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The prevalence of laterality defects in patients with congenital heart disease

Journal of Human Genetics volumeΒ 70,Β pages 453–461 (2025)Cite this article

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Abstract

Congenital heart disease (CHD) affects approximately 1% of liveborn infants. Among primary ciliary dyskinesia (PCD) cases, about 50% present with situs inversus totalis, and 6.3% have heterotaxy with CHD. The incidence of CHD is significantly higher in heterotaxy patients compared to the general population (57% vs. 1%). However, comprehensive studies on CHD related to laterality defects are still limited. In this study, we retrospectively analyzed 18,781 CHD patients to determine the prevalence of laterality defects. To evaluate the association between specific complex CHD phenotypes and laterality defects, we utilized a binary logistic regression model. Additionally, we performed whole-exome sequencing (WES) on 121 CHD patients with laterality defects. The results showed that 1.1% of CHD patients had laterality defects (206/18,781), with 0.4% presenting as situs inversus totalis and 0.7% as situs ambiguus. The prevalence of laterality defects was higher in complex CHD cases (5.4%) compared to simple CHD (0.4%). Notably, single atrium with single ventricle (SA+SV) was strongly associated with laterality defects (OR = 48.23, p < 0.001). Among the 121 CHD patients with situs abnormalities, WES identified pathogenic gene variants in 13.2%, with 9.1% harboring known pathogenic genes (ZIC3, NODAL, NKX2-5, GDF1, MMP21, PKD1L1, CCDC151, DNAAF4, LRRC56) and 4.1% exhibiting variants in candidate genes (FMNL3, C1ORF127, CFAP157, C10ORF107, MYO1D). This study revealed both established and novel gene candidates, contributing to our understanding of the genetic basis of laterality defects in CHD.

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Data are available upon reasonable request from the corresponding author.

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Acknowledgements

The authors express their sincere gratitude to all patients and their families for their invaluable support and cooperation.

Funding

This study was supported by the National Natural Science Foundation of China (No. 81970268, to Dr. Tan) and Natural Science Foundation of Hunan Provincial (No.2023JJ30781, to Dr. Tan).

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Authors and Affiliations

  1. Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China

    Xiao-hui Xie,Β Heng Gu,Β Jun-lin Yang,Β Jin-lan Chen,Β Wei-zhi Zhang,Β Li Xie,Β Yi-feng YangΒ &Β Zhi-ping Tan

  2. Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China

    Xiao-hui Xie,Β Heng Gu,Β Zhuang-zhuang Yuan,Β Jun-lin Yang,Β Jin-lan Chen,Β Wei-zhi Zhang,Β Li Xie,Β Yi-feng YangΒ &Β Zhi-ping Tan

  3. Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China

    Zhuang-zhuang Yuan

  4. The Second Department of Thoracic Surgery, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China

    Ke-le Qin

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  1. Xiao-hui Xie
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Contributions

Z-PT designed the overall study and performed data analysis. X-HX processed the WES data, validated the mutation, and drafted the manuscript. Y-FY, J-LC, L-X and W-ZZ enrolled the subjects. H-G, J-LY, K-LQ carried out the clinical data analysis. Z-ZY analyzed the data and edited the manuscript. All authors read and approved the final version of the manuscript. All authors contributed to the article and approved the submitted version.

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Correspondence to Zhi-ping Tan.

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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics statement

The study involving human subjects were reviewed and approved by Ethics Committee of the Second Xiangya Hospital of the Central South University (Approval No. 322, 2021). A signed written informed consent was obtained from the legal guardians of the patient for the publication of any potentially identifiable images or data included in this article.

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Xie, Xh., Gu, H., Yuan, Zz. et al. The prevalence of laterality defects in patients with congenital heart disease. J Hum Genet 70, 453–461 (2025). https://doi.org/10.1038/s10038-025-01351-z

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