Prognostic prediction of genotype versus phenotype in genetic cardiomyopathies

Abstract Background In cardiomyopathies (CMPs), the diverse genetic background often leads to phenotypic heterogeneity. Currently, genotype-phenotype studies are founded on clinical phenotype-based classification of CMPs, contributing possible biases due exclusion specific and unascertained expressions CMP genes. Purpose We sought define differences in outcome when stratifying patients based phenotype at presentation compared with genotype a large cohort positive testing. Methods this study, we included whole spectrum non-hypertrophic phenotypes, genetically determined: dilated cardiomyopathy (DCM), arrhythmogenic right ventricular (ARVC), left (ALVC) biventricular ARVC (BiV). The primary secondary outcomes were: 1) all-cause mortality/heart transplant (D/HT); 2) heart failure-related death/heart transplant/left assist device implantation (DHF/HT/VAD); 3) sudden cardiac death/life-threatening arrhythmias (SCD/MVA). Results Two hundred eighty-one (80% DCM) carrying pathogenic or likely variants were study. was classified as DCM, ARVC, ALVC BiV according current consensus criteria. median follow-up 188 months. Variants titin (TTN; 34%) sarcomeric genes (SARC; 22%) most frequent genotypes almost invariably associated DCM phenotype. DSP, LMNA FLNC displayed more heterogeneous presentations, including ALVC, BiV. At survival analysis, arrhythmic occurred frequently without carriers PKP2, variants. However, after adjustment for age sex, genotype-based but not predictive outcome. showed worst trend term D/HT DHF/HT/LVAD. Conclusions cardiomyopathies, is significant Nevertheless, our genotypic-based higher precision predicting patients' respect classification. These findings add understanding inherited CMPs may implement risk stratification Funding Acknowledgement Type funding sources: None.