Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers

The Netherlands A. C. M./P. L. N. Registry, Lifelines Cohort Study, Esteban A. Lopera-Maya, Shuang Li, Remco de Brouwer, Ilja M. Nolte, Justin van Breen, Jan D.H. Jongbloed, Morris A. Swertz, Harold Snieder, Lude Franke, Cisca Wijmenga, Rudolf A. de Boer, Patrick Deelen, Paul A. van der Zwaag*, Serena Sanna*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

2 Citations (Scopus)
8 Downloads (Pure)


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.

Original languageEnglish
Pages (from-to)1251–1266
Number of pages16
JournalJournal of cardiovascular translational research
Publication statusPublished - Dec-2023


  • Cardiomyopathy
  • Genome-wide association study
  • Incomplete penetrance
  • Modifiers of Mendelian disorders
  • Polygenic score


Dive into the research topics of 'Phenotypic and Genetic Factors Associated with Absence of Cardiomyopathy Symptoms in PLN:c.40_42delAGA Carriers'. Together they form a unique fingerprint.

Cite this