Hoorntje, Edgar T. and Burns, Charlotte and Marsili, Luisa and Corden, Ben and Parikh, Victoria N. and te Meerman, Gerard J. and Gray, Belinda and Adiyaman, Ahmet and Bagnall, Richard D. and Barge-Schaapveld, Daniela Q.C.M. and van den Berg, Maarten P. and Bootsma, Marianne and Bosman, Laurens P. and Correnti, Gemma and Duflou, Johan and Eppinga, Ruben N. and Fatkin, Diane and Fietz, Michael and Haan, Eric and Jongbloed, Jan D.H. and Hauer, Arnaud D. and Lam, Lien and van Lint, Freyja H.M. and Lota, Amrit and Marcelis, Carlo and McCarthy, Hugh J. and van Mil, Anneke M. and Oldenburg, Rogier A. and Pachter, Nicholas and Planken, R. Nils and Reuter, Chloe and Semsarian, Christopher and van der Smagt, Jasper J. and Thompson, Tina and Vohra, Jitendra and Volders, Paul G.A. and van Waning, Jaap I. and Whiffin, Nicola and van den Wijngaard, Arthur and Amin, Ahmad S. and Wilde, Arthur A.M. and van Woerden, Gijs and Yeates, Laura and Zentner, Dominica and Ashley, Euan A. and Wheeler, Matthew T. and Ware, James S. and van Tintelen, J. Peter and Ingles, Jodie (2023) Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin ( DSP ) Truncating Variant. Circulation: Genomic and Precision Medicine, 16 (1). ISSN 2574-8300
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| Subjects: | R Medicine > R Medicine (General) |
| Depositing User: | Repository Administrator |
| Date Deposited: | 27 Apr 2023 04:35 |
| Last Modified: | 27 Apr 2023 04:35 |
| URI: | https://eprints.victorchang.edu.au/id/eprint/1380 |
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