{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T02:09:17Z","timestamp":1773194957066,"version":"3.50.1"},"reference-count":15,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T00:00:00Z","timestamp":1773100800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Pathogenic variants in the X-linked\n                      <jats:italic>USP9X<\/jats:italic>\n                      gene, which evades X-chromosome inactivation, have been predominantly linked to neurodevelopmental disorders (NDDs). Accumulating evidence has linked\n                      <jats:italic>USP9X<\/jats:italic>\n                      dysfunction to congenital heart disease (CHD), yet the specific genotype-phenotype correlations in this context remain poorly characterized. Pulmonary atresia with ventricular septal defect (PA\/VSD) represents a severe and complex form of congenital heart disease (CHD), characterized by heterogeneous etiological mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Case presentation<\/jats:title>\n                    <jats:p>\n                      A 34-year-old G2P1L1 woman was referred at 22 weeks of gestation for prenatal echocardiography due to suspected fetal cardiac anomaly. Echocardiographic evaluation identified a male fetus with PA\/VSD. Following detailed counseling, the couple elected to terminate the pregnancy due to the poor prognosis and opted for subsequent genetic testing. Trio whole-exome sequencing (WES) identified a\n                      <jats:italic>de novo<\/jats:italic>\n                      hemizygous missense variant in\n                      <jats:italic>USP9X<\/jats:italic>\n                      (NM_001039590.3: c.5186A\u2009&amp;gt;\u2009G; p.His1729Arg; rs2147230302) in the male fetus. This variant is categorized as \u201cLikely Pathogenic\u201d in ClinVar for female-restricted syndromic neurodevelopmental disorders (NDDs), yet it has not been previously linked to congenital heart diseases (CHDs), specifically PA\/VSD. The p.His1729Arg substitution impacts a conserved residue within the structurally critical zinc-finger domain of the\n                      <jats:italic>USP9X<\/jats:italic>\n                      protein. Comprehensive genetic screening failed to identify additional pathogenic variants that could explain the observed phenotype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This case represents the first report establishing a link between the\n                      <jats:italic>de novo<\/jats:italic>\n                      p.His1729Arg variant in\n                      <jats:italic>USP9X<\/jats:italic>\n                      and the CHD phenotype of PA\/VSD in a male fetus. This finding broadens the known phenotypic spectrum of this likely pathogenic\n                      <jats:italic>USP9X<\/jats:italic>\n                      variant, underscoring its pleiotropic effects and implicating the gene in critical cardiac developmental pathways. Routine cardiac assessment is recommended for individuals harboring pathogenic\n                      <jats:italic>USP9X<\/jats:italic>\n                      variants.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fcvm.2026.1726544","type":"journal-article","created":{"date-parts":[[2026,3,10]],"date-time":"2026-03-10T05:30:00Z","timestamp":1773120600000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Case Report: De novo USP9X missense mutation in a male fetus with pulmonary atresia and ventricular septal defect: expanding the genotype-phenotype spectrum of USP9X-related disorders"],"prefix":"10.3389","volume":"13","author":[{"given":"Tingting","family":"Man","sequence":"first","affiliation":[{"name":"Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hairui","family":"Sun","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoyan","family":"Hao","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaowei","family":"Liu","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yihua","family":"He","sequence":"additional","affiliation":[{"name":"Maternal-Fetal Medicine Center in Fetal Heart Disease, Beijing Anzhen Hospital, Capital Medical University","place":["Beijing, China"]},{"name":"Beijing Lab for Cardiovascular Precision Medicine, Capital Medical University","place":["Beijing, China"]},{"name":"Key Laboratory of Maternal-Fetal Medicine in Fetal Heart Disease","place":["Beijing, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1533","DOI":"10.3390\/jcm9051533","article-title":"Tetralogy of fallot or pulmonary 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