Advances in genetic mechanisms and precision medicine research for cleft lip and palate.

Abstract

Cleft Lip and Palate (CL/P) is the most common congenital craniofacial malformation. However, a central challenge remains in understanding how this multi-layered, dynamically interactive gene network is precisely modulated across specific cell lineages and developmental time windows, and how environmental factors integrate with genetic susceptibilities to drive phenotypic outcomes. Its etiology originates from an imbalance in a multi-layered, dynamically interactive gene network composed of core transcription factors (the p63-IRF6-GRHL3 axis), key signaling pathways (Wnt, BMP/TGF-β, FGF, Shh), and epigenetic regulation. This network precisely controls epithelial integrity, mesenchymal patterning, and epithelial-mesenchymal crosstalk. Variations at its key nodes (such as IRF6, SATB2, MSX1, PAX9, etc.) disrupt the developmental program, leading to the malformation. Single-cell and multi-omics technologies have revealed the cell-type specificity and spatiotemporal dynamics of disease-causing genes. Animal models (mice, zebrafish) provide essential tools for functional validation and mechanistic studies. These advances are driving CL/P research towards molecular subtype-based precise risk assessment, targeted intervention, and personalized treatment.