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

Truncating variants in desmoplakin (Individuals withThere were 98 probands and 72 family members (mean age at diagnosis 43±8 years, 59% women) with aIn the largest series of individuals with

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.

The aim of this cohort study was to evaluate the value of echocardiographic multilayer strain analysis in the identification of arrhythmogenic cardiomyopathy (AC) in its earliest stages in which sudden cardiac death can occurs. Twenty seven asymptomatic relatives of AC probands (mean age 39.6 ± 19.5 years, 37 % male) with a desmosomal pathogenic mutation but no additional criteria for AC (group II) were compared to age and sex-matched healthy controls (group I). In addition, 70 patients harboring a pathogenic desmosomal mutation with "definitive" diagnosis of AC (group IV), and 19 subjects with "borderline" diagnosis (group III) were also studied. A standard echocardiographic evaluation plus left (LV) and right ventricular global and regional transmural, endocardial, and epicardial longitudinal strain (LS) analysis, was performed. In group II, while LV ejection fraction, fractional shortening, and S' were not significantly reduced compared to controls, transmural global LS was significantly reduced to 19.3 ± 1.8 % in group II versus 20.9 ± 1.1 % in controls (p = 0.0003). Compared to controls, group II presented significant (p < 0.05) regional LS decrease in the basal infero-lateral, antero-lateral, latero-apical, infero-septal, and septo-apical segments. Moreover, LS of the latero-apical and the basal antero-lateral segments was significantly altered in the epicardium (p < 0.05) but not significantly in the endocardium. Global and regional LV LS analysis allows detection of AC in an early or non-diagnostic stage of the disease. Moreover, epicardial LS analysis allows the detection of abnormalities earlier than endocardial LS.