Abstract 14249: Sex and Gene Based Differences in Age Related Penetrance of Dilated and Arrhythmogenic Cardiomyopathy

Abstract

Background: Approximately 40% of cases of dilated (DCM) and arrhythmogenic cardiomyopathy (AC) are caused by rare genetic variants of large-effect. Sex-based differences in the penetrance of genetic DCM and AC have been described, however, findings have been inconsistent. Age at the time of diagnosis can be used as an indicator of age-related penetrance. In this study we aimed to describe differences in age at diagnosis in subgroups of patients with DCM and AC; the latter defined as ventricular arrhythmias preceding or superseding systolic LV dysfunction. Methods: Patients with DCM and AC were identified using data from 3 centers participating in the international SHaRe registry. Age at diagnosis and other baseline characteristics were compared across genetic subtypes; including patients with pathogenic and likely pathogenic (LP/P) variants (G+), variants of unknown significance (VUS), without identifiable genetic cause (G-) and subgroups with LP/P variants in 3 genes most frequent in this cohort ( TTN , LMNA , and DSP ). Results: Of 3662 patients with DCM and AC, 1341 were females (37%) and 3551 probands (97%). There were no significant differences in LVEF (38±14 vs. 41±14, p=0.07) or NYHA III-IV symptoms (14% vs. 11%, p=0.2). Genetic testing was performed more frequently in females (27% vs. 22%; p<0.01) but the frequency of LP/P variants did not differ significantly by sex (female 49% vs. male 38%, p=0.07). In the entire cohort, the age of diagnosis did not vary between females and males; however, females with LP/P variants in TTN were 9 years older (p<0.01) whereas females with LP/P variants in DSP were 10 years younger (p=0.037) at diagnosis than males (figure). Conclusion: Sex-based differences in age related penetrance of DCM and AC may differ across disease genes. Increased vigilance is warranted for early presentation of AC. Future research should examine the factors that underlie this heterogeneity and determine associated differences in clinical outcomes.