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<p>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 <i>FAT3</i> gene, all of which were located within the extracellular cadherin domains of the <i>FAT3</i> protein. Sanger sequencing confirmed the authenticity of these variants, while bioinformatic predictions and protein structural modeling suggested potential disruption of <i>FAT3</i> function.Using in vivo animal models, we demonstrated that reduced <i>fat3</i> function impairs cranial neural crest cells (CNCCs) induction and migration processes. Further investigation revealed that <i>fat3</i> 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 <i>FAT3</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月3日

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  • Qianying Kong,
  • Chunhui Qi,
  • Qian Zhao,
  • Huifang Peng,
  • Yanying Dong,
  • Hongwei Jiang,
  • Xuechen Zhu

摘要

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.