Genotype-phenotype correlation in arrhythmogenic right ventricular cardiomyopathy-risk of arrhythmias and heart failure

Alex Hørby Christensen*, Pyotr G Platonov, Henrik Kjærulf Jensen, Monica Chivulescu, Anneli Svensson, Pia Dahlberg, Trine Madsen, Tanja Charlotte Frederiksen, Tiina Heliö, Øyvind Haugen Lie, Kristina H Haugaa, Jesper Hastrup Svendsen, Henning Bundgaard

*Corresponding author for this work


BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is predominantly caused by desmosomal genetic variants, and clinical hallmarks include arrhythmias and systolic dysfunction. We aimed at studying the impact of the implicated gene(s) on the disease course.

METHODS: The Nordic ARVC Registry holds data on a multinational cohort of ARVC families. The effects of genotype on electrocardiographic features, imaging findings and clinical events were analysed.

RESULTS: We evaluated 419 patients (55% men), with a mean follow-up of 11.2±7.4 years. A pathogenic desmosomal variant was identified in 62% of the 230 families: <i>PKP2</i> in 41%, <i>DSG2</i> in 13%, <i>DSP</i> in 7% and <i>DSC2</i> in 3%. Reduced left ventricular ejection fraction (LVEF) ≤45% on cardiac MRI was more frequent among patients with <i>DSC2</i>/<i>DSG2</i>/<i>DSP</i> than <i>PKP2</i> ARVC (27% vs 4%, p&lt;0.01). In contrast, in Cox regression modelling of patients with definite ARVC, we found a higher risk of arrhythmias among <i>PKP2</i> than <i>DSC2</i>/<i>DSG2</i>/<i>DSP</i> carriers: HR 0.25 (0.10-0.68, p&lt;0.01) for atrial fibrillation/flutter, HR 0.67 (0.44-1.0, p=0.06) for ventricular arrhythmias and HR 0.63 (0.42-0.95, p&lt;0.05) for any arrhythmia. Gene-negative patients had an intermediate risk (16%) of LVEF ≤45% and a risk of the combined arrhythmic endpoint comparable with <i>DSC2</i>/<i>DSG2</i>/<i>DSP</i> carriers. Male sex was a risk factor for both arrhythmias and reduced LVEF across all genotype groups (p&lt;0.01).

CONCLUSION: In this large cohort of ARVC families with long-term follow-up, we found <i>PKP2</i> genotype to be more arrhythmic than <i>DSC2</i>/<i>DSG</i>2/<i>DSP</i> or gene-negative carrier status, whereas reduced LVEF was mostly seen among <i>DSC2</i>/<i>DSG</i>2/<i>DSP</i> carriers. Male sex was associated with a more severe phenotype.

Original languageEnglish
JournalJournal of Medical Genetics
Issue number9
Pages (from-to)858-864
Number of pages7
Publication statusPublished - Sep 2022


  • cardiomyopathy
  • genetics


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