Presentation: Sudden unexplained death or survived cardiac arrest

A 38-year-old man collapses while attending a school play. CPR is started by a first aider and two direct current shocks are given by an automated defibrillator. Return of spontaneous circulation is achieved by the time the ambulance arrives. Subsequent analysis of the automated external defibrillator demonstrates ventricular fibrillation.

• Consider testing in survivors of proven cardiac arrest (idiopathic ventricular fibrillation):
  • with no phenotype detectable on comprehensive evaluation – which includes coronary assessment, cardiac imaging and electrocardiogram (ECG) provocation testing; and
  • who are under 45 years of age.
• Consider testing after sudden death in individuals with a normal post-mortem who are either:
• • under 40 years of age;
• • under 60 years of age and have a family history of sudden unexplained death in a first- or second-degree relative under 40 years of age in whom no post-mortem was carried out; or
• • under 60 years of age and have a family history of sudden unexplained death in a first- or second-degree relative under 60 years of age in whom a normal post-mortem was carried out.
• Following an unexplained sudden death, the post-mortem should include assessment by an expert in cardiac autopsy and splenic tissue should be retained for molecular autopsy.
• • This excludes babies under 12 months of age with a brief, resolved, unexplained event (BRUE) and normal cardiac investigations because different protocols apply (please refer to the American Academy of Pediatrics BRUE guidelines).
• Genomic testing should be carried out in parallel with expert phenotypic assessment of the cardiac arrest survivor and/or the surviving first-degree relatives – for example, in an inherited cardiac conditions (ICC) clinic – and with support from clinical genetics services. Note that testing may occasionally be appropriate outside these criteria, following discussion in an ICC multidisciplinary team meeting.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• If the relevant eligibility criteria are met, discuss the case with or refer it to your local ICC clinical service for genomic testing and family screening. You will need to provide details confirming that your patient fulfils the eligibility criteria.
• Where an underlying cause is identified through post-mortem or clinical phenotyping, targeted genomic testing for that condition should be undertaken.
• For sudden unexplained death or unexplained cardiac arrest without a cardiac phenotype, the clinical indication R138 should be requested for the patient only (singleton testing).
  • This indication includes the test code R138.1 Sudden unexplained death or survivors of a cardiac event. The test involves whole exome sequencing and medium gene panel sequencing, which look for variants known to be associated with cardiac phenotypes that can cause sudden death, and multiplex ligation-dependent probe amplification (MLPA) or equivalent to detect copy number variants.
• Because this test does not include whole genome sequencing, you will need to:
  • complete a test order form and consent (record of discussion) form, available from your local Genomic Laboratory Hub; and
  • include on the test order form details of the phenotype (refer to human phenotype ontology (HPO) terms or the clinical summary) as well as the appropriate panel name(s) with associated R number.
• These tests are DNA based, and an EDTA sample (purple-topped tube) is required.
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NHS England: National Genomic Test Directory

References:

• Fellmann F, van El CG, Charron P and others. ‘European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death’. European Journal of Human Genetics 2019: volume 27, issue 12, pages 1,763–1,773. DOI: 10.1038/s41431-019-0445-y
• Tate C and Sunley R. ‘Brief resolved unexplained events (formerly apparent life-threatening events) and evaluation of lower-risk infants’. Archives of Disease in Childhood – Education and Practice 2018: volume 103, issue 2, pages 95–98. DOI: 10.1136/archdischild-2016-311249
• Tieder JS, Bonkowsky JL, Etzel RA and others. ‘Brief resolved unexplained events (formerly apparent life-threatening events) and evaluation of lower-risk infants‘. Pediatrics (from the American Academy of Pediatrics) 2016: volume 137, issue 5, page e20160590. DOI: 10.1542/peds.2016-0590
• Zeppenfeld K, Tfelt-Hansen J, de Riva M and others. ‘2022 ESC guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Developed by the task force for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death of the European Society of Cardiology (ESC) endorsed by the Association for European Paediatric and Congenital Cardiology (AEPC)’. European Heart Journal 2022: volume 43, issue 40, pages 3,997–4,126. DOI: 10.1093/eurheartj/ehac262

For patients

• British Heart Foundation: Sudden arrhythmic death syndrome
• Cardiac Risk in the Young
• Sudden Arrhythmic Death (SADS) UK