Rare variants in FAT3 as possible contributors to non-syndromic orofacial cleft risk

Non-syndromic orofacial clefts (NSOFCs) represent the most common human craniofacial malformations, yet the majority of their genetic causes remain unclear. This study, by analyzing whole-exome sequencing (WES) data from multiple patients with NSOFCs, identified eight de novo low-frequency missense variants in the FAT3 gene, all of which were located within the extracellular cadherin domains of the FAT3 protein. Sanger sequencing confirmed the authenticity of these variants, while bioinformatic predictions and protein structural modeling suggested potential disruption of FAT3 function.Using in vivo animal models, we demonstrated that reduced fat3 function impairs cranial neural crest cells (CNCCs) induction and migration processes. Further investigation revealed that fat3 knockdown leads to reduced β-catenin levels, a key regulator of craniofacial development and CNCCs induction, migration, and fate determination. Collectively, these findings suggest that FAT3 represents a previously underappreciated genetic contributor to NSOFCs risk and may influence craniofacial development, at least in part, through modulation of β-catenin abundance and canonical Wnt/β-catenin signaling.