Next-generation sequencing of a large gene panel in patients initially diagnosed with idiopathic ventricular...

Idiopathic ventricular fibrillation (IVF) is a rare primary cardiac arrhythmia syndrome that is diagnosed in a resuscitated cardiac arrest victim, with documented ventricular fibrillation, in whom no underlying cause is identified after comprehensive clinical evaluation. In some patients, causative genetic mutations are detected that facilitate patient treatment and follow-up. The feasibility of next-generation sequencing (NGS) has increased with its greater availability and decreasing costs.

The aim of this study was to assess the diagnostic yield of NGS in patients with IVF.

A total of 33 patients initially diagnosed with IVF were included (mean age 53 ± 15 years; 14(42%) men). In all included patients, NGS of 33 genes and the DPP6 haplotype revealed no pathogenic mutations. Genetic screening comprised NGS of a panel of 179 additional genes. Variants with a minor allele frequency of <0.05% were assessed for pathogenicity by using existing mutation databases and in silico predictive algorithms.

In 1 of 33 patients, a likely pathogenic mutation was detected. The added yield of genetic testing with NGS of 179 additional genes is 3% in patients with IVF. In 15% of patients, 1 or multiple variants of uncertain clinical significance were detected.

The added yield of genetic screening of extended NGS panels in patients initially diagnosed with IVF is minimal. Routine analysis of large diagnostic NGS panels is therefore not recommended.