Povysil G, Chazara O, Carss KJ, et al. - In this retrospective study of clinical trials and a prospective epidemiological resource (UK Biobank), researchers examined the contribution of rare genetic variants to all-cause heart failure (HF) with and without reduced left ventricular ejection fraction. Participants were 5,942 patients with HF and 13,156 controls. Whole-exome sequencing was applied. Findings of this gene-based collapsing analysis revealed not only a significant enrichment of rare protein-truncating variants in the TTN gene but also in general an elevated burden of mendelian cardiomyopathy variants in HF cases of mostly presumed ischemic cause vs controls. This study offers further evidence that an essential subset of complex late-onset diseases such as HF may be represented by mendelian genetic conditions, regardless of the clinical presentation.