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.

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases

“…liver or spleen) should be retained for potential genetic analysis. Other sources of DNA such as blood spots and tissue stored in suitable media at room temperature may suffice. 15 , 413–416 When a SCD could be attributable to a likely genetic cause, post‐mortem genetic testing in the deceased individual targeted to the likely cause should be performed. 414 , expert opinionWhen a SCD remains unexplained despite an autopsy and toxicology, post‐mortem genetic testing in the deceased individual targeted to channelopathy genes should be performed when the circumstances and/or family history support a primary electrical disease. 15 , 415 , 416 When a SCD <50 years old remains unexplained despite an autopsy, toxicology and channelopathy gene panel testing, post‐mortem genetic testing in the deceased individual may be extended to a wider panel including cardiomyopathy genes. 15 , 415 , 416 In a decedent with unexplained SCD or an UCA survivor, hypothesis‐free (post‐mortem) genetic testing using exome or genome sequencing should not be performed. Expert opinionIn selected UCA survivors with idiopathic VF, genetic testing for founder variants, a where relevant, should be considered. 417 In UCA survivors, genetic testing of channelopathy and cardiomyopathy genes may be considered. 418–421 In relatives of UCA survivors or SCD decedents in whom a pathogenic variant has been identified, predictive genetic testing should be performed. 413 , 422 In relatives of UCA survivors or SCD decedents, clinical evaluation of 1st degree family members should be performed, and targeted to the index case’s phenotype if present. 422–427 In decedents with SCD or survivors with cardiac arrest in whom a non‐genetic cause has been identified, genetic testing of the index case and clinical evaluation of relatives should not be performed. Expert opinion…”

“…Recently, WES with virtual panel analysis performed systematically in 228 survivors of cardiac arrest of uncertain aetiology was shown to identify a pathogenic variant in 10% of cases. 421…”

“…The role of genetic testing after a sudden unexpected death or cardiac arrest is visualized in Figure . Recently, WES with virtual panel analysis performed systematically in 228 survivors of cardiac arrest of uncertain aetiology was shown to identify a pathogenic variant in 10% of cases 421 …”

Screening for Pathogenic Variants in Cardiomyopathy Genes Predicts Mortality and Composite Outcomes in UK Biobank

“…(34) Studies found pathogenic and likely pathogenic variants in CMP genes in patients with unexplained cardiac arrest, highlighting the arrhythmogenic potential of such variants in the absence of apparent CMP features. (35,36) Other effect modifiers in the clinical setting include exercise and inflammation, which might promote development of phenotype or CMP-related complications. (30) However, the increased mortality may not necessarily be due to higher rates of sudden cardiac death—it is all-cause in this study, and this warrants further investigation.…”

European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the State of Genetic Testing for Cardiac Diseases

“…Recently, WES with virtual panel analysis performed systematically in 228 survivors of cardiac arrest of uncertain aetiology was shown to identify a pathogenic variant in 10% of cases. 421 Trio WES on amniocentesis or CVS samples may be performed in prenatal cases with syndromic and/or complex CHD.…”