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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<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>

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