Publications
Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant
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.
Type | Journal |
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ISBN | 2574-8300 (Electronic) 2574-8300 (Linking) |
Authors | Hoorntje, E. T.; Burns, C.; Marsili, L.; Corden, B.; Parikh, V. N.; Te Meerman, G. J.; Gray, B.; Adiyaman, A.; Bagnall, R. D.; Barge-Schaapveld, Dqcm; van den Berg, M. P.; 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.; van Lint, F. H. M.; Lota, A.; Marcelis, C.; McCarthy, H. J.; van Mil, A. M.; Oldenburg, R. A.; Pachter, N.; Planken, R. N.; Reuter, C.; Semsarian, C.; van der Smagt, J. J.; Thompson, T.; Vohra, J.; Volders, P. G. A.; van Waning, J. I.; Whiffin, N.; van den Wijngaard, A.; Amin, A. S.; Wilde, A. A. M.; van Woerden, G.; Yeates, L.; Zentner, D.; Ashley, E. A.; Wheeler, M. T.; Ware, J. S.; van Tintelen, J. P.; Ingles, J. |
Publisher Name | Circulation. Genomic and Precision Medicine |
Published Date | 2023-02-28 |
Published Volume | 16 |
Published Issue | 1 |
Published Pages | e003672 |
Status | Published in-print |
DOI | 10.1161/CIRCGEN.121.003672 |
URL link to publisher's version | https://www.ncbi.nlm.nih.gov/pubmed/36580316 |