Phenotypic and genetic factors are associated with absence of cardiomyopathy symptoms in PLN c.40_42delAGA carriers

The phospholamban (PLN) c.40_42delAGA variant has been associated with dilated and arrhythmogenic cardiomyopathy. Up to 70% of the carriers have manifested a major cardiac event by age 70, while others remain asymptomatic or show only mild symptoms at old age. To understand the mechanisms behind this incomplete penetrance, we evaluated potential phenotypic and genetic modifiers in 74 PLN c.40_42delAGA carriers identified in 36,339 participants of the Lifelines population cohort. Asymptomatic carriers (N=48) showed shorter QRS duration (-5.73 ms, p=0.001) compared to the asymptomatic non-carriers and symptomatic carriers (N=26). This was replicated in another subset of 21,771 samples from the Lifelines cohort (-3.87 ms, p=0.028) and in 592 carriers from the Arrhythmogenic Cardiomyopathy (ACM) patient registry (-6.91 ms, p=0.0002). Furthermore, symptomatic carriers showed a higher correlation between genetic predisposition to higher QRS duration (PGSQRS) and QRS (p=1.98x10-8), suggesting that symptomatic PLN c.40_42delAGA carriers may have an increased sensitivity for the effect of genetic variation in cardiac rhythm. These results may improve risk prediction models for cardiac outcomes for future studies, whereas our approach could guide studies on genetic diseases with incomplete penetrance.