Variant Location Is a Novel Risk Factor for Individuals with Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant

Edgar T. Hoorntje, Charlotte Burns, Luisa Marsili, Ben Corden, Victoria N. Parikh, Gerard J. Te Meerman, Belinda Gray, Ahmet Adiyaman, Richard D. Bagnall, Daniela Q.C.M. Barge-Schaapveld, Maarten P. Van Den Berg, Marianne Bootsma, Laurens P. Bosman, Gemma Correnti, Johan Duflou, Ruben N. Eppinga, Diane Fatkin, Michael Fietz, Eric Haan, Jan D.H. JongbloedArnaud D. Hauer, Lien Lam, Freyja H.M. Van Lint, Amrit Lota, Carlo Marcelis, Hugh J. McCarthy, Anneke M. Van Mil, Rogier A. Oldenburg, Nicholas Pachter, R. Nils Planken, Chloe Reuter, Christopher Semsarian, Jasper J. Van Der Smagt, Tina Thompson, Jitendra Vohra, Paul G.A. Volders, Jaap I. Van Waning, Nicola Whiffin, Arthur Van Den Wijngaard, Ahmad S. Amin, Arthur A.M. Wilde, Gijs Van Woerden, Laura Yeates, Dominica Zentner, Euan A. Ashley, Matthew T. Wheeler, James S. Ware, J. Peter Van Tintelen, Jodie Ingles*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

9 Citations (Scopus)
72 Downloads (Pure)


Background: Truncating variants in desmoplakin (DSPtv) 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 DSPtv cardiomyopathy. Methods: Individuals with DSPtv 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 DSPtv performed. Results: There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a DSPtv, 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. 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 DSPtv, 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.

Original languageEnglish
Pages (from-to)E003672
JournalCirculation: Genomic and Precision Medicine
Issue number1
Publication statusPublished - Feb 2023

Bibliographical note

Funding Information:
Dr Ingles receives research grant support from Bristol Myers Squibb, unrelated to this study. Dr Ware reports research grant support and consultancy fees from Bristol Myers Squibb, unrelated to this study. Dr Reuter is a consultant for My Gene Counsel. Dr Wheeler is a stockholder of Personalis Inc. The remaining authors have nothing to disclose.

Funding Information:
Dr Burns is the recipient of an Australia Postgraduate Award (APA). Dr Bagnall is supported by a grant from New South Wales Health. Dr Semsarian is the recipient of a National Health and Medical Research Council (NHMRC) Practitioner Fellowship (#1154992). Dr Ware is supported by the Wellcome Trust, the Medical Research Council (UK), the British Heart Foundation, the NIHR Royal Brompton Biomedical Research Unit, and the NIHR Imperial College Biomedical Research Centre. Drs van Tintelen, Wilde, Volders, van den Berg, and Hoorntje acknowledge the support from the Netherlands Cardiovascular Research Initiative, an initiative with support of the Dutch Heart Foundation (2014-40 DOSIS; 2012-10 PREDICT; 2018-30 PREDICT2; 2015-12 eDETECT). Dr Ingles is the recipient of an NHMRC Career Development Fellowship (#1162929). The other authors report no conflicts.

Publisher Copyright:
© 2023 Lippincott Williams and Wilkins. All rights reserved.


Dive into the research topics of 'Variant Location Is a Novel Risk Factor for Individuals with Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant'. Together they form a unique fingerprint.

Cite this