Defects in PDIA4 increase individuals’ susceptibility to congenital heart disease

Introduction Congenital heart disease (CHD) comprises structural abnormalities of the heart and major blood vessels arising during fetal development. Protein disulfide isomerase family member 4 (PDIA4) facilitates protein folding processes. However, its potential involvement in CHD has not been investigated. In this study, we identified PDIA4 as a candidate gene potentially involved in cardiac development. Methods Whole-exome sequencing and targeted sequencing were performed to identify PDIA4 as a candidate gene of CHD. To investigate the functional role of PDIA4 , PDIA4 -knockdown human umbilical vein endothelial cells were generated, followed by cellular and transcriptomic analyses. Results A de novo PDIA4 mutation (NM004911: c.1249G>A: p.V417I) was found in a patient with complex CHD. Burden analysis demonstrated a significant enrichment of rare deleterious PDIA4 variants in patients with CHD compared with controls (Person’s chi-squared test: OR: 4.08, 95% CI: 2.23–4.76, p = 7.46e−7). Deficiency of PDIA4 in human umbilical vein endothelial cells suppressed functionality and inhibited the protein levels of both total and nuclear β-catenin as well as the downstream activity of the WNT/β-catenin signaling pathway. Conclusion Our study suggests that PDIA4 may act as a susceptibility gene for CHD, and its deficiency may contribute to abnormal cardiac development by modulating the WNT/β-catenin signaling pathway.