{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T22:57:50Z","timestamp":1772578670460,"version":"3.50.1"},"reference-count":42,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T00:00:00Z","timestamp":1772582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Genet."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      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\n                      <jats:italic>PDIA4<\/jats:italic>\n                      as a candidate gene potentially involved in cardiac development.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Whole-exome sequencing and targeted sequencing were performed to identify\n                      <jats:italic>PDIA4<\/jats:italic>\n                      as a candidate gene of CHD. To investigate the functional role of\n                      <jats:italic>PDIA4<\/jats:italic>\n                      ,\n                      <jats:italic>PDIA4<\/jats:italic>\n                      -knockdown human umbilical vein endothelial cells were generated, followed by cellular and transcriptomic analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A\n                      <jats:italic>de novo PDIA4<\/jats:italic>\n                      mutation (NM004911: c.1249G&amp;gt;A: p.V417I) was found in a patient with complex CHD. Burden analysis demonstrated a significant enrichment of rare deleterious\n                      <jats:italic>PDIA4<\/jats:italic>\n                      variants in patients with CHD compared with controls (Person\u2019s chi-squared test: OR: 4.08, 95% CI: 2.23\u20134.76,\n                      <jats:italic>p<\/jats:italic>\n                      = 7.46e\u22127). Deficiency of\n                      <jats:italic>PDIA4<\/jats:italic>\n                      in human umbilical vein endothelial cells suppressed functionality and inhibited the protein levels of both total and nuclear \u03b2-catenin as well as the downstream activity of the WNT\/\u03b2-catenin signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      Our study suggests that\n                      <jats:italic>PDIA4<\/jats:italic>\n                      may act as a susceptibility gene for CHD, and its deficiency may contribute to abnormal cardiac development by modulating the WNT\/\u03b2-catenin signaling pathway.\n                    <\/jats:p>\n                  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