Phenotypic and Genetic Factors 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, there are carriers who remain asymptomatic at older ages. 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, q value = 0.001) compared to asymptomatic non-carriers, an effect we could replicate in two different independent cohorts. Furthermore, symptomatic carriers showed a higher correlation (rPearson = 0.17) between polygenic predisposition to higher QRS (PGSQRS) and QRS (p value = 1.98 × 10–8), suggesting that the effect of the genetic variation on cardiac rhythm might be increased in symptomatic carriers. Our results allow for improved clinical interpretation for asymptomatic carriers, while our approach could guide future studies on genetic diseases with incomplete penetrance. Graphical abstract

Phospholamban R14del disease: The past, the present and the future

“…It is still unclear what factors define and/or influence phenotypic expression of this disease, and why there is such a high phenotypic variability exhibited by PLN-R14del patients. This is expected to be addressed by extensive genotype-phenotype correlation analysis following in-depth clinical and genomic studies that are currently being performed on symptomatic carriers, asymptomatic carriers, as well as non-carrier members from within PLN-R14del families ( 31 , 89 ). The outcome of this work is anticipated to unveil valuable information on genomic, genetic and/or epigenetic factors influencing disease manifestation.…”