{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,22]],"date-time":"2026-10-22T13:44:37Z","timestamp":1792676677842,"version":"4.5.0"},"reference-count":33,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2026,8,1]],"date-time":"2026-08-01T00:00:00Z","timestamp":1785542400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circ: Genomic and Precision Medicine"],"published-print":{"date-parts":[[2026,8]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND:<\/jats:title>\n                    <jats:p>\n                      RBM20 (RNA binding motif protein 20) is a cardiac splicing factor responsible for the splicing of several cardiac genes such as titin (\n                      <jats:italic toggle=\"yes\">TTN<\/jats:italic>\n                      ), triadin (\n                      <jats:italic toggle=\"yes\">TRDN<\/jats:italic>\n                      ), ryanodine receptor 2 (\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      ), PDZ and LIM domain protein 1 (\n                      <jats:italic toggle=\"yes\">PDLIM1<\/jats:italic>\n                      ), and calcium\/calmodulin-dependent protein kinase II (\n                      <jats:italic toggle=\"yes\">CAMK2D<\/jats:italic>\n                      ). Pathogenic variants in\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      are a major cause of familial dilated cardiomyopathy, and lead to missplicing of RBM20 target genes.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS:<\/jats:title>\n                    <jats:p>\n                      We identified a patient with a novel\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      variant, and expressed the human and mouse-equivalent variant in neonatal rat cardiomyocytes and HEK293 cells. We performed splicing assays, and assessed protein expression and stability. Furthermore, we generated heterozygous\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      -c.1222DupC human induced pluripotent stem cells, differentiated these into human induced pluripotent stem cell-derived cardiomyocytes, and evaluated splicing changes and calcium handling.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS:<\/jats:title>\n                    <jats:p>\n                      We describe a novel heterozygous truncating variant,\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      -c.1222DupC, identified in a patient with mitral valve prolapse and late-onset familial dilated cardiomyopathy. The variant introduces a premature termination codon and generates a truncated protein of \u224855 kDa in vitro. Splicing assays demonstrated complete loss of activity and no dominant-negative effect on wild-type RBM20. The truncated protein localized to both the cytoplasm and nucleus, partially colocalizing with wild-type RBM20, despite lacking the RS and RRM domains. Western blot analysis of endogenous RBM20 in human induced pluripotent stem cell-derived cardiomyocytes carrying the variant revealed a strong reduction in RBM20 protein levels. Reverse transcriptase-polymerase chain reaction revealed splicing defects in canonical RBM20 targets, and RNA sequencing identified widespread splicing abnormalities, including in established RBM20 targets (\n                      <jats:italic toggle=\"yes\">TTN<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">RYR2<\/jats:italic>\n                      ,\n                      <jats:italic toggle=\"yes\">CAMK2D<\/jats:italic>\n                      , and\n                      <jats:italic toggle=\"yes\">CACNA1G<\/jats:italic>\n                      ). Finally, we observed increased calcium transients.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSIONS:<\/jats:title>\n                    <jats:p>\n                      Together, these findings establish\n                      <jats:italic toggle=\"yes\">RBM20<\/jats:italic>\n                      c.1222DupC as a truncating variant that causes dilated cardiomyopathy likely through haploinsufficiency.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1161\/circgen.125.005471","type":"journal-article","created":{"date-parts":[[2026,4,30]],"date-time":"2026-04-30T09:01:19Z","timestamp":1777539679000},"update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Novel Truncating Variant c.1222DupC in\n                    <i>RBM20<\/i>\n                    Causes Cardiomyopathy Consistent With Haploinsufficiency"],"prefix":"10.1161","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3271-3259","authenticated-orcid":true,"given":"Priyanka","family":"Pant","sequence":"first","affiliation":[{"name":"Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."},{"name":"Department of Internal Medicine VIII (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.), Heidelberg University Hospital, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (P.P., Z.G., A.A., R.K., T.S., M.M.G.v.d.H.)."},{"name":"Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbr\u00fcck Centre for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-6727-4960","authenticated-orcid":true,"given":"Yong","family":"Huang","sequence":"additional","affiliation":[{"name":"Stanford Centre for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, CA (Y.H., F.B., V.N.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zakiya","family":"Ghouse","sequence":"additional","affiliation":[{"name":"Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."},{"name":"Department of Internal Medicine VIII (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.), Heidelberg University Hospital, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (P.P., Z.G., A.A., R.K., T.S., M.M.G.v.d.H.)."},{"name":"Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbr\u00fcck Centre for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0639-8104","authenticated-orcid":true,"given":"Fang","family":"Bai","sequence":"additional","affiliation":[{"name":"Stanford Centre for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, CA (Y.H., F.B., V.N.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-4952-306X","authenticated-orcid":true,"given":"Elena","family":"Kemmling","sequence":"additional","affiliation":[{"name":"Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."},{"name":"Department of Internal Medicine VIII (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.), Heidelberg University Hospital, Germany."},{"name":"Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbr\u00fcck Centre for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-4700-7433","authenticated-orcid":true,"given":"Laura","family":"Konrad","sequence":"additional","affiliation":[{"name":"Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."},{"name":"Department of Internal Medicine VIII (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.), Heidelberg University Hospital, Germany."},{"name":"Helmholtz-Institute for Translational AngioCardioScience (HI-TAC) of the Max Delbr\u00fcck Centre for Molecular Medicine in the Helmholtz Association (MDC) at Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0026-7501","authenticated-orcid":true,"given":"Ahmed","family":"Alameldeen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III (A.A., R.K., T.S.), Heidelberg University Hospital, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (P.P., Z.G., A.A., R.K., T.S., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Kistler","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III (A.A., R.K., T.S.), Heidelberg University Hospital, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (P.P., Z.G., A.A., R.K., T.S., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timon","family":"Seeger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine III (A.A., R.K., T.S.), Heidelberg University Hospital, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (P.P., Z.G., A.A., R.K., T.S., M.M.G.v.d.H.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1788-3172","authenticated-orcid":true,"given":"Michael","family":"Gotthardt","sequence":"additional","affiliation":[{"name":"Translational Cardiology and Functional Genomics, Max Delbr\u00fcck Centre for Molecular Medicine, Germany (M.G.)."},{"name":"DHZC, Charite Universit\u00e4tsmedizin Berlin, Germany (M.G.)."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Germany (M.G.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5138-5559","authenticated-orcid":true,"given":"Victoria N.","family":"Parikh","sequence":"additional","affiliation":[{"name":"Stanford Centre for Inherited Cardiovascular Disease and Department of Medicine, Stanford School of Medicine, CA (Y.H., F.B., V.N.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2768-3457","authenticated-orcid":true,"given":"Maarten M.G.","family":"van den Hoogenhof","sequence":"additional","affiliation":[{"name":"Medical Faculty Heidelberg, Institute of Experimental Cardiology, Heidelberg University, Germany (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.)."},{"name":"Department of Internal Medicine VIII (P.P., Z.G., E.K., L.K., M.M.G.v.d.H.), Heidelberg University Hospital, Germany."},{"name":"German Centre for Cardiovascular Research (DZHK), Partner Site Heidelberg\/Mannheim, Germany (P.P., Z.G., A.A., R.K., T.S., 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