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Whole exome sequencing improves genetic diagnosis of fetal clubfoot

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Abstract

Objective

This retrospective study aimed to investigate the value of whole exome sequencing (WES) for clubfoot (CF) fetuses with or without other structural abnormalities and to further explore the genetic causes of fetal CF. Methods: this study included 83 singleton pregnancies diagnosed with fetal CF referred to our center between January 2016 and March 2022; cases were divided into two groups: isolated CF and non-isolated CF. After excluding cases with positive karyotyping and chromosomal microarray analysis results, WES was performed for the eligible fetuses and parents. Monogenic variants detected by WES and perinatal outcomes were recorded and evaluated at postnatal follow-up. Results: overall, clinically significant variations were identified in 12.0% (10/83) of fetuses, and the detection rate was significantly higher in the non-isolated than in the isolated CF group (8/36, 22.2% vs. 2/47, 4.3%, p = 0.031). We additionally detected eight (9.6%) fetuses harboring variants of unknown significance. We identified 11 clinically significant variations correlating with clinical phenotypes in nine genes from ten fetuses, with KLHL40 being the most frequent (n = 2). Furthermore, we observed a significant difference in termination and survival rates between isolated and non-isolated CF cases (27.6 vs. 77.8% and 59.6 vs. 19.4%, p < 0.001 for both). Conclusion: our data indicate that WES has a high additional diagnostic yield for the molecular diagnosis of fetal CF, markedly enhancing existing prenatal diagnostic capabilities and expanding our understanding of intrauterine genetic disorders, thus assisting us to better interpret fetal phenotype in the future.

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Data Availability

The data that support the findings of this study are not publicly available as the information contained could compromise the privacy of research participants. Further inquiries can be directed to the corresponding author.

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Acknowledgements

We thank all the participants in this study.

Funding

This research was funded by the sub-project of the National Key R&D Program (2021YFC2701002), the National Natural Science Foundation of China (81801461, 81873836, 81771594, 81671474, 81501267), the Natural Science Foundation of Guangdong Province (2019A1515012034), the Project of Guangzhou Science and Technology Bureau (201607010341, 202201020643).

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  1. Ruibin Huang, Hang Zhou, and Chunling Ma have contributed equally to this work.

Authors and Affiliations

  1. Prenatal Diagnostic Center, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangdong, 510620, Guangdong, China

    Ruibin Huang, Hang Zhou, Chunling Ma, Fang Fu, Ken Cheng, You Wang, Ru Li, Tingying Lei, Qiuxia Yu, Dan Wang, Shujuan Yan, Xin Yang, Dongzhi Li & Can Liao

  2. The First Clinical Medical College, Southern Medical University, Guangzhou, 510515, Guangdong, China

    Chunling Ma & You Wang

  3. School of Medicine, South China University of Technology, Guangzhou, 510641, Guangdong, China

    Ken Cheng

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Contributions

Manuscript writing: RH., HZ. and CM.; Study design and manuscript editing: FF. and CL.; Document retrieval: YW., SY. and KC; Exome sequence variants classification: RL., QY. and DW.; Clinical data statistics: TL., XY. and DL. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Can Liao.

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Huang, R., Zhou, H., Ma, C. et al. Whole exome sequencing improves genetic diagnosis of fetal clubfoot. Hum Genet 142, 407–418 (2023). https://doi.org/10.1007/s00439-022-02516-y

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