Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant. (29th December 2022)

• Record Type: Journal Article
• Authors: Hoorntje, Edgar T.; Burns, Charlotte; Marsili, Luisa; Corden, Ben; Parikh, Victoria N.; te Meerman, Gerard J.; Gray, Belinda; Adiyaman, Ahmet; Bagnall, Richard D.; Barge-Schaapveld, Daniela Q.C.M.; van den Berg, Maarten P.; Bootsma, Marianne; Bosman, Laurens P.; Correnti, Gemma; Duflou, Johan; Eppinga, Ruben N.; Fatkin, Diane; Fietz, Michael; Haan, Eric; Jongbloed, Jan D.H.; Hauer, Arnaud D.; Lam, Lien; van Lint, Freyja H.M.; Lota, Amrit; Marcelis, Carlo; McCarthy, Hugh J.; van Mil, Anneke M.; Oldenburg, Rogier A.; Pachter, Nicholas; Planken, R. Nils; Reuter, Chloe; Semsarian, Christopher; van der Smagt, Jasper J.; Thompson, Tina; Vohra, Jitendra; Volders, Paul G.A.; van Waning, Jaap I.; Whiffin, Nicola; van den Wijngaard, Arthur; Amin, Ahmad S.; Wilde, Arthur A.M.; van Woerden, Gijs; Yeates, Laura; Zentner, Dominica; Ashley, Euan A.; Wheeler, Matthew T.; Ware, James S.; van Tintelen, J. Peter; Ingles, Jodie;
• Is Part Of: Circulation. Volume 16:Number 1(2023)
• Page Start: e003672
• Publication Date: 2022-12-29
• Subjects: cardiomyopathies -- primary -- death, sudden cardiac -- desmoplakins -- genetic testing; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.121.003672
• Languages: English
• ISSNs: 2574-8300

Abstract

Abstract : Background: Truncating variants in desmoplakin ( DSP tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of DSP tv cardiomyopathy. Methods: Individuals with DSP tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers. Clinical data and family history information were collected. Event-free survival from ventricular arrhythmia was assessed. Variant location was compared between cases and controls, and literature review of reported DSP tv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSP tv, of which 146 were considered clinically affected. Ventricular arrhythmia (sudden cardiac arrest, sustained ventricular tachycardia, appropriate implantable cardioverter defibrillator therapy) occurred in 56 (33%) individuals. DSP tv location and proband status were independent risk factors for ventricular arrhythmia. Further, gene region was important with variants in cases (cohort n=98; Clinvar n=167) more likely to occur in the regions resulting in nonsense mediated decay of both major DSP isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; P <0.0001). Conclusions: In the largest series of individuals with DSP tv, we demonstrate that variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow for precision-based clinical management.