Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (             <i>DSP</i>             ) Truncating Variant

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

doi:10.1101/2021.10.16.21264154

<jats:sec> <jats:title>Background:</jats:title> <jats:p> Truncating variants in desmoplakin ( <jats:italic>DSP</jats:italic> 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 <jats:italic>DSP</jats:italic> tv cardiomyopathy. </jats:p> </jats:sec> <jats:sec> <jats:title>Methods:</jats:title> <jats:p> Individuals with <jats:italic>DSP</jats:italic> 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 <jats:italic>DSP</jats:italic> tv performed. </jats:p> </jats:sec> <jats:sec> <jats:title>Results:</jats:title> <jats:p> There were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with a <jats:italic>DSP</jats:italic> 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. <jats:italic>DSP</jats:italic> 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 <jats:italic>DSP</jats:italic> isoforms, compared with n=124 genome aggregation database control variants (148 [83.6%] versus 29 [16.4%]; <jats:italic>P</jats:italic> <0.0001). </jats:p> </jats:sec> <jats:sec> <jats:title>Conclusions:</jats:title> <jats:p> In the largest series of individuals with <jats:italic>DSP</jats:italic> 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. </jats:p> </jats:sec>

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( <i>DSP</i> ) Truncating Variant

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