Pergola Valerio, Trancuccio Alessandro, Kukavica Deni, Mazzanti Andrea, Napolitano Carlo, Scilabra Gabriele Gaetano, Steele Kenneth, Memmi Mirella, Gambelli Patrick, Sugamiele Andrea, Latini Alessia Chiara, Pisani Nicola, Mazzotta Giulio, Bloise Raffaella, Morini Massimo, Marino Maira, Priori Silvia G
Molecular Cardiology Unit, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy (V.P., A.T., D.K., A.M., C.N., G.G.S., K.S., M. Memmi, P.G., A.C.L., R.B., M. Morini, M. Marino, S.G.P.).
Department of Advanced Biomedical Sciences, University of Naples Federico II, Italy (V.P.).
Circulation. 2025 Jul 29;152(4):233-245. doi: 10.1161/CIRCULATIONAHA.124.073475. Epub 2025 May 23.
Desmosomal gene variants (DGVs) have been associated with a diverse spectrum of phenotypic manifestations within arrhythmogenic cardiomyopathy, but data on genotype-specific outcomes are lacking. We investigated genotype-specific arrhythmic and heart failure (HF) outcomes in DGV carriers.
This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency <10) variants of uncertain significance were included. The arrhythmic end point was the occurrence of a life-threatening arrhythmic event, defined as sudden cardiac death, aborted cardiac arrest, or hemodynamically unstable ventricular tachycardia. The end-stage HF outcome was the composite of a fatal HF episode or cardiac transplantation.
We included 533 DGV carriers (59% male; median [interquartile range] age, 39 [22-54] years) from 214 families: 503 of 533 (94%) had a single DGV (212 [40%] , 160 [30%] , 97 [18%] , 34 [6%] ) and 30 of 533 (6%) double DGVs. Overall, 83 of 533 (16%) experienced a life-threatening arrhythmic event (at age 40 [33-51] years), and 14 of 533 (3%) experienced end-stage HF (at age 57 [50-60] years). Multivariable analysis demonstrated that, compared with nonmissense variants, nonmissense variants (hazard ratio [HR], 2.3 [95% CI, 1.3-4.1]; =0.008), missense variants in hotspot domains in (HR, 2.7 [95% CI, 1.2-6.2]; =0.010) and (HR, 3.6 [95% CI, 2.0-6.5]; <0.001), male sex (HR, 1.7 [95% CI, 1.1-2.8]; =0.021), and double DGVs (HR, 3.4 [95% CI, 1.7-6.9]; <0.001) were associated with a higher risk of a life-threatening arrhythmic event. Nonmissense variants (HR, 5.0 [95% CI, 1.5-18.2]; =0.009) and double DGVs (HR, 4.7 [95% CI, 1.0-19.3]; =0.044) were also associated with increased risk of end-stage HF.
Among carriers of DGVs, genotype was associated with arrhythmic and HF outcomes, with type and location of the variant further modulating the natural history.
