TY - JOUR
T1 - The genetic basis of apparently idiopathic ventricular fibrillation
T2 - a retrospective overview
AU - Verheul, Lisa M
AU - van der Ree, Martijn H
AU - Groeneveld, Sanne A
AU - Mulder, Bart A
AU - Christiaans, Imke
AU - Kapel, Gijs F L
AU - Alings, Marco
AU - Bootsma, Marianne
AU - Barge-Schaapveld, Daniela Q C M
AU - Balt, Jippe C
AU - Yap, Sing-Chien
AU - Krapels, Ingrid P C
AU - Ter Bekke, Rachel M A
AU - Volders, Paul G A
AU - van der Crabben, Saskia N
AU - Postema, Pieter G
AU - Wilde, Arthur A M
AU - Dooijes, Dennis
AU - Baas, Annette F
AU - Hassink, Rutger J
PY - 2023/11/2
Y1 - 2023/11/2
N2 - 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.
AB - 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.
KW - Genetic testing
KW - Idiopathic ventricular fibrillation
KW - Sudden cardiac arrest
KW - Humans
KW - Male
KW - Adult
KW - Middle Aged
KW - Female
KW - Retrospective Studies
KW - Ventricular Fibrillation/diagnosis genetics epidemiology
KW - Arrhythmias, Cardiac/genetics
KW - Genetic Testing
U2 - 10.1093/europace/euad336
DO - 10.1093/europace/euad336
M3 - Article
SN - 1099-5129
VL - 25
JO - EP Europace
JF - EP Europace
IS - 11
M1 - euad336
ER -