The “negative” side of cardiomyopathy: phenotype and arrhythmic risk in gene-elusive patients

Background Although current literature increasingly supports genotype-driven risk stratification in cardiomyopathies, a substantial proportion of patients remain gene-elusive despite comprehensive genetic testing. In this subgroup, clinical phenotype, prognosis, and arrhythmic risk are less clearly defined compared with genotype-positive individuals, making risk stratification particularly challenging. Purpose To compare clinical phenotype and outcomes between gene-elusive and genotype-positive patients, and to identify predictors of life-threatening arrhythmias (LTAs) among the gene-elusive cohort. Methods We retrospectively analysed patients referred to our Cardiomyopathy Unit who underwent comprehensive genetic testing. A total of 266 gene-elusive patients were identified and compared with 141 genotype-positive individuals from the same institutional registry. Phenotype was classified according to the 2023 ESC cardiomyopathy classification. LTAs were defined as sustained ventricular tachycardia, ventricular fibrillation or appropriate ICD therapy. Logistic regression analysis was performed to identify independent predictors of LTAs in the gene-elusive subgroup. Results Phenotypic distribution was comparable between gene-elusive and genotype-positive patients (dilated cardiomyopathy (DCM) 20% vs 18%, p=0.62; non dilated left ventricular cardiomyopathy (NDLVC) 28% vs 21%, p=0.14; arrhythmogenic right ventricular cardiomyopathy (ARVC) 28% vs 36%, p=0.10). Gene-elusive patients were more frequently probands (68% vs 56%, p=0.01), whereas genotype-positive individuals more often presented through family screening (51% vs 34%, p=0.001). On cardiovascular magnetic resonance, biventricular function and fibrosis prevalence were similar between groups. During a median follow-up of 4.9 [2.1–9.8] years, rates of LTAs (22% vs 22%, p=1.00) and heart failure (HF) (10% vs 12%, p=0.67) were comparable. Hot phase episodes were more frequent among genotype-positive patients (9% vs 4%, p=0.03). Within the gene-elusive cohort, the ARVC phenotype was associated with significantly higher rates of LTAs and HF outcomes compared with DCM and NDLVC (all p<0.01). In univariable analysis, ARVC phenotype, proband status, and low QRS voltages in peripheral leads were associated with LTAs. In multivariable logistic regression, only proband status remained independently associated with LTAs (OR 11.5, 95% CI 1.5–89.0, p=0.02). Conclusions Despite the increasing emphasis on genotype-driven risk stratification, gene-elusive patients demonstrate a clinical course comparable to genotype-positive individuals. Although ARVC phenotype influences arrhythmic burden, proband status emerges as the main independent predictor of LTAs, suggesting the need for careful monitoring of patients presenting with overt disease.Genotype distribution