{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,4]],"date-time":"2026-09-04T15:48:50Z","timestamp":1788536930914,"version":"build-2803163510"},"reference-count":39,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,6]],"date-time":"2022-01-06T00:00:00Z","timestamp":1641427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["KL2TR001879"],"award-info":[{"award-number":["KL2TR001879"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiogenetics"],"abstract":"<jats:p>Background: Variants in the desmoplakin (DSP) gene have been recognized in association with the pathogenesis of arrhythmogenic right ventricular cardiomyopathy (ARVC) for nearly 20 years. More recently, genetic variation in DSP has also been associated with left-dominant arrhythmogenic cardiomyopathy. Data regarding the cardiac phenotypes associated with genetic variation in DSP have been largely accumulated from phenotype-first studies of ARVC. Methods: We aimed to evaluate the clinical manifestations of cardiac disease associated with variants in DSP through a genotype-first approach employed in the University of Pennsylvania Center for Inherited Cardiovascular Disease registry. We performed a retrospective study of 19 individuals with \u201cpathogenic\u201d or \u201clikely pathogenic\u201d variants in DSP identified by clinical genetic testing. Demographics and clinical characteristics were collected. Results: Among individuals with disease-causing variants in DSP, nearly 40% had left ventricular enlargement at initial assessment. Malignant arrhythmias were prevalent in this cohort (42%) with a high proportion of individuals undergoing primary and secondary prevention implantable cardioverter defibrillator implantation (68%) and ablation of ventricular arrhythmias (16%). Probands also experienced end-stage heart failure requiring heart transplantation (11%). Conclusions: Our data suggest DSP cardiomyopathy may manifest with a high burden of heart failure and arrhythmic events, highlighting its importance in the pathogenesis of dilated and arrhythmogenic cardiomyopathies. Targeted strategies for diagnosis and risk stratification for DSP cardiomyopathy should be investigated.<\/jats:p>","DOI":"10.3390\/cardiogenetics12010003","type":"journal-article","created":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T01:15:26Z","timestamp":1641518126000},"page":"24-36","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Cardiovascular Characteristics of Patients with Genetic Variation in Desmoplakin (DSP)"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2942-3731","authenticated-orcid":false,"given":"Nosheen","family":"Reza","sequence":"first","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alejandro","family":"de Feria","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica L.","family":"Chowns","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily","family":"Hoffman-Andrews","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Vann","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Marzolf","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjali Tiku","family":"Owens","sequence":"additional","affiliation":[{"name":"Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1161\/CIRCRESAHA.116.309396","article-title":"Dilated Cardiomyopathy: Genetic Determinants and Mechanisms","volume":"121","author":"McNally","year":"2017","journal-title":"Circ. Res."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1053\/euhj.1998.1145","article-title":"Guidelines for the study of familial dilated cardiomyopathies","volume":"20","author":"Mestroni","year":"1999","journal-title":"Eur. Heart J."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e002149","DOI":"10.1161\/JAHA.115.002149","article-title":"Arrhythmogenic Phenotype in Dilated Cardiomyopathy: Natural History and Predictors of Life-Threatening Arrhythmias","volume":"4","author":"Spezzacatene","year":"2015","journal-title":"J. Am. Heart Assoc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"e301","DOI":"10.1016\/j.hrthm.2019.05.007","article-title":"2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy","volume":"16","author":"Towbin","year":"2019","journal-title":"Heart Rhythm"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1229","DOI":"10.1083\/jcb.141.5.1229","article-title":"Defining the interactions between intermediate filaments and desmosomes","volume":"141","author":"Smith","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"983","DOI":"10.1007\/s12551-018-0429-0","article-title":"Molecular insights into cardiomyopathies associated with desmin (DES) mutations","volume":"10","author":"Brodehl","year":"2018","journal-title":"Biophys. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1007\/s12170-021-00669-5","article-title":"Arrhythmogenic Cardiomyopathy: Mechanisms, Genetics, and Their Clinical Implications","volume":"15","author":"Reuter","year":"2021","journal-title":"Curr. Cardiovasc. Risk Rep."