1. Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant
- Author
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Jasper J. van der Smagt, Gemma Correnti, Diane Fatkin, E. Haan, Paul G.A. Volders, Jodie Ingles, Euan A. Ashley, Nicola Whiffin, Laura Yeates, Daniela Q.C.M. Barge-Schaapveld, Nicholas Pachter, Jan D. H. Jongbloed, Jaap I. van Waning, Arthur van den Wijngaard, Ahmet Adiyaman, Belinda Gray, Ben Corden, Victoria N. Parikh, Chloe M. Reuter, Amrit Lota, Maarten P. van den Berg, Johan Duflou, Luisa Marsili, Freyja H.M. van Lint, Ahmad S. Amin, Matthew T. Wheeler, Christopher Semsarian, Charlotte Burns, James S. Ware, Michael Fietz, Marianne Bootsma, Carlo Marcelis, Jitendra K. Vohra, Rogier A. Oldenburg, Dominica Zentner, Arthur A.M. Wilde, Laurens P Bosman, Arnaud D. Hauer, Gijs van Woerden, J. Peter van Tintelen, Edgar T. Hoorntje, R. Nils Planken, Richard D. Bagnall, Anneke M. van Mil, Gerard J. te Meerman, Hugh J. McCarthy, Ruben N. Eppinga, T. Thompson, and Lien Lam
- Subjects
Proband ,medicine.medical_specialty ,biology ,business.industry ,Desmoplakin ,medicine.medical_treatment ,Cardiomyopathy ,Sudden cardiac arrest ,medicine.disease ,Implantable cardioverter-defibrillator ,Internal medicine ,Cohort ,biology.protein ,Cardiology ,Medicine ,Family history ,Risk factor ,medicine.symptom ,business - Abstract
BackgroundTruncating variants in desmoplakin (DSPtv) are an important cause of arrhythmogenic cardiomyopathy (ACM), however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics ofDSPtv cardiomyopathy.MethodsIndividuals withDSPtv 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 reportedDSPtv performed.ResultsThere were 98 probands and 72 family members (mean age at diagnosis 43 ± 18 years, 59% female) with aDSPtv, 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.DSPtv location and proband status were independent risk factors for ventricular arrhythmia, while prior risk factors showed no association. Further, gene region was important with variants in cases (cohort n=98, Clinvar n=168) more likely to occur in the regions resulting in nonsense mediated decay of both majorDSPisoforms, compared to n=124 gnomAD control variants (148 [83.6%] versus 29 [16.4%], pConclusionsIn the largest series of individuals withDSPtv, we demonstrate variant location is a novel risk factor for ventricular arrhythmia, can inform variant interpretation, and provide critical insights to allow precision-based clinical management.
- Published
- 2021
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