In a combined US and Dutch cohort of 577 patients with P/LP variants in the desmosomal genes, TMEM43, or PLN, the 4% of patients with more than one variant had significantly earlier occurrence of sustained VT (mean age 28 ± 12 years), worse survival free from a first sustained ventricular arrhythmia, and more frequent LV dysfunction (29%), heart failure (19%) and cardiac transplantation (9%) when compared with those with only one P/LP variant (32). The gene discussed is TMEM43; the disease is heart failure.