Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant

Hoorntje, E.T.; Burns, C.; Marsili, L.; Corden, B.; Parikh, V.N.; Meerman, G.J. te; Gray, B.; Adiyaman, A.; Bagnall, R.D.; Barge-Schaapveld, D.Q.C.M.; Berg, M.P. van den; Bootsma, M.; Bosman, L.P.; Correnti, G.; Duflou, J.; Eppinga, R.N.; Fatkin, D.; Fietz, M.; Haan, E.; Jongbloed, J.D.H.; Hauer, A.D.; Lam, L.; Lint, F.H.M. van; Lota, A.; Marcelis, C.; McCarthy, H.J.; Mil, A.M. van; Oldenburg, R.A.; Pachter, N.; Planken, R.N.; Reuter, C.; Semsarian, C.; Smagt, J.J. van der; Thompson, T.; Vohra, J.; Volders, P.G.A.; Waning, J.I. van; Whiffin, N.; Wijngaard, A. van den; Amin, A.S.; Wilde, A.A.M.; Woerden, G. van; Yeates, L.; Zentner, D.; Ashley, E.A.; Wheeler, M.T.; Ware, J.S.; Tintelen, J.P. van; Ingles, J.

doi:doi:10.1161/CIRCGEN.121.003672

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...Show moreBackground: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.Show less

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Variant location is a novel risk factor for individuals with arrhythmogenic cardiomyopathy due to a desmoplakin (DSP) truncating variant