Functional Variant at 19q13.3 Confers Nonsyndromic Cleft Palate Susceptibility by Regulating HIF3A

This study investigates the genetic factors associated with nonsyndromic cleft palate only (NSCPO) through a two-stage genome-wide association study (GWAS) and functional experiments. A total of 311 NSCPO cases and 1,136 controls were included, and we identified rs3826795 in HIF3A significantly associated with NSCPO risk (p = 4.27E-09). Functional assays showed that the A allele of rs3826795 reduced VEZF1 binding to the HIF3A promoter, thereby enhancing HIF3A expression. Additionally, we demonstrated that HIF3A significantly influenced cellular processes, including apoptosis, proliferation, and migration, in both in vitro and in vivo models. Pathway enrichment analysis indicated that HIF3A suppressed the GABAergic synapse pathway, which plays a crucial role in embryonic development. These findings provide valuable insights into the genetic mechanisms underlying NSCPO susceptibility and suggest potential targets for future therapeutic interventions.