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

P A van der Zwaag, K Y van Spaendonck-Zwarts, J D H Jongbloed, J P van Tintelen, A A M Wilde, E van Drie, E Hoorntje, M G P J Cox, R H Lekanne Deprez, A C Houweling, V P Proost, D Dooijes, A F Baas, A S J M Te Riele, E M Lodder

Journal: International journal of cardiology 2025;432():133264

PMID: 40222661

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Abstract

AIMS

To evaluate the prevalence and clinical consequences of additional rare genetic variants in cardiomyopathy- and/or channelopathy-related genes in PLN p.(Arg14del) patients.

METHODS

In PLN p.(Arg14del) index patients (n = 160), additional rare genetic variants in cardiomyopathy- or channelopathy-related genes were collected. These variants were (re)classified as either variants of uncertain significance (VUS) or (likely) pathogenic ((L)P). VUS were further subcategorized in low, mid or high suspicion VUS. Cascade genetic testing results were studied in families with an additional (L)P variant. The occurrence and onset of malignant ventricular arrhythmias (MVA) or severe heart failure (HF)-related events in PLN index patients with and without additional (L)P variants were compared. In addition, extended genetic testing was performed in PLN relatives (n = 8) with major cardiac events <45 year.

RESULTS

In 6 % (6/106) of PLN index patients in whom targeted gene panel analysis was performed, an additional (L)P variant was identified. These patients showed a non-significant trend towards earlier onset of MVA or a severe HF-related event versus those without an additional variant. Incorporating VUS subclassification did not alter either of these trends. Two out of 8 PLN relatives with a major cardiac event <45 year had an additional P variant.

CONCLUSION

Additional (L)P variants in established cardiomyopathy- or channelopathy-related genes were found in 6 % of PLN p.(Arg14del) index patients, which is higher than in control populations. These patients showed a trend towards earlier onset of MVA or HF-related symptoms.

Address: Department 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. Electronic address: [email protected].; Department of Genetics, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.; Department of Cardiology, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.; Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.; Amsterdam UMC location University of Amsterdam, Department of Cardiology, Meibergdreef 9, 1105 AZ Amsterdam, 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; Amsterdam UMC location University of Amsterdam, Department of Cardiology, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX 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.; 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; Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.; Department of Genetics, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands; Netherlands Heart Institute, Moreelsepark 1, 3511 EP Utrecht, the Netherlands; Department of Genetics, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the Netherlands.; Department of Human Genetics, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands; Department of Experimental Cardiology, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.; Department 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.

DOI: 10.1016/j.ijcard.2025.133264

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MeSH Terms: Humans, Male, Female, Middle Aged, Adult, Cardiomyopathies, Genetic Variation, Genetic Testing, Aged, Founder Effect, Young Adult, Calcium-Binding Proteins