Genetic Evaluation for Sudden Cardiac Death

Considerations for genetic evaluation for sudden cardiac death in deceased persons, sudden cardiac arrest survivors, and family members.

Risk Assessment for Sudden Cardiac Death

Sudden cardiac death red flags in a deceased person

Sudden cardiac death (SCD) is a death due to cardiac causes that occurs within one hour of onset of symptoms in witnessed cases and within 24 hours of last being seen alive when it is unwitnessed. The National Association of Medical Examiners (NAME) recommends referral to cardiac genetics and post-mortem genetic testing if any of the following red flags are present in cases of sudden cardiac death:

  • Death younger than 40 years 
  • Idiopathic dilated cardiomyopathy
  • Hypertrophic cardiomyopathy
  • Arrhythmogenic right ventricular cardiomyopathy
  • Aortic dissection
  • Family history of cardiomyopathies, arrhythmias, aortic dissections
  • Drowning, particularly in the case of a sober or experienced swimmer
  • Single motor vehicle accidents when no causative factors are present (toxicology negative, favorable road conditions)
  • Unexplained seizure in a young person
  • Triggers for sudden death: exercise, emotional stress (fright, anger), acoustic stimuli
  • Autopsy negative for a cause of death

Sudden cardiac arrest red flags in survivors 

Sudden cardiac arrest (SCA) is defined as sudden halt of cardiac activity with hemodynamic collapse, typically due to a sustained ventricular arrhythmia. 

Individuals with SCA who are found to have a disease that could have a genetic cause should be referred to cardiac genetics. 

The following red flags should also prompt referral to cardiac genetics:

  • History of unexplained syncope
  • Negative cardiac evaluation 
  • Family history of cardiomyopathies, arrhythmias, aortic dissections
  • Drowning, particularly in the case of a sober or experienced swimmer
  • Single motor vehicle accidents when no causative factors are present (toxicology negative, favorable road conditions)
  • Unexplained seizure in an adult
  • Triggers for sudden death: exercise, emotional stress (fright, anger), acoustic stimuli

Postmortem Genetic Testing Considerations 

Sample collection

NAME recommends retaining appropriate post-mortem samples for genetic testing when any of the above risk factors are present. 

Recommended postmortem samples to be saved for future genetic testing:

  • 5-10 mL blood collected at autopsy, preserved with K2EDTA (purple top tube) stored short term in a refrigerator (up to 4 weeks) or long term in a -20 to -80 degrees C freezer. 
  • If possible, a small piece of fresh frozen heart/spleen/liver/thymus stored at -20 or -80 degrees C.

Cost

Typically, insurance does not cover the cost for post-mortem genetic testing because the patient is deceased, and insurance is no longer active. Many genetic testing companies have more affordable out of pocket pricing for genetic testing. Prices are anticipated to continue to decrease as competition continues in the market. 

Top 10 Take-Home Messages for Sudden Death Risk Assessment 

In 2020, the Asia Pacific Heart Rhythm Society (APHRS) and the Heart Rhythm Society (HRS) wrote an expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest and of their families. This consensus statement lists 10 take-home messages for arrest survivors, decedents, and their family members, which is provided in the excerpt below. These take-home messages provide practical guidance for this subset of patients.

Top 10 Take-Home Messages
  1. Sudden cardiac death (SCD) is an important public health issue and warrants further study to better quantify its occurrence, its impact on society, and the opportunities for improving outcomes through public education and provision of automated external defibrillators and cardiopulmonary resuscitation (CPR) training.
  2. For SCA survivors, SUD victims, and their relatives, a multidisciplinary team is central to thorough investigation, so as to maximize the opportunity to make a diagnosis. Where there has been an SCD or resuscitated SCA and a genetic cause is suspected, genetic testing and counseling is essential for families, to ensure that risks, benefits, results, and the clinical significance of genetic testing can be discussed.
  3. The psychological care of families affected by SUD and survivors of SCA (and their families) should run in parallel with the investigation process. Assessment by professionals trained in psychological care should be offered, as well as grief counseling and peer support, where appropriate.
  4. For the investigation of SUD, a detailed personal and family history is essential, with attention to sentinel symptoms during life such as syncope or seizures, witness accounts, premorbid investigations, and inspection of any cardiac rhythm monitoring around the time of death.
  5. A comprehensive autopsy is an essential part of the investigation of SUD and should include collection and storage of tissue suitable for genetic analysis. When the autopsy suggests a possible genetic cause, or no cause and the heart is normal, referral to a multidisciplinary team for further investigation is indicated.
  6. For victims of SCD or survivors of cardiac arrest where the phenotype is known, genetic testing of the proband focused on likely candidate genes, along with clinical evaluation of family members, aids in identifying family members with, or at risk of developing, the same condition.
  7. For victims of SCD or survivors of cardiac arrest where the phenotype is not known, arrhythmia syndrome–focused genetic testing may help arrive at a secure diagnosis, whereas wider testing without careful consideration of the implications of indeterminate results by experienced clinicians may only serve to add uncertainty and lead to misinterpretation of results.
  8. For the investigation of SCA survivors, essential inquiry includes detailed personal and family history, witness accounts, physical examination, multiple electrocardiograms (ECGs), and cardiac imaging. Ambulatory monitoring and/or provocative testing (exercise, pharmacological, and invasive electrophysiological) may provide additional useful information. A sample suitable for future DNA testing should be taken early in the patient’s course and stored.
  9. Genetic investigation of SCA survivors is best undertaken at a center with multidisciplinary care infrastructure and should focus on likely candidate genes known to be causally related to the suspected phenotype. In some cases, genetic evaluation without a suspected phenotype may be undertaken with appropriate genetic counseling, although genetic evaluation of patients with a known nongenetic cause of cardiac arrest is discouraged.
  10. The investigation of the families of victims of SUD and survivors of SCA should include clinical and, if known, genetic cascade testing. If the cause of SUD (or rarely, SCA) is unknown, then clinical investigation of first-degree relatives may include physical examination, ECGs, cardiac imaging, ambulatory monitoring, and provocative testing (exercise, pharmacological, and rarely invasive electrophysiological) with multidisciplinary team supervision. Follow-up and periodic re-evaluation are important and are directed by initial findings.

This content was reproduced with permission from Heart Rhythm Journal, which is licensed under Creative Commons CC-BY-NC-ND. Read the full text. 

Resources

Accessing Genetic Services. Lists tools and websites to help find genetics professionals and provides patient talking points about referring to genetics.

Postmortem Genetic Testing FAQs (National Society of Genetic Counselors). Outlines frequently asked questions about postmortem genetic testing.

References

Stiles MK, Wilde AAM, Abrams DJ, et al. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. Heart Rhythm. 2021;18(1):e1-e50. doi:10.1016/j.hrthm.2020.10.010

Middleton O, Baxter S, Demo E, et al. National Association of Medical Examiners Position Paper: Retaining Postmortem Samples for Genetic Testing. Academic Forensic Pathology. 2013;3(2):191-194. doi:10.23907/2013.024


Published November 2022