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

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

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Article in Human genomics, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

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7 authors.

Qianying Kong *Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.

Chunhui Qi *Henan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.

Qian ZhaoHenan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.

Huifang PengHenan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China.

Yanying DongBlood Transfusion Department, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shanxi, 710004, China. dongyanying0906@xjtu.edu.cn.

Hongwei JiangHenan Key Laboratory of Rare Diseases, Endocrinology and Metabolism Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang, 471003, China. jianghw@haust.edu.cn.

Xuechen ZhuState Key Laboratory of Female Fertility Promotion, Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, 100191, China. zhuxc@bjmu.edu.cn.

Funding

Beijing Natural Science Foundation Z240020Clinical Medicine Plus X - Young Scholars Project of Peking University PKU2024LCXQ005Peking University Medicine plus X Pilot Program-Platform Construction Project 2024YXXLHPT012Sponsored by Beijing Nova Program 20250484784the Fundamental Research Funds for the Central Universities PKU2025PKULCXQ036

6 · The paper itself

Abstract

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.

Indexed as

CadherinsCleft LipCleft PalateAnimalsbeta CateninCell MovementExome SequencingFemaleGenetic Predisposition to DiseaseHumansMiceMutation, MissenseNeural CrestWnt Signaling Pathwaybeta CateninCadherinsCNCCsFAT3 geneNon-syndromic orofacial cleftsWnt/β-catenin signaling pathway

Identifiers

PMID41933378

DOI10.1186/s40246-026-00956-5

PMCPMC13173973

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LicenceCC BY-NC-ND

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.