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We previously identified a homozygous <jats:italic>DSG2<\/jats:italic> p.Arg119Ter stop-gain variant in a patient with juvenile-onset cardiomyopathy and advanced biventricular heart failure. However, the pathological significance and prevalence of the heterozygous <jats:italic>DSG2<\/jats:italic> p.Arg119Ter variant remains uncertain. Here, we identified four unrelated patients with cardiomyopathy with heterozygous <jats:italic>DSG2<\/jats:italic> p.Arg119Ter variants among 808 patients with nonischemic cardiomyopathy; the allele frequency was 0.0037, which is more than 50-fold greater than that reported in the general Japanese population. These patients were clinically diagnosed with arrhythmogenic right ventricular cardiomyopathy (Pt-1), dilated cardiomyopathy (DCM) after ventricular septum defect closure surgery (Pt-2), DCM (Pt-3), and end-stage hypertrophic cardiomyopathy (Pt-4). The patients also exhibited reduced left ventricular contractile function and varying clinical courses. Genetic analysis identified additional possible causative variants, <jats:italic>DSG2<\/jats:italic> p.Arg292Cys in Pt-1 and <jats:italic>BAG3<\/jats:italic> p.His166SerfsTer6 in Pt-3. Immunohistochemical analysis of endomyocardial biopsy samples revealed that the expression of not only desmoglein-2 but also desmoplakin was markedly reduced. Transmission electron microscopy revealed pale and fragmented desmosomes and widened gaps between intercalated discs in the myocardium. A microforce test using human cardiomyocytes differentiated from induced pluripotent stem cells (iPSC-CMs) demonstrated reduced contractility in iPSC-CMs carrying a heterozygous truncating variant in <jats:italic>DSG2<\/jats:italic>. These data suggest that the <jats:italic>DSG2<\/jats:italic> p.Arg119Ter variant is concealed in patients with cardiomyopathy with heart failure, and desmosome impairment may be a latent exacerbating factor of contractile dysfunction and disease progression.<\/jats:p>","DOI":"10.1038\/s41439-024-00304-w","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T07:34:02Z","timestamp":1734680042000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Four cardiomyopathy patients with a heterozygous DSG2 p.Arg119Ter variant"],"prefix":"10.1038","volume":"11","author":[{"given":"Takuya","family":"Sumida","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shou","family":"Ogawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7473-7983","authenticated-orcid":false,"given":"Shuichiro","family":"Higo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Kuramoto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Eto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiko","family":"Ikeda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Congcong","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junjun","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoka","family":"Tabata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoshihiro","family":"Asano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikio","family":"Shiba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasuhiro","family":"Akazawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daisuke","family":"Nakamura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takafumi","family":"Oka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomohito","family":"Ohtani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yasushi","family":"Sakata","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,12,20]]},"reference":[{"key":"304_CR1","doi-asserted-by":"publisher","first-page":"1123","DOI":"10.1093\/eurheartj\/ehu301","volume":"36","author":"J Haas","year":"2015","unstructured":"Haas, J. et al. Atlas of the clinical genetics of human dilated cardiomyopathy. Eur. Heart J. 36, 1123\u20131135 (2015).","journal-title":"Eur. Heart J."},{"key":"304_CR2","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-20114-9","volume":"8","author":"T Tobita","year":"2018","unstructured":"Tobita, T. et al. Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling. Sci. Rep. 8, 1998 (2018).","journal-title":"Sci. Rep."},{"key":"304_CR3","doi-asserted-by":"publisher","first-page":"4006","DOI":"10.1016\/j.jmb.2013.07.035","volume":"425","author":"C Al-Jassar","year":"2013","unstructured":"Al-Jassar, C., Bikker, H., Overduin, M. & Chidgey, M. Mechanistic basis of desmosome-targeted diseases. J. Mol. Biol. 425, 4006\u20134022 (2013).","journal-title":"J. Mol. 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