The prevalence of laterality defects in patients with congenital heart disease

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.