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

Abstract

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)69-79
Number of pages11
JournalCirculation: Genomic and Precision Medicine
Volume16
Issue number1
Early online date29 Dec 2022
DOIs
Publication statusPublished - Feb 2023

Keywords

  • Cardiomyopathies
  • Death
  • Desmoplakins
  • Genetic testing
  • Primary
  • Sudden cardiac

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