{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T20:20:40Z","timestamp":1792268440144,"version":"4.4.0"},"reference-count":50,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"4","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"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":["Circulation"],"published-print":{"date-parts":[[2025,7,29]]},"abstract":"<jats:sec>\n            <jats:title>BACKGROUND:<\/jats:title>\n            <jats:p>Desmosomal gene variants (DGVs) have been associated with a diverse spectrum of phenotypic manifestations within arrhythmogenic cardiomyopathy, but data on genotype-specific outcomes are lacking. We investigated genotype-specific arrhythmic and heart failure (HF) outcomes in DGV carriers.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>METHODS:<\/jats:title>\n            <jats:p>\n              This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency &lt;10\n              <jats:sup>\u2212<\/jats:sup>\n              <jats:sup>4<\/jats:sup>\n              ) variants of uncertain significance were included. The arrhythmic end point was the occurrence of a life-threatening arrhythmic event, defined as sudden cardiac death, aborted cardiac arrest, or hemodynamically unstable ventricular tachycardia. The end-stage HF outcome was the composite of a fatal HF episode or cardiac transplantation.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>RESULTS:<\/jats:title>\n            <jats:p>\n              We included 533 DGV carriers (59% male; median [interquartile range] age, 39 [22\u201354] years) from 214 families: 503 of 533 (94%) had a single DGV (212 [40%]\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              , 160 [30%]\n              <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n              , 97 [18%]\n              <jats:italic toggle=\"yes\">DSG2<\/jats:italic>\n              , 34 [6%]\n              <jats:italic toggle=\"yes\">DSC2<\/jats:italic>\n              ) and 30 of 533 (6%) double DGVs. Overall, 83 of 533 (16%) experienced a life-threatening arrhythmic event (at age 40 [33\u201351] years), and 14 of 533 (3%) experienced end-stage HF (at age 57 [50\u201360] years). Multivariable analysis demonstrated that, compared with nonmissense\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              variants, nonmissense\n              <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n              variants (hazard ratio [HR], 2.3 [95% CI, 1.3\u20134.1];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.008), missense variants in hotspot domains in\n              <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n              (HR, 2.7 [95% CI, 1.2\u20136.2];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.010) and\n              <jats:italic toggle=\"yes\">PKP2<\/jats:italic>\n              (HR, 3.6 [95% CI, 2.0\u20136.5];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.001), male sex (HR, 1.7 [95% CI, 1.1\u20132.8];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.021), and double DGVs (HR, 3.4 [95% CI, 1.7\u20136.9];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              &lt;0.001) were associated with a higher risk of a life-threatening arrhythmic event. Nonmissense\n              <jats:italic toggle=\"yes\">DSP<\/jats:italic>\n              variants (HR, 5.0 [95% CI, 1.5\u201318.2];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.009) and double DGVs (HR, 4.7 [95% CI, 1.0\u201319.3];\n              <jats:italic toggle=\"yes\">P<\/jats:italic>\n              =0.044) were also associated with increased risk of end-stage HF.\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>CONCLUSIONS:<\/jats:title>\n            <jats:p>Among carriers of DGVs, genotype was associated with arrhythmic and HF outcomes, with type and location of the variant further modulating the natural history.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/circulationaha.124.073475","type":"journal-article","created":{"date-parts":[[2025,5,23]],"date-time":"2025-05-23T06:16:55Z","timestamp":1747981015000},"page":"233-245","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":16,"title":["Genotype-Specific Outcomes of Desmosomal Cardiomyopathies"],"prefix":"10.1161","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6688-8454","authenticated-orcid":true,"given":"Valerio","family":"Pergola","sequence":"first","affiliation":[{"name":"Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. Marino, S.G.P.)."},{"name":"Department of Advanced Biomedical Sciences, University of Naples Federico II, Italy (V.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2181-8245","authenticated-orcid":true,"given":"Alessandro","family":"Trancuccio","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. Marino, S.G.P.)."},{"name":"Department of Molecular Medicine, University of Pavia, Italy (A.T., D.K., A.M., C.N., G.G.S., A.S., N.P., G.M., S.G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7152-5934","authenticated-orcid":true,"given":"Deni","family":"Kukavica","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. Marino, S.G.P.)."},{"name":"Department of Molecular Medicine, University of Pavia, Italy (A.T., D.K., A.M., C.N., G.G.S., A.S., N.P., G.M., S.G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0208-2172","authenticated-orcid":true,"given":"Andrea","family":"Mazzanti","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. Marino, S.G.P.)."},{"name":"Department of Molecular Medicine, University of Pavia, Italy (A.T., D.K., A.M., C.N., G.G.S., A.S., N.P., G.M., S.G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7643-4628","authenticated-orcid":true,"given":"Carlo","family":"Napolitano","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. Marino, S.G.P.)."},{"name":"Department of Molecular Medicine, University of Pavia, Italy (A.T., D.K., A.M., C.N., G.G.S., A.S., N.P., G.M., S.G.P.)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5836-2448","authenticated-orcid":true,"given":"Gabriele Gaetano","family":"Scilabra","sequence":"additional","affiliation":[{"name":"Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. 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