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1872","DOI":"10.1161\/CIRCULATIONAHA.119.044934","article-title":"Desmoplakin Cardiomyopathy, a Fibrotic and Inflammatory Form of Cardiomyopathy Distinct From Typical Dilated or Arrhythmogenic Right Ventricular Cardiomyopathy","volume":"141","author":"Smith","year":"2020","journal-title":"Circulation"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"857","DOI":"10.1016\/j.cjca.2020.11.017","article-title":"The Novel Desmin Variant p.Leu115Ile Is Associated with a Unique Form of Biventricular Arrhythmogenic Cardiomyopathy","volume":"37","author":"Protonotarios","year":"2020","journal-title":"Can. J. Cardiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1595","DOI":"10.1161\/CIRCULATIONAHA.117.028719","article-title":"Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy\/Dysplasia","volume":"137","author":"Carriel","year":"2018","journal-title":"Circulation"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.ijcard.2017.05.018","article-title":"Desmoplakin missense and non-missense mutations in arrhythmogenic right ventricular cardiomyopathy: Genotype-phenotype correlation","volume":"249","author":"Castelletti","year":"2017","journal-title":"Int. J. Cardiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.1093\/eurheartj\/ehi341","article-title":"Clinical profile of four families with arrhythmogenic right ventricular cardiomyopathy caused by dominant desmoplakin mutations","volume":"26","author":"Bauce","year":"2005","journal-title":"Eur. Heart J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1710","DOI":"10.1161\/CIRCULATIONAHA.106.660241","article-title":"Clinical and Genetic Characterization of Families with Arrhythmogenic Right Ventricular Dysplasia\/Cardiomyopathy Provides Novel Insights into Patterns of Disease Expression","volume":"115","author":"Syrris","year":"2007","journal-title":"Circulation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2701","DOI":"10.1161\/CIRCULATIONAHA.110.976936","article-title":"Familial Evaluation in Arrhythmogenic Right Ventricular Cardiomyopathy","volume":"123","author":"Quarta","year":"2011","journal-title":"Circulation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1093\/eurheartj\/ehu509","article-title":"Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia\/cardiomyopathy-associated mutation carriers","volume":"36","author":"Bhonsale","year":"2015","journal-title":"Eur. Heart J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1086","DOI":"10.1093\/europace\/euv205","article-title":"Phenotypic expression is a prerequisite for malignant arrhythmic events and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy","volume":"18","author":"Zorzi","year":"2016","journal-title":"EP Europace"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"437","DOI":"10.1161\/CIRCGENETICS.114.001003","article-title":"Clinical Presentation, Long-Term Follow-Up, and Outcomes of 1001 Arrhythmogenic Right Ventricular Dysplasia\/Cardiomyopathy Patients and Family Members","volume":"8","author":"Groeneweg","year":"2015","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1161\/CIRCGENETICS.109.858217","article-title":"Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia\/cardiomyopathy","volume":"2","author":"Haan","year":"2009","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1038\/gim.2015.30","article-title":"Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology","volume":"17","author":"Richards","year":"2015","journal-title":"Genet. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.cardfail.2018.03.004","article-title":"Genetic Evaluation of Cardiomyopathy\u2014A Heart Failure Society of America Practice Guideline","volume":"24","author":"Hershberger","year":"2018","journal-title":"J. Card. Fail."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.echo.2014.10.003","article-title":"Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging","volume":"28","author":"Lang","year":"2015","journal-title":"J. Am. Soc. Echocardiogr."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"D835","DOI":"10.1093\/nar\/gkz972","article-title":"ClinVar: Improvements to accessing data","volume":"48","author":"Landrum","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1161\/CIRCULATIONAHA.108.840827","article-title":"Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy\/Dysplasia","volume":"121","author":"Marcus","year":"2010","journal-title":"Circulation"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1093\/europace\/euq104","article-title":"Desmosomal gene analysis in arrhythmogenic right ventricular dysplasia\/cardiomyopathy: Spectrum of mutations and clinical impact in practice","volume":"12","author":"Fressart","year":"2010","journal-title":"EP Europace"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2175","DOI":"10.1016\/j.jacc.2008.09.019","article-title":"Left-dominant arrhythmogenic