Importance of genetic testing in unexplained cardiac arrest

Abstract

Aims: Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES).

Methods and results: Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of 'explained' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest.

Conclusions: Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.

Keywords: Arrhythmia; Cardiac arrest; Cardiomyopathy; Cardiovascular genetics; Genetic testing; Ventricular fibrillation.

Structured Graphical Abstract

Study flowchart and summary results. ARVC, arrhythmogenic right ventricular cardiomyopathy; BrS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; CRDS, RYR2 Ca²⁺ release deficiency syndrome; DCM, dilated cardiomyopathy; ECG, electrocardiogram; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; LV, left ventricular; MRI, magnetic resonance imaging; MVP, mitral valve prolapse; SQTS, short QT syndrome; UCM, unclassified cardiomyopathy; WES, whole-exome sequencing.

Figure 1

Number of rare unique variants identified in each gene. Genes are selected based on two panels signed off by PanelApp consensus: Sudden cardiac death (V 9.46) and cardiomyopathies—including childhood onset (V 1.5). Genes are ordered alphabetically within the panel in which they appear first as well as PanelApp grade (Green or Amber). Green represents diagnostic-grade genes and Amber represents those with borderline clinical actionability. Variants classified as pathogenic/likely pathogenic are shown in dark colour, and variants of uncertain significance are shown in light colour (see legend). Genes where no rare variants are identified are not shown (full list in Supplementary material online, Table S3). Variants that are low quality (see Supplementary material online, Note) are not shown, unless they were validated using Sanger sequencing (a full list of such variants appears in Supplementary material online, Table S5). Genes classified by the ClinGen cardiovascular clinical domain working group as having moderate evidence in cardiac arrhythmia syndromes or cardiomyopathies are marked with as asterisk. CM, cardiomyopathy; P/LP, pathogenic/likely pathogenic variant; SCD, sudden cardiac death; VUS, variant of uncertain significance.

Figure 2

Proportion of cardiac arrest survivors carrying pathogenic/likely pathogenic variants in the overall study population and clinically relevant subgroups. Proportions are shown as red bars and 95% confidence interval as brackets. Left: proportion of cases carrying a pathogenic/likely pathogenic variant in the overall cohort with apparent unexplained cardiac arrest (23/228). Middle: proportion of cases with pathogenic/likely pathogenic variants among cases where the cardiac arrest remained unexplained following advanced phenotypic testing (17/207). Right: proportion of cases with pathogenic/likely pathogenic variants among those with unexplained arrest despite complete advanced phenotypic testing including cardiac magnetic resonance, stress (or epinephrine), and procainamide testing (7/120).

Figure 3

Proportion of patients carrying genetic variants by varying virtual gene panels. Proportion of cases carrying at least one variant classified as pathogenic/likely pathogenic and/or at least one variant of uncertain significance for each of the four virtual gene panels based on PanelApp gene panels and restricted to genes classified by ClinGen as having moderate, strong, or definitive evidence in arrhythmias or cardiomyopathies. Note that larger panels increase the rate of patients with variants of uncertain significance with little change in the rate of pathogenic/likely pathogenic variants. Dx, diagnosis/diagnostic; SCD, sudden cardiac death.