserved clinical phenotype. This observation leads us to hypothesize a potential connection between phex variants and NSTA. Materials and methods Whole-exome sequencing and genetic co-segregation analysis were employed to investigate the genetic basis of NSTA in this family. To further explore this hypothesis, we used phex knockdown zebrafish models and dental pulp stem cells (DPSCs) from the patient (DPSCs-MUT) and normal control (DPSCs-CON) to assess tooth development and cellular functions. Results We identified a novel PHEX variant (NM_000444.5 c.1763 A > T, p.N588I) that co-segregated with the NSTA phenotype. The phex knockdown zebrafish displayed a tooth loss phenotype, which closely aligns with characteristics of NSTA. Additionally, DPSCs-MUT exhibited significantly reduced mineralization and proliferation capabilities compared to DPSCs-CON, along with increased enzymatic activity. These findings suggest that PHEX variants adversely affect DPSC function. Transcriptome sequencing analysis of the DPSCs revealed significant differences in gene expression between DPSCs-MUT and DPSCs-CON. Specifically, genes linked to the cGMP-PKG signaling pathway were abnormally expressed, implicating this pathway in the potential pathogenesis of NSTA due to PHEX variants. Conclusions Collectively, this study offers a foundation for further research on the relationship between PHEX variants and NSTA, which could enhance the diagnosis and treatment strategies for this condition in the future.