cardiomyopathy: An under-recognized clinical entity","volume":"52","author":"Syrris","year":"2008","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1161\/CIRCGENETICS.110.937805","article-title":"Prevalence of desmosomal protein gene mutations in patients with dilated cardiomyopathy","volume":"3","author":"Elliott","year":"2010","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1838","DOI":"10.1093\/europace\/euu128","article-title":"Desmoplakin truncations and arrhythmogenic left ventricular cardiomyopathy: Characterizing a phenotype","volume":"16","author":"Monserrat","year":"2014","journal-title":"EP Europace"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1744","DOI":"10.1136\/hrt.2011.227967","article-title":"Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: A clinicopathological study","volume":"97","author":"Syrris","year":"2011","journal-title":"Heart"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1002\/ajmg.a.38719","article-title":"Autosomal-dominant biventricular arrhythmogenic cardiomyopathy in a large family with a novel in-frame DSP nonsense mutation","volume":"176","author":"Singh","year":"2018","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e128643","DOI":"10.1172\/jci.insight.128643","article-title":"Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation","volume":"4","author":"Ng","year":"2019","journal-title":"JCI Insight"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Wang, W., Murray, B., Tichnell, C., Gilotra, N.A., Zimmerman, S.L., Gasperetti, A., Scheel, P., Tandri, H., Calkins, H., and James, C.A. (2021). Clinical characteristics and risk stratification of desmoplakin cardiomyopathy. EP Europace, euab183.","DOI":"10.1093\/europace\/euab183"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1690","DOI":"10.1093\/eurheartj\/ehz172","article-title":"A novel genotype-based clinicopathology classification of arrhythmogenic cardiomyopathy provides novel insights into disease progression","volume":"40","author":"Chen","year":"2019","journal-title":"Eur. Heart J."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1161\/CIRCGEN.120.003017","article-title":"Left-Dominant Arrhythmogenic Cardiomyopathy, Palmoplantar Keratoderma, and Curly Hair Associated with a Rare Autosomal Dominant Truncating Variant in Desmoplakin","volume":"13","author":"Reza","year":"2020","journal-title":"Circ. Genomic. Precis. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1016\/j.hrthm.2015.01.001","article-title":"Genetics of myocarditis in arrhythmogenic right ventricular dysplasia","volume":"12","author":"Gimeno","year":"2015","journal-title":"Heart Rhythm"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1238","DOI":"10.1161\/CIRCULATIONAHA.119.043931","article-title":"Evidence From Family Studies for Autoimmunity in Arrhythmogenic Right Ventricular Cardiomyopathy: Associations of Circulating Anti-Heart and Anti-Intercalated Disk Autoantibodies With Disease Severity and Family History","volume":"141","author":"Caforio","year":"2020","journal-title":"Circulation"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1016\/j.jacc.2009.11.020","article-title":"Compound and digenic heterozygosity contributes to arrhythmogenic right ventricular cardiomyopathy","volume":"55","author":"Xu","year":"2010","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1253\/circj.CJ-11-0927","article-title":"Compound and digenic heterozygosity in desmosome genes as a cause of arrhythmogenic right ventricular cardiomyopathy in Japanese patients","volume":"76","author":"Nakajima","year":"2012","journal-title":"Circ. J."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1161\/CIRCGENETICS.113.000288","article-title":"Compound and digenic heterozygosity predicts lifetime arrhythmic outcome and sudden cardiac death in desmosomal gene-related arrhythmogenic right ventricular cardiomyopathy","volume":"6","author":"Rigato","year":"2013","journal-title":"Circ. Cardiovasc. Genet."},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"K\u00f6nig, E., Volpato, C.B., Motta, B.M., Blankenburg, H., Picard, A., Pramstaller, P., Casella, M., Rauhe, W., Pompilio, G., and Meraviglia, V. (2017). Exploring digenic inheritance in arrhythmogenic cardiomyopathy. BMC Med. Genet., 18.","DOI":"10.1186\/s12881-017-0503-7"}],"container-title":["Cardiogenetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2035-8148\/12\/1\/3\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T14:00:35Z","timestamp":1760364035000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2035-8148\/12\/1\/3"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,6]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,3]]}},"alternative-id":["cardiogenetics12010003"],"URL":"https:\/\/doi.org\/10.3390\/cardiogenetics12010003","relation":{},"ISSN":["2035-8148"],"issn-type":[{"value":"2035-8148","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,6]]}}}