Genotype-Specific Outcomes of Desmosomal Cardiomyopathies

Abstract

BACKGROUND: 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. METHODS: This cohort study included consecutive patients referred for screening for desmosomal genes. Carriers of pathogenic and rare (allele frequency <10 − 4 ) 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. RESULTS: 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%] PKP2 , 160 [30%] DSP , 97 [18%] DSG2 , 34 [6%] DSC2 ) 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 PKP2 variants, nonmissense DSP variants (hazard ratio [HR], 2.3 [95% CI, 1.3–4.1]; P =0.008), missense variants in hotspot domains in DSP (HR, 2.7 [95% CI, 1.2–6.2]; P =0.010) and PKP2 (HR, 3.6 [95% CI, 2.0–6.5]; P <0.001), male sex (HR, 1.7 [95% CI, 1.1–2.8]; P =0.021), and double DGVs (HR, 3.4 [95% CI, 1.7–6.9]; P <0.001) were associated with a higher risk of a life-threatening arrhythmic event. Nonmissense DSP variants (HR, 5.0 [95% CI, 1.5–18.2]; P =0.009) and double DGVs (HR, 4.7 [95% CI, 1.0–19.3]; P =0.044) were also associated with increased risk of end-stage HF. CONCLUSIONS: Among carriers of DGVs, genotype was associated with arrhythmic and HF outcomes, with type and location of the variant further modulating the natural history.