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

Abstract

The c.40_42delAGA variant in the phospholamban gene (PLN) has been associated with dilated and arrhythmogenic cardiomyopathy, with up to 70% of carriers experiencing a major cardiac event by age 70. However, other carriers remain asymptomatic or show only mild symptoms in 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-value=0.001) compared to asymptomatic non-carriers and symptomatic carriers (N=26), and we replicated this in different subset of 21,771 participants from the Lifelines cohort (-3.87 ms, p-value=0.028) and in 592 carriers from the Arrhythmogenic Cardiomyopathy (ACM) PLN patient registry (-6.91 ms, p-value=0.0002). Furthermore, symptomatic carriers showed a higher correlation between genetic predisposition to higher QRS duration (PGSQRS) and QRS (p-value=1.98x10-8), suggesting that symptomatic PLN c.40_42delAGA carriers may have an increased sensitivity to the effect of genetic variation in cardiac rhythm. Our results may help improve risk prediction models for cardiac outcomes for future studies, while our approach could guide studies on genetic diseases with incomplete penetrance.