# Defects in PDIA4 increase individuals’ susceptibility to congenital heart disease

## TL;DR

Defects in the PDIA4 gene increase the risk of congenital heart disease by affecting protein folding and disrupting heart development.

## Contribution

This study identifies PDIA4 as a novel susceptibility gene for CHD and links its deficiency to impaired WNT/β-catenin signaling.

## Key findings

- A de novo PDIA4 mutation was found in a patient with complex CHD.
- PDIA4 deficiency suppressed endothelial cell function and reduced β-catenin levels.
- Rare deleterious PDIA4 variants were significantly enriched in CHD patients compared to controls.

## Abstract

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.

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.

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.

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.