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Comment
. 2023 Nov 2;25(11):euad336.
doi: 10.1093/europace/euad336.

The genetic basis of apparently idiopathic ventricular fibrillation: a retrospective overview

Lisa M Verheul  1 , Martijn H van der Ree  2   3 , Sanne A Groeneveld  1 , Bart A Mulder  4 , Imke Christiaans  5 , Gijs F L Kapel  6 , Marco Alings  7 , Marianne Bootsma  8 , Daniela Q C M Barge-Schaapveld  9 , Jippe C Balt  10 , Sing-Chien Yap  11 , Ingrid P C Krapels  12 , Rachel M A Ter Bekke  13 , Paul G A Volders  13 , Saskia N van der Crabben  14 , Pieter G Postema  2   3 , Arthur A M Wilde  2   3 , Dennis Dooijes  15 , Annette F Baas  15 , Rutger J Hassink  1
Affiliations
Comment

The genetic basis of apparently idiopathic ventricular fibrillation: a retrospective overview

Lisa M Verheul et al. Europace. .

Abstract

Aims: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients.

Methods and results: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001).

Conclusion: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.

Keywords: Genetic testing; Idiopathic ventricular fibrillation; Sudden cardiac arrest.

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Conflict of interest statement

Conflict of interest: P.G.P. is an associate editor of Europace and was not involved in the peer review process or publication decision. S.-C.Y. is a consultant for Boston Scientific and has received lecture fees and research grants from Medtronic, Biotronik, and Boston Scientific. All remaining authors have declared no conflicts of interest.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Flowchart presenting genetic evaluation with results from all patients with genetic testing. Patients with LP/P variants and VUS are shown; colours represent percentages. No abnormalities, benign, or likely benign variants were found in the remaining patients. Three patients had additional single-gene testing besides panel testing which revealed an LP/P variant, highlighted in the figure with *. Three patients with unknown type of panel testing are not shown in this figure.
Figure 2
Figure 2
Clinical course of patients with variants in genes associated with a cardiomyopathy or cardiac arrhythmia. The clinical course of each patient with an LP/P variant is shown. Each patient is represented by a line; the line starts at the moment of VF. The development of phenotypic characteristics (imaging abnormalities or electrical abnormalities), the initiation of genetic testing, ventricular arrhythmia recurrence, and the establishment of a diagnosis are plotted over follow-up years. Electrical abnormalities are premature ventricular contractions or (non-sustained) arrhythmias on Holter or exercise treadmill test. Imaging modalities are structural abnormalities determined by echocardiography or CMR imaging.
Figure 3
Figure 3
Proposed flowchart for the genetic evaluation of SCA survivors. Triggers associated with familial arrhythmia syndromes and young age are added to guide indication for genetic testing. When applicable, our proposed idiopathic VF panel can be performed. Modified from Stiles et al., 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families, 2021, with permission from Elsevier. SCA, sudden cardiac arrest; VF, ventricular fibrillation.
See this image and copyright information in PMC

Comment on

  • Genetics in Probands With Idiopathic Ventricular Fibrillation: A Multicenter Study.
    Pannone L, Gauthey A, Conte G, Osei R, Campanale D, Baldi E, Berne P, Vicentini A, Vergara P, Sorgente A, Rootwelt-Norberg C, Della Rocca DG, Monaco C, Bisignani A, Miraglia V, Spolverini M, Paparella G, Overeinder I, Bala G, Almorad A, Ströker E, de Ravel T, Medeiros-Domingo A, Sieira J, Haugaa KH, Brugada P, La Meir M, Auricchio A, Chierchia GB, Van Dooren S, de Asmundis C. Pannone L, et al. JACC Clin Electrophysiol. 2023 Aug;9(8 Pt 1):1296-1306. doi: 10.1016/j.jacep.2023.03.008. Epub 2023 May 24. JACC Clin Electrophysiol. 2023. PMID: 37227348

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Supplementary concepts