What is the clinical evidence from this study?

Study design: Cohort. Population: Unexplained cardiac arrest (n=228). Intervention: Whole-exome sequencing (WES) vs. Phenotypic testing alone. Primary outcome: Identification of a pathogenic or likely pathogenic (P/LP) variant (95% CI 6.5-14.8).

March 8, 2022European Heart Journal70 citationsOpen Access

Importance of genetic testing in unexplained cardiac arrest

SGSteffany GrondinUniversité du Québec à Montréal BDBrianna DaviesUniversity of British Columbia JCJulia Cadrin‐TourignyElectrophysiology

Key Result

Whole-exome sequencing identified a pathogenic or likely pathogenic variant in 10.1% of unexplained cardiac arrest survivors, increasing the proportion of explained cases from 9% to 18%.

Study Design

Type

Cohort (n=228)

Multicenter

Yes

Structured PICO

Does whole-exome sequencing increase the diagnostic yield in survivors of unexplained cardiac arrest?

Population

228 survivors of unexplained cardiac arrest (mean age 39 years, 34% female) with preserved ejection fraction and no obstructive coronary disease underwent whole-exome sequencing.

Intervention

Whole-exome sequencing (WES) followed by assessment of rare variants in previously reported cardiovascular disease genes.

Comparator

Advanced clinical testing (phenotyping) at baseline.

Outcome

Yield and clinical utility of genetic testing (identification of pathogenic or likely pathogenic variants).surrogate

Whole-exome sequencing identifies a disease-causing variant in 10% of unexplained cardiac arrest survivors, often in cardiomyopathy-associated genes, supporting the use of genetic testing in this population.

Limitations

Descriptive study without a control population precludes case-control statistical assessment of gene-disease association.
Whole-exome sequencing and virtual panel approach misses deep intronic, intergenic small variants, and large insertions/deletions.
Phenotypic evaluation was performed at the discretion of the treating physician, leading to incomplete testing in some cases.
Diagnostic utility was determined at the time of arrest, which may differ from utility in cases where the arrest occurred years prior.

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.

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