{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T20:02:02Z","timestamp":1791316922184,"version":"4.3.1"},"update-to":[{"DOI":"10.1371\/journal.pgen.1011579","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2025,9,2]],"date-time":"2025-09-02T00:00:00Z","timestamp":1756771200000}}],"reference-count":92,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T00:00:00Z","timestamp":1756166400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-20-1-0433"],"award-info":[{"award-number":["W81XWH-20-1-0433"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020415","name":"Additional Ventures","doi-asserted-by":"publisher","award":["SVRF"],"award-info":[{"award-number":["SVRF"]}],"id":[{"id":"10.13039\/100020415","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020415","name":"Additional Ventures","doi-asserted-by":"publisher","award":["Expansion Award"],"award-info":[{"award-number":["Expansion Award"]}],"id":[{"id":"10.13039\/100020415","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010514","name":"Seattle Children\u00e2\u20ac\u2122s Hospital","doi-asserted-by":"publisher","award":["Heart Center"],"award-info":[{"award-number":["Heart Center"]}],"id":[{"id":"10.13039\/100010514","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosgenetics.org"],"crossmark-restriction":false},"short-container-title":["PLoS Genet"],"abstract":"<jats:p>\n                    Congenital heart defects (CHDs) occur in about 1% of live births and are the leading cause of infant death due to birth defects. While there have been remarkable efforts to pursue large-scale whole-exome and genome sequencing studies on CHD patient cohorts, it is estimated that these approaches have thus far accounted for only about 50% of the genetic contribution to CHDs. We sought to take a new approach to identify genetic causes of CHDs. By combining analyses of genes that are under strong selective constraint along with published embryonic heart transcriptomes, we identified over 200 new candidate genes for CHDs. We utilized protein-protein interaction (PPI) network analysis to identify a functionally-related subnetwork consisting of known CHD genes as well as genes encoding proteasome factors, in particular\n                    <jats:italic>POMP<\/jats:italic>\n                    ,\n                    <jats:italic>\n                      <jats:italic>PSMA6<\/jats:italic>\n                    <\/jats:italic>\n                    ,\n                    <jats:italic>PSMA7<\/jats:italic>\n                    ,\n                    <jats:italic>PSMD3<\/jats:italic>\n                    , and\n                    <jats:italic>PSMD6<\/jats:italic>\n                    . We used CRISPR targeting in zebrafish embryos to preliminarily identify roles for the PPI subnetwork genes in heart development. We then used CRISPR to create new mutant zebrafish strains for two of the proteasome genes in the subnetwork:\n                    <jats:italic>\n                      <jats:italic>pomp<\/jats:italic>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:italic>psmd6<\/jats:italic>\n                    <\/jats:italic>\n                    . We show that loss of proteasome gene functions leads to defects in zebrafish heart development, including dysmorphic hearts, myocardial cell blebbing, and reduced outflow tracts. We also identified deficits in cardiac function in\n                    <jats:italic>\n                      <jats:italic>pomp<\/jats:italic>\n                    <\/jats:italic>\n                    and\n                    <jats:italic>\n                      <jats:italic>psmd6<\/jats:italic>\n                    <\/jats:italic>\n                    mutants. These heart defects resemble those seen in zebrafish mutants for known CHD genes and other critical heart development genes. Our study provides a novel systems genetics approach to further our understanding of the genetic causes of human CHDs.\n                  <\/jats:p>","DOI":"10.1371\/journal.pgen.1011579","type":"journal-article","created":{"date-parts":[[2025,8,26]],"date-time":"2025-08-26T17:46:42Z","timestamp":1756230402000},"page":"e1011579","update-policy":"https:\/\/doi.org\/10.1371\/journal.pgen.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["A systems genetics approach identifies roles for proteasome factors in heart development and congenital heart defects"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3265-1495","authenticated-orcid":true,"given":"Gist 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