"Re-evaluation of variants of uncertain significance in patients with hereditary arrhythmogenic disorders"

Abstract

Background: Genetic diagnostics support the diagnosis of hereditary arrhythmogenic diseases, but variants of uncertain significance (VUS) complicate matters, emphasising the need for regular reassessment. Our study aims to reanalyse rare variants in different genes in order to decrease VUS diagnoses and thus improve risk stratification and personalized treatment for patients with arrhythmogenic disorders.

Methods: Genomic DNA was analysed using Sanger sequencing and next-generation sequencing (NGS). The Data was evaluated using various databases and in silico prediction tools and classified according to current ACMG standards by two independent experts.

Results: We identified 53 VUS in 30 genes, of which 17 variants (32%) were reclassified. 13% each were downgraded to likely benign (LB) and benign (B) and 6% were upgraded to likely pathogenic (LP). Reclassifications mainly occurred among variants initially classified in 2017-2019, with rates ranging from 50 to 60%.

Conclusion: The results support the assumption that regular reclassification of VUS is important, as it provides new insights for genetic diagnostics, that benefit patients and guide therapeutic approach.

Keywords: Arrhythmia syndromes; Genetics; Reclassification; Sudden cardiac death; Variants of uncertain significance.

Fig.1

Distribution of VUS in the suspected primary indicated Diagnosis. VUS = Variants of unknown significance

Fig.2

Number of VUS in the respective genes involved. Core Genes are highlighted in black. VUS = Variants of unknown significance

Fig. 3

a Reclassification of VUS. White colour represents the percentage of variants that have been reclassified. Grey colour illustrates the percentage of variants that remained VUS. b Division of the VUS into LB, B and LP. White colour represents the variants that were reclassified as B, light grey colour represents the variants that were reclassified as LB and black colour represents the variants that were reclassified as LP. VUS = Variants of unknown significance, B = Benign, LB = likely Benign, LP = likely pathogenic

Fig. 4

Reclassification in the respective gene panels. White colour represents the variants that were reclassified as B, light grey colour represents the variants that were reclassified as LB and black colour represents the variants that were reclassified as LP. Dark grey colour represents the VUS. VUS = Variants of unknown significance, B = Benign, LB = likely Benign, LP = likely pathogenic