Truncating Variants in the Desmoplakin Gene Cause a Distinct Arrhythmogenic Cardiomyopathy

Abstract

Background: Variants in DSP cause arrhythmogenic cardiomyopathy (ACM) and phenotype data derived largely from arrhythmogenic right ventricular cardiomyopathy (ARVC) patient cohorts. We hypothesised that patients with DSP truncating variants (DSPtv) express a wider phenotype spectrum. We report penetrance, phenotype spectrum and genetic architecture of DSPtv. Methods and Results: Unrelated patients with a DSPtv and any cardiac phenotype were sought from international centres (n = 98). Primary diagnosis for n = 32 included dilated cardiomyopathy (n = 19), ARVC (n = 10), ACM (n = 1), unexplained VF (n = 1) and Carvajal syndrome (n = 1). Fifteen (47%) experienced sudden cardiac death (SCD) events, including 7 (22%) with SCD as the presenting symptom. All had left ventricular (LV) involvement. A family history was reported in 22 (69%). In the total cohort (n = 98), there were 68 unique DSPtv (29 frameshift, 25 nonsense, 12 splice, two insertion/deletions) classified using ACMG criteria (5 pathogenic, 62 likely pathogenic, 1 uncertain significance). We investigated localisation of DSPtv to key functional gene regions (G1, CR and G2) in cases compared to controls. Case variants were more common in G1 and CR (84–72% vs 16–28%) while control variants were more frequent in G2 (58% vs 42%) (p < 0.0001). Event-free survival from SCD events was worse when DSPtv occurred in G1/CR, compared to G2 (log-rank p = 0.016). Conclusion: In the largest series of DSPtv carriers, we show a wide phenotype spectrum. It should be considered a distinct gene-specific cardiomyopathy characterised by LV dysfunction with high risk of ventricular arrhythmias. DSPtv are highly penetrant and gene location is associated with worse clinical outcomes.