The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?

Jaakko T. Leinonen, Lia Crotti, Aurora Djupsjöbacka, Silvia Castelletti, Nella Junna, Alice Ghidoni, Annukka M. Tuiskula, Carla Spazzolini, Federica Dagradi, Matti Viitasalo, Kimmo Kontula, Maria Christina Kotta, Elisabeth Widén, Heikki Swan, Peter J. Schwartz

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Background Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. Methods and results The study included 76 Finnish and Italian patients with a mean age of 31.2 years at the time of the VF event, collected between the years 1996–2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF < 0.005%) variants that were classified as of unknown significance (VUS). Conclusion The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.

Original languageEnglish
Pages (from-to)139-145
Number of pages7
JournalInternational Journal of Cardiology
Volume250
DOIs
Publication statusPublished - Jan 1 2018

Fingerprint

Ventricular Fibrillation
Channelopathies
Cardiac Arrhythmias
Genes
Exome
Sudden Cardiac Death
Disease Susceptibility
Cardiomyopathies
Polymorphic catecholergic ventricular tachycardia
Paroxysmal ventricular fibrillation
Mutation
Population

Keywords

  • Catecholaminergic polymorphic ventricular tachycardia
  • Genetic testing
  • Genetics
  • Idiopathic ventricular fibrillation
  • RYR2

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

The genetics underlying idiopathic ventricular fibrillation : A special role for catecholaminergic polymorphic ventricular tachycardia? / Leinonen, Jaakko T.; Crotti, Lia; Djupsjöbacka, Aurora; Castelletti, Silvia; Junna, Nella; Ghidoni, Alice; Tuiskula, Annukka M.; Spazzolini, Carla; Dagradi, Federica; Viitasalo, Matti; Kontula, Kimmo; Kotta, Maria Christina; Widén, Elisabeth; Swan, Heikki; Schwartz, Peter J.

In: International Journal of Cardiology, Vol. 250, 01.01.2018, p. 139-145.

Research output: Contribution to journalArticle

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title = "The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?",
abstract = "Background Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. Methods and results The study included 76 Finnish and Italian patients with a mean age of 31.2 years at the time of the VF event, collected between the years 1996–2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9{\%}). Most of them (5, 71{\%}) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8{\%}) we detected 10 novel or extremely rare (MAF < 0.005{\%}) variants that were classified as of unknown significance (VUS). Conclusion The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.",
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AU - Leinonen, Jaakko T.

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AU - Djupsjöbacka, Aurora

AU - Castelletti, Silvia

AU - Junna, Nella

AU - Ghidoni, Alice

AU - Tuiskula, Annukka M.

AU - Spazzolini, Carla

AU - Dagradi, Federica

AU - Viitasalo, Matti

AU - Kontula, Kimmo

AU - Kotta, Maria Christina

AU - Widén, Elisabeth

AU - Swan, Heikki

AU - Schwartz, Peter J.

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N2 - Background Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. Methods and results The study included 76 Finnish and Italian patients with a mean age of 31.2 years at the time of the VF event, collected between the years 1996–2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF < 0.005%) variants that were classified as of unknown significance (VUS). Conclusion The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.

AB - Background Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. Methods and results The study included 76 Finnish and Italian patients with a mean age of 31.2 years at the time of the VF event, collected between the years 1996–2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF < 0.005%) variants that were classified as of unknown significance (VUS). Conclusion The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.

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