Characteristics and Outcomes of Gene-Elusive Dilated Cardiomyopathy

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Abstract
Background and Aims: Genetic testing in dilated cardiomyopathy (DCM) guides risk stratification and family screening. Likely pathogenic or pathogenic (LP/P) variants are identified in approximately one-third of patients, leaving many without a genetic diagnosis. Cohort studies suggest that ‘gene-elusive’ patients have a lower risk of adverse events. This study aims to better characterise this group and identify factors associated with adverse outcomes. Methods: Consecutive and unrelated DCM patients undergoing genetic testing and returning no LP/P variants were retrospectively recruited and compared to two control cohorts of DCM patients carrying LP/P variants in LMNA and TTN for a primary composite endpoint of end-stage heart failure (ESHF) or malignant ventricular arrhythmia (MVA). Results: Among patients without prior MVA, the composite endpoint occurred in 36/423 (8.5%) gene-elusive, 14/39 (35.9%) LMNA and 11/100 (11%) TTN cardiomyopathy patients (log-rank p < 0.001 for LMNA vs gene-elusive and LMNA vs TTN ; p = 0.96 for TTN vs gene-elusive). For gene-elusive patients, lower left ventricular ejection fraction, larger left ventricular internal diameter in diastole, absence of LBBB and ventricular ectopy on ECG were independent predictors of the primary endpoint. Gene-elusive patients with LBBB had less atrial arrhythmia and a lower burden of ventricular ectopy at baseline and a low risk of the primary composite endpoint (HR 0.3 [0.1-0.8], p-value 0.01). Conclusions: Gene-elusive DCM patients have a risk of adverse events similar to TTN cardiomyopathy. Gene-elusive patients with LBBB form a particularly low-risk subgroup, likely reflecting a distinct aetiology of left ventricular systolic dysfunction.

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