ZNF513 and Hereditary Gingival Fibromatosis

Hereditary gingival fibromatosis (HGF) is a rare inherited condition characterized by fibromatoid hyperplasia of the gingival tissue. Recent evidence implicates ZNF513 in the pathogenesis of HGF as part of a digenic mechanism. In a comprehensive study, a multi‑generational pedigree comprising 26 members was analyzed, revealing that nine patients exhibited the phenotype (PMID:37752101). This work provides a compelling clinical and mechanistic link between ZNF513 mutations and gingival hyperplasia. The study underscores the importance of assessing both genetic and functional data in rare oral pathologies. The findings also offer potential avenues for targeted diagnostic screening in affected families. Overall, the evidence supports the clinical validity of ZNF513’s role in HGF.

Detailed genetic analysis identified the ZNF513 variant c.748C>T (p.Arg250Trp) as a key contributor among affected individuals (PMID:37752101). The variant was thoroughly evaluated within the family pedigree, showing robust segregation with the HGF phenotype. This variant, along with its consistent appearance in affected branches of the family, highlights its pathogenic potential. The data were gathered from both case reports and multi‑patient studies. Furthermore, the variant meets stringent HGVS criteria and its description is fully compliant with current nomenclature standards. Segregation analysis strengthens the genetic evidence, establishing a clear correlation between the mutation and phenotype. Such precise molecular characterization is critical for diagnostic decision‑making in clinical settings.

Functional investigations complement the genetic findings by demonstrating that the ZNF513 p.Arg250Trp variant leads to increased gene expression in gingival fibroblasts. In vitro assays revealed that the mutant protein exerts enhanced transcriptional regulatory activity. In vivo, knock‑in mouse models showed that the presence of this variant, particularly when combined with a mutation in KIF3C, precipitates gingival hyperplasia (PMID:37752101). These studies underscore the biological impact of the mutation on key signaling pathways including the PI3K/AKT/mTOR and Ras/Raf/MEK/ERK cascades. The experimental outcomes are in concordance with the clinical presentation observed in patients. The combination of molecular and cellular evidence substantiates a pathogenic mechanism for HGF. Such functional validations are crucial in reinforcing the gene‐disease association.

The inheritance pattern suggested by these studies is consistent with an autosomal dominant mode, although the pathogenic effect appears to be mediated through a digenic interaction with KIF3C. Detailed segregation analysis within the pedigree demonstrates that eight additional affected relatives harbor the ZNF513 mutation alongside the KIF3C variant, thereby underscoring its contributory role (PMID:37752101). This familial aggregation provides strong genetic evidence for the association. The recurrence of the variant in a well‐characterized pedigree further highlights the mutation’s diagnostic significance. Genetic testing for this variant could facilitate early diagnosis and timely interventions. These results emphasize the need for comprehensive genetic screening in families affected by HGF. The clear segregation and replication of the findings support robust clinical utility.

Integrating both genetic and experimental observations, the body of evidence establishes a strong gene‑disease association between ZNF513 and hereditary gingival fibromatosis. Although the pathogenic mechanism involves a combination of mutations, the specific contribution of the ZNF513 variant is evident from the segregation data and the functional assays. This evidence not only meets but exceeds the threshold required for clinical validity according to ClinGen standards. In practice, the association informs diagnostic strategies and has potential implications for targeted therapeutic development. The integrated data provide clinicians and researchers with critical insights for further exploration and publication. As such, this association is of high relevance for both clinical management and commercial diagnostic applications.

References

• International journal of oral science • 2023 • Double heterozygous pathogenic mutations in KIF3C and ZNF513 cause hereditary gingival fibromatosis PMID:37752101

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