Tracing the pathogenic PLN p.(Arg14del) variant across the globe; more than just a local curiosity
The c.40_42delAGA p.(Arg14del) variant in the phospholamban (PLN) gene is associated with PLN cardiomyopathy, predisposing individuals to life-threatening arrhythmia and/or heart failure (a weak heart which is not able to pump blood well). This genetic variant was first described in a large Greek family in 2006. Subsequently, it was found to be highly prevalent in the northern region of the Netherlands. Disease severity varies strongly among PLN p.(Arg14del)-positive individuals, even within the same family, and factors that lead to such different disease courses remain largely unknown. This study examined the global distribution of the pathogenic PLN p.(Arg14del) variant to provide insights into factors contributing to this clinical variability.
So far, more than 2000 PLN p.(Arg14del)-positive individuals have been identified in 21 countries across four continents. Our study suggests that most analyzed individuals, except those from Greece, share a common ancestor who lived between 275-425 years ago. The observed geographic distribution is consistent with historical trade and migration patterns. Besides understanding its geographic and ancestral distribution, this study also helps to identify patient cohorts from different geographic regions that can support further research into factors underlying its varying disease courses. Ultimately, such efforts may be used to identify which individuals most likely benefit from therapies such as an implantable cardioverter-defibrillator to prevent life-threatening arrhythmia or gene therapy.
Its global prevalence, along with increasing availability of genetic testing, underscores the importance for geneticists and cardiologists worldwide to be aware of PLN p.(Arg14del)-associated cardiomyopathy. Because PLN was recently included in updated guidelines for clinical geneticists, it is anticipated that more cases will be identified.
van Drie E, van Lint FHM, Zwart R, Wang J, Chen Y, Postma AV, Elferink MG, van Steenbrugge JJM, van der Zwaag PA, Jongbloed JDH, Dooijes D, van der Heide MYC, Houweling AC, Haugaa KH, Leren IS, Kostareva A, Milting H, Nguyen TV, Ho Huynh TD, Chevalier P, Delinière A, Gimeno-Blanes JR, Sabater-Molina M, Barriales-Villa R, Mazzanti A, Memmi M, Kuramoto Y, Tabata T, Wilde AAM, van Spaendonck-Zwarts KY, van Tintelen JP. Tracing the pathogenic PLN p.(Arg14del) variant across the globe; more than just a local curiosity.
J Cardiovasc Transl Res. 2026 Jun 25;19(1):78. doi: 10.1007/s12265-026-10792-6. PMID: 42350697
Prepared by Esmee van Drie and Ruth Biller