LAUSR

Desmoplakin (DSP) truncating variants have been associated with arrhythmogenic cardiomyopathy (ACM), which can exclusively affect the left ventricle up to 30% of the cases. Nonetheless, data on prognosis in carriers is still limited. To evaluate survival free of cardiovascular events in carriers of pathogenic DSP truncating variants. Clinical and genetic data on families carrying DSP truncating variants (nonsense, frameshift, and splicing-site) in the literature were systematically revised and collected in a dedicated database. Classification of variant pathogenicity was in accordance with ACMG criteria. We evaluated available follow-up data and constructed Kaplan-Meier survival curves free from cardiovascular death (sudden death, appropriate cardiodefibrillator shock, heart failure death, and stroke-related death) or heart transplant based. Long-rank test was used to compare event-free survival time between genders. 707 carriers (336 index cases and 371 relatives; 51.1% were female carriers) were identified carrying 198 variants (90 nonsense, 89 frameshift, 19 splicing-site). 292 had ACM, 136 dilated cardiomyopathy (DCM), eight cases of unexplained sudden death, 120 were unaffected carriers, and no clinical data was reported in 151 carriers. In addition, 73 affected relatives without genetic testing were reported (28 had ACM, 28 DCM, and 17 unexplained sudden deaths). Survival data was reported for 449 individuals (221 males; 228 females). Eight-one had suffered events: 57 sudden cardiac death (32 males), 10 heart failure deaths (7 males), 7 transplants (5 males), 6 cardiodefibrillator shock (4 females), and one stroke-related death (1 female). Incidence of cardiovascular death or transplant was higher in males than females (p=0.012), with annual incidence between ages 30–70 of 0.84%/year in males and 0.72%/year in females. Mortality at the age of 50 years was 31% for males and 16% for females. DSP truncating variants are associated with a relevant risk of cardiovascular death, which is higher in males, especially after age 30. More than 70% of the events were sudden deaths. DSP truncating variants survival curves Type of funding source: Private company. Main funding source(s): Health in Code SA