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Recent studies have identified mutations in cardiac desmosomes as key players in the pathogenesis of AC. However, the specific etiology in individual families remains largely unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A 4-generation family presenting with syncope, lethal ventricular arrhythmia and SCD was recruited. Targeted next generation sequencing (NGS) was performed and validated by Sanger sequencing. Plasmids containing the mutation and wild type (WT) were constructed. Real-time PCR, western-blot and immunofluorescence were performed to detect the functional change due to the mutation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The proband, a 56-year-old female, presented with recurrent palpitations and syncope. An ICD was implanted due to her family history of SCD\/ aborted SCD. NGS revealed a novel heterozygous frame-shift variant (\n                      <jats:italic>c.832delG<\/jats:italic>\n                      ) in Desmoplakin (\n                      <jats:italic>DSP<\/jats:italic>\n                      ) among 5 family members. The variant led to frame-shift and premature termination, producing a truncated protein. Cardiac magnetic resonance (CMR) of the family members carrying the same variant shown myocardium thinning and fatty infiltration in the right ventricular, positive bi-ventricular late gadolinium enhancement and severe RV dysfunction, fulfilling the diagnostic criteria of AC. HEK293T cells transfected with mutant plasmids expressed truncated\n                      <jats:italic>DSP<\/jats:italic>\n                      mRNA and protein, upregulation of nuclear junction plakoglobin (\n                      <jats:italic>JUP<\/jats:italic>\n                      ) and downregulation of \u03b2-catenin, when compared with WT.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      We infer that the novel\n                      <jats:italic>c.832delG<\/jats:italic>\n                      variant in\n                      <jats:italic>DSP<\/jats:italic>\n                      was associated with AC in this family, likely through Wnt\/\u03b2-catenin signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12872-020-01369-5","type":"journal-article","created":{"date-parts":[[2020,2,11]],"date-time":"2020-02-11T07:02:52Z","timestamp":1581404572000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Next-generation sequencing identified novel Desmoplakin frame-shift variant in patients with Arrhythmogenic cardiomyopathy"],"prefix":"10.1186","volume":"20","author":[{"given":"Xiaoping","family":"Lin","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuankun","family":"Ma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhejun","family":"Cai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qiyuan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lihua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhaoxia","family":"Huo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Hu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian\u2019an","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0255-6056","authenticated-orcid":false,"given":"Meixiang","family":"Xiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2020,2,11]]},"reference":[{"issue":"1","key":"1369_CR1","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1056\/NEJMra1509267","volume":"376","author":"D Corrado","year":"2017","unstructured":"Corrado D, Link MS, Calkins H. 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