{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T15:44:35Z","timestamp":1787499875226,"version":"build-2736575974"},"reference-count":22,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2023,6,1]],"date-time":"2023-06-01T00:00:00Z","timestamp":1685577600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2023,6]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>Known genetic causes of congenital heart disease (CHD) explain &lt;40% of CHD cases, and interpreting the clinical significance of variants with uncertain functional impact remains challenging. We aim to improve diagnostic classification of variants in patients with CHD by assessing the impact of noncanonical splice region variants on RNA splicing.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We tested de novo variants from trio studies of 2649 CHD probands and their parents, as well as rare (allele frequency, &lt;2\u00d710\n                      <jats:sup>\u2212<\/jats:sup>\n                      <jats:sup>6<\/jats:sup>\n                      ) variants from 4472 CHD probands in the Pediatric Cardiac Genetics Consortium through a combined computational and in vitro approach.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      We identified 53 de novo and 74 rare variants in CHD cases that alter splicing and thus are loss of function. Of these, 77 variants are in known dominant, recessive, and candidate CHD genes, including\n                      <jats:italic>KMT2D<\/jats:italic>\n                      and\n                      <jats:italic>RBFOX2<\/jats:italic>\n                      . In 1 case, we confirmed the variant\u2019s predicted impact on RNA splicing in RNA transcripts from the proband\u2019s cardiac tissue. Two probands were found to have 2 loss-of-function variants for recessive CHD genes\n                      <jats:italic>HECTD1<\/jats:italic>\n                      and\n                      <jats:italic>DYNC2H1<\/jats:italic>\n                      . In addition, SpliceAI\u2014a predictive algorithm for altered RNA splicing\u2014has a positive predictive value of \u224893% in our cohort.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>Through assessment of RNA splicing, we identified a new loss-of-function variant within a CHD gene in 78 probands, of whom 69 (1.5%; n=4472) did not have a previously established genetic explanation for CHD. Identification of splice-altering variants improves diagnostic classification and genetic diagnoses for CHD.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Registration:<\/jats:title>\n                    <jats:p>\n                      URL:\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\">https:\/\/clinicaltrials.gov<\/jats:ext-link>\n                      ; Unique identifier: NCT01196182.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.122.003924","type":"journal-article","created":{"date-parts":[[2023,5,11]],"date-time":"2023-05-11T05:04:12Z","timestamp":1683781452000},"page":"224-231","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":19,"title":["Contribution of Previously Unrecognized RNA Splice-Altering Variants to Congenital Heart Disease"],"prefix":"10.1161","volume":"16","clinical-trial-number":[{"clinical-trial-number":"nct01196182","registry":"10.18810\/clinical-trials-gov"}],"author":[{"given":"Min Young","family":"Jang","sequence":"first","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."},{"name":"Department of Medicine (M.Y.J., A.H.), Brigham and Women\u2019s Hospital, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3561-796X","authenticated-orcid":true,"given":"Parth N.","family":"Patel","sequence":"additional","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."},{"name":"Division of Cardiology, Massachusetts General Hospital, Boston, MA (P.N.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandre C.","family":"Pereira","sequence":"additional","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jon A.L.","family":"Willcox","sequence":"additional","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0683-4922","authenticated-orcid":true,"given":"Alireza","family":"Haghighi","sequence":"additional","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."},{"name":"Department of Medicine (M.Y.J., A.H.), Brigham and Women\u2019s Hospital, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela C.","family":"Tai","sequence":"additional","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical School, Boston, MA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1843-773X","authenticated-orcid":true,"given":"Kaoru","family":"Ito","sequence":"additional","affiliation":[{"name":"Laboratory for Cardiovascular Diseases, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan (K.I.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah U.","family":"Morton","sequence":"additional","affiliation":[{"name":"Departments of Genetics (M.Y.J., P.N.P., A.C.P., J.A.L.W., A.H., A.C.T., S.U.M., J.M.G., D.M.M., S.R.D., C.E.S., J.G.S.), Harvard Medical 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The ubiquitin ligase HECTD1 promotes retinoic acid signaling required for development of the aortic arch. 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