Clinical presentation and outcomes of patients with homozygous cadherin variants in arrhythmogenic cardiomyopathy (ACM): insights from the Zurich ACM registry
S Zafeiropoulos, A M Domingo, D Parianos, D Akdis, S M Fokstuen, F Tanner, R Manka, R Biller, A Giannopoulos, A Flammer, F Ruschitzka, C Brunckhorst, F Duru, A M SagunerAbstract
Background
Homozygous variants in desmosomal cadherins – desmoglein 2 (DSG2) and desmocollin 2 (DSC2) – constitute a rare subset of arrhythmogenic cardiomyopathy (ACM), indicating early-onset biventricular disease. However, granular phenotypic characterization remains poorly reported.
Objective
To describe the clinical presentation and outcomes of ACM patients carrying homozygous cadherin variants.
Methods
We retrospectively analyzed all patients carrying homozygous DSG2 or DSC2 variants enrolled in the Zurich ACM Registry. Demographics, genetics, ECG/Holter, echocardiography, CMR, 18F-FDG-PET/CT, endomyocardial biopsy, and outcomes were extracted from clinical records. Descriptive statistics were used for analysis.
Results
Six unrelated male patients (median age at symptom onset 22 [IQR, 17-26] years, median age of diagnosis 26 [19-28]) with pathogenic/likely pathogenic (P/LP) homozygous DSG2 or DSC2 variants were identified. Four carried homozygous DSG2, and two homozygous DSC2 variants. Three patients were of Swiss origin (all from the same region sharing an identical DSG2 variant suggesting a common founder variant), two were of Turkish origin (one of Kurdish ethnicity), and one was Somali. All patients exhibited severe biventricular involvement at diagnosis with right ventricular (RV) dilatation, RV dysfunction (median FAC 26 [23–30]%) and a median LVEF of 35 [33-51] % with predominant wall motion at the apex. Three patients (50%) showed sustained ventricular arrhythmias and ICDs were implanted in all. Myocardial inflammation was demonstrated in 3/6 patients (50%), with two patients (33.3%) showing inflammation on 18F-FDG-PET/CT mimicking isolated cardiac sarcoidosis and one patient showing borderline lymphocytic myocarditis without granuloma formation on endomyocardial biopsy. One patient exhibited woolly hair, and palmoplantar keratosis (Fig. 1) and was born to consanguineous parents . Regarding outcomes, one patient underwent heart transplantation at age 39, one died at age 23 after declining transplantation, one is currently evaluated for transplantation at age 41, and three remain clinically stable with heart failure. Two patients (33.3%) experienced ischemic stroke at a median age of 31 in the absence of atrial fibrillation/flutter most likely due to LV thrombus formation, prior to systemic anticoagulation. Ultimately, four patients (66.7%) received anticoagulation.
Conclusions
Homozygous cadherin-related ACM presented as an early-onset, severe biventricular arrhythmogenic cardiomyopathy, frequently complicated by rapid heart failure progression and thromboembolic events at a young age irrespective of the presence of atrial fibrillation/flutter. These findings support (i) liberal anticoagulation in advanced phenotypes with this genotype and (ii) screening for myocardial inflammation and evaluation of immunomodulatory strategies alongside guideline-directed medical therapy with early involvement of heart transplant specialists.Table 1Figure 1