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Additional genetic variants in cardiomyopathy patients with the pathogenic PLN p.(Arg14del) founder variant

E van Drie1, J D H Jongbloed2, E Hoorntje2

  • 1Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands; Member of the European Reference Network for Rare, Low Prevalence and Complex Diseases of the Heart: ERN GUARD-Heart' (ERN GUARDHEART; http://guardheart.ern-net.eu), the Netherlands.

International Journal of Cardiology
|April 13, 2025
PubMed

Insights

Genetic variants in PLN p.(Arg14del) patients were analyzed. Six percent of patients had additional pathogenic variants, showing a trend towards earlier cardiac events.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Epidemiology

Background:

  • PLN p.(Arg14del) is a known genetic variant associated with cardiac conditions.
  • The clinical significance of additional rare genetic variants in these patients is not fully understood.
  • Understanding these variants can improve risk stratification and patient management.

Purpose of the Study:

  • To determine the prevalence of additional rare genetic variants in cardiomyopathy- and channelopathy-related genes in PLN p.(Arg14del) patients.
  • To evaluate the clinical consequences of these additional variants, focusing on malignant ventricular arrhythmias (MVA) and severe heart failure (HF).

Main Methods:

  • Collected data on additional rare genetic variants in 160 PLN p.(Arg14del) index patients.
  • Classified variants as variants of uncertain significance (VUS) or (likely) pathogenic ((L)P).
  • Compared the occurrence and onset of MVA or severe HF events in patients with and without additional (L)P variants.

Main Results:

  • An additional (L)P variant was identified in 6% of PLN index patients.
  • Patients with additional (L)P variants showed a non-significant trend towards earlier MVA or severe HF events.
  • Cascade testing in relatives revealed additional pathogenic variants in 2 out of 8 individuals with major cardiac events before age 45.

Conclusions:

  • Additional (L)P variants are more prevalent in PLN p.(Arg14del) patients than in control populations.
  • These variants may be associated with an earlier onset of MVA or HF-related symptoms.
  • Further research is warranted to fully elucidate the impact of these genetic findings.
Abstract

Keywords:
Additional variantsArrhythmiaCardiomyopathyGeneticsHeart failurePLN

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