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We hypothesized that the contribution of a major genetic locus modulates the manifestation of the CHDs. After genome-wide linkage mapping, fine mapping, and high-throughput targeted sequencing, a recessive frameshift mutation of the heterogeneous nuclear ribonucleoprotein A1 (\n                    <jats:italic>Hnrnpa1<\/jats:italic>\n                    ) gene was confirmed (\n                    <jats:italic>\n                      Hnrnpa1\n                      <jats:sup>ct<\/jats:sup>\n                    <\/jats:italic>\n                    ).\n                    <jats:italic>Hnrnpa1<\/jats:italic>\n                    was expressed in both the first heart field (FHF) and second heart field (SHF) at the cardiac crescent stage but was only maintained in SHF progenitors after heart tube formation.\n                    <jats:italic>\n                      Hnrnpa1\n                      <jats:sup>ct\/ct<\/jats:sup>\n                    <\/jats:italic>\n                    homozygous mutants displayed complete CHD penetrance, including truncated and incomplete looped heart tube at E9.5, ventricular septal defect (VSD) and persistent truncus arteriosus (PTA) at E13.5, and VSD and double outlet right ventricle at P0. Impaired development of the dorsal mesocardium and sinoatrial node progenitors was also observed. Loss of\n                    <jats:italic>Hnrnpa1<\/jats:italic>\n                    expression leads to dysregulation of cardiac transcription networks and multiple signaling pathways, including BMP, FGF, and Notch in the SHF. Finally, two rare heterozygous mutations of\n                    <jats:italic>HNRNPA1<\/jats:italic>\n                    were detected in human CHDs. These findings suggest a role of\n                    <jats:italic>Hnrnpa1<\/jats:italic>\n                    in embryonic heart development in mice and humans.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.98555","type":"journal-article","created":{"date-parts":[[2018,1,24]],"date-time":"2018-01-24T11:00:56Z","timestamp":1516791656000},"source":"Crossref","is-referenced-by-count":19,"title":["Mutations in Hnrnpa1 cause congenital heart defects"],"prefix":"10.1172","volume":"3","author":[{"given":"Zhe","family":"Yu","sequence":"first","affiliation":[{"name":"School of Biomedical Sciences, Joint Laboratories of Matrix Biology and Diseases, The University of Hong Kong, Hong Kong, China."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul L.F.","family":"Tang","sequence":"additional","affiliation":[{"name":"School of Biomedical Sciences, Joint Laboratories of Matrix Biology and Diseases, The University of Hong Kong, Hong Kong, 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