The prevalence of laterality defects in patients with congenital heart disease

Xiao-Hui Xie; Heng Gu; Zhuang-Zhuang Yuan; Jun-Lin Yang; Ke-le Qin; Jin-Lan Chen; Wei-Zhi Zhang; Li Xie; Yi-Feng Yang; Zhi-Ping Tan

doi:10.1038/s10038-025-01351-z

The prevalence of laterality defects in patients with congenital heart disease

J Hum Genet. 2025 Jun 5. doi: 10.1038/s10038-025-01351-z. Online ahead of print.

Authors

Xiao-Hui Xie^{1

2}, Heng Gu^{1

2}, Zhuang-Zhuang Yuan^{2

3}, Jun-Lin Yang^{1

2}, Ke-le Qin⁴, Jin-Lan Chen^{1

2}, Wei-Zhi Zhang^{1

2}, Li Xie^{1

2}, Yi-Feng Yang^{1

2}, Zhi-Ping Tan^{5

6}

Affiliations

¹ Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China.
² Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China.
³ Department of Cell Biology, School of Life Sciences, Central South University, Changsha, China.
⁴ The Second Department of Thoracic Surgery, Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
⁵ Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, China. zhipingtan@csu.edu.cn.
⁶ Clinical Center for Gene Diagnosis and Therapy, Department of Cardiovascular Surgery, The Second Xiangya Hospital of Central South University, Changsha, China. zhipingtan@csu.edu.cn.

PMID: 40467998
DOI: 10.1038/s10038-025-01351-z

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.