ORIGINAL RESEARCH article
Front. Genet.
Sec. Genetics of Common and Rare Diseases
This article is part of the Research TopicNew Insights in Rare Genes Involved in Inherited Cardiac DiseasesView all 9 articles
Defects in PDIA4 enhance Individuals' susceptibility to Congenital Heart Disease
Provisionally accepted
Yuquan Lu
Jiangjie LiuSiyu SunZhiyu FengYuan Gao
Shao MinQuannan ZhuangSiyi Lin
Quming Zhao
Xianghui Huang
Wei Sheng*
Guoying Huang*- Children's Hospital of Fudan University, Shanghai, China
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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, accompanied by inhibiting 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 the abnormal cardiac development through modulation of the WNT/β-catenin signaling pathway.
Keywords: Congenital heartdisease, Protein Disulfide Isomerase Family Member 4, targeted sequencing, variants, Whole-exome sequencing, Wnt/β-catenin signaling pathway
Received: 25 Nov 2025; Accepted: 23 Jan 2026.
Copyright: © 2026 Lu, Liu, Sun, Feng, Gao, Min, Zhuang, Lin, Zhao, Huang, Sheng and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Wei Sheng
Guoying Huang
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