Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin (DSP) Truncating Variant.
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Hoorntje Edgar T, Burns Charlotte, Marsili Luisa, Corden Ben, Parikh Victoria N, Te Meerman Gerard J, Gray Belinda, Adiyaman Ahmet, Bagnall Richard D, Barge-Schaapveld Daniela Q C M, van den Berg Maarten P, Bootsma Marianne, Bosman Laurens P, Correnti Gemma, Duflou Johan, Eppinga Ruben N, Fatkin Diane, Fietz Michael, Haan Eric, Jongbloed Jan D H, Hauer Arnaud D, Lam Lien, van Lint Freyja H M, Lota Amrit, Marcelis Carlo, McCarthy Hugh J, van Mil Anneke M, Oldenburg Rogier A, Pachter Nicholas, Planken R Nils, Reuter Chloe, Semsarian Christopher, van der Smagt Jasper J, Thompson Tina, Vohra Jitendra, Volders Paul G A, van Waning Jaap I, Whiffin Nicola, van den Wijngaard Arthur, Amin Ahmad S, Wilde Arthur A M, van Woerden Gijs, Yeates Laura, Zentner Dominica, Ashley Euan A, Wheeler Matthew T, Ware James S, van Tintelen J Peter, Ingles Jodie
Аннотация
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.