Background: Evidence increasingly suggests genetic variants desmoplakin (DSP) are associated with left ventricular arrhythmogenic cardiomyopathy (ACM).
Objective: To assess probands and family members (FM) with DSP variants in regard to age at penetrance and disease severity.
Methods: Chart review was performed to identify patients with a pathogenic or likely pathogenic DSP variant in probands and FM. Disease penetrance was defined by any of the following: (i) ECG - T-wave morphological changes in leads 1, aVL and/or V4-V6 (ii) Arrhythmic - >500 VPBs/24 hours, non-sustained or sustained VT, cardiac arrest (CA) (iii) Imaging - LV EF <50%, wall motion abnormalities, sub-epicardial delayed enhancement (iv) Histology - fibrofatty/fibrous replacement. Major cardiac events (MCE) were: arrhythmia - sustained VT, CA or appropriate ICD therapy; heart failure (HF) - LVEF<35%, NYHA class 3/4, transplant. Follow up was censored at transplant or death.
Results: Sixty-six (66) patients (48 female, 26 probands) aged 40.4 ± 18.3 years followed for 4.3 ± 3.4 years were included. A history of sudden death was present in 12 families. All probands and 24/40 (60%) FM had penetrant disease, seen earlier in probands (27.5 ± 15.4 v 38.8 ± 17.3 years, p=0.02). There was no age difference between penetrant and non-penetrant FM (43.6 ± 19.3 v 38.5 ± 19.0 years, p=0.41). Penetrant disease was evident <18 years in 8 (29%) probands and 5 (13%) FM, (p=0.21). Only 2 (13%) FM with no disease were <18 years. MCE occurred in 19 (73%) probands and 5 (13%) FM (p<0.001). In probands these were arrhythmic (10), HF (4) or both (5), and in FM were arrhythmic (1) and HF (4). CA occurred in 8 probands and 1 FM. In those <18 years, MCE were seen in 8 probands and 5 FM. There were 4 transplants and no deaths. DSP variants were frameshift (34), truncating (31), splice (1). Additional desmosomal variants were seen in 10, and not associated with proband status (p=0.15), penetrance (p=0.73) or MCE (p=0.79).
Conclusion: Probands with DSP-mediated ACM have a high rate of life-threatening arrhythmia and heart failure, and although penetrance in FM is high the clinical course is much less severe. It is more common in females and may present at a young age. Genetic factors do not influence penetrance, age of onset or severity.