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Pathogenic variants in SHROOM3 associated with hemifacial microsomia

Journal of Human Genetics volume 70, pages 189–194 (2025)Cite this article

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Abstract

Hemifacial microsomia (HFM) is a rare congenital disorder that affects facial symmetry, ear development, and other congenital anomalies. However, known causal genes account for only approximately 6% of patients, indicating the need to discover more pathogenic genes. Association tests demonstrated an association between common variants in SHROOM3 and HFM (P = 1.02E-4 for the lead SNP), while gene burden analysis revealed a significant enrichment of rare variants in HFM patients compared to healthy controls (P = 2.78E-5). We then evaluated the expression patterns of SHROOM3 and the consequences of its deleterious variants. Our study identified 7 deleterious variants in SHROOM3 among the 320 Chinese HFM patients and 2 deleterious variants in two HFM trios, respectively, suggesting a model of dominant inheritance with incomplete penetrance. These variants were predicted to significantly impact SHROOM3 function. Furthermore, the gene expression pattern of SHROOM3 in the pharyngeal arches and the presence of facial abnormalities in gene-edited mice suggest that SHROOM3 plays important roles in facial development. Our findings suggest that SHROOM3 is a likely pathogenic gene for HFM.

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Acknowledgements

We thank the patients and their guardians for their participation in this research. This work was supported by the National Natural Science Foundation of China (81701930 to B.Q.W.).

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Author notes

  1. These authors contributed equally: Qin Li, Bing-Hua Zhang.

Authors and Affiliations

  1. Department of Stomatology, Eye&ENT Hospital, Fudan University, Shanghai, 200031, China

    Qin Li, Xiang Zuo & Weiwei Zhang

  2. Shanghai Xuhui District Dental Center, Shanghai, 200032, China

    Bing-Hua Zhang

  3. Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100144, China

    Qi Chen, Peng Lu & Bingqing Wang

  4. Department of facial plastic and reconstructive surgery, Eye&ENT Hospital, Fudan University, Shanghai, 200031, China

    Yaoyao Fu

Authors
  1. Qin Li
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  2. Bing-Hua Zhang
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  3. Qi Chen
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  4. Yaoyao Fu
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  5. Xiang Zuo
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  6. Peng Lu
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  7. Weiwei Zhang
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  8. Bingqing Wang
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Contributions

Conceptualization: B.W., W.Z.; Sample collection: W.Z., B.-H.Z., P.L.; Experiments: Q.L., B.-H.Z., Q.C.; Data analysis: Q.L., B.-H.Z., X.Z.; Writing-original draft: B.W., Q.L., W.Z.; Writing-reviewing and editing: W.Z., B.W.

Corresponding authors

Correspondence to Weiwei Zhang or Bingqing Wang.

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All human studies were reviewed and approved by the Ethics Committee of the Eye & ENT Hospital of Fudan University. An informed consent form was signed by all individuals, and explicit written consent was provided for publication of clinical images.

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Li, Q., Zhang, BH., Chen, Q. et al. Pathogenic variants in SHROOM3 associated with hemifacial microsomia. J Hum Genet 70, 189–194 (2025). https://doi.org/10.1038/s10038-025-01317-1

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