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Original Investigation
June 2, 2021

Genetic Variants Associated With Unexplained Sudden Cardiac Death in Adult White and African American Individuals

Author Affiliations
  • 1CVPath Institute, Gaithersburg, Maryland
  • 2currently with Bioscience Cardiovascular Research and Early Development, Cardiovascular, Renal, and Metabolism, BioPharmaceuticals Research and Development, AstraZeneca, Gaithersburg, Maryland
  • 3currently with Department of Cardiology, Tokai University School of Medicine, Kanagawa, Japan
  • 4Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
  • 5Institute for Precision Cardiovascular Medicine, American Heart Association, Dallas, Texas
  • 6currently with Department of Internal Medicine, Division of Cardiology, Showa University Fujigaoka Hospital, Kanagawa, Japan
  • 7Office of the Chief Medical Examiner, Baltimore, Maryland
JAMA Cardiol. Published online June 2, 2021. doi:10.1001/jamacardio.2021.1573
Key Points

Question  What is the association between pathogenic or likely pathogenic variants of inherited cardiomyopathies and arrhythmia syndromes and the risk of unexplained sudden cardiac death (SCD)?

Findings  In this genetic association study of 413 adults who had unexplained SCD, nearly one-fifth of individuals had pathogenic or likely pathogenic genetic variants consistent with inherited cardiomyopathies or arrhythmia syndromes, despite having normal cardiac findings. These clinically significant variants were predominantly associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and long QT syndrome.

Meaning  Further research is needed to assess the utility of integrating genetic testing into risk assessment for the prevention of unexplained sudden cardiac death.


Importance  Unexplained sudden cardiac death (SCD) describes SCD with no cause identified. Genetic testing helps to diagnose inherited cardiac diseases in unexplained SCD; however, the associations between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies (CMs) and arrhythmia syndromes and the risk of unexplained SCD in both White and African American adults living the United States has never been systematically examined.

Objective  To investigate cases of unexplained SCD to determine the frequency of P/LP genetic variants of inherited CMs and arrhythmia syndromes.

Design, Setting, and Participants  This genetic association study included 683 African American and White adults who died of unexplained SCD and were included in an autopsy registry. Overall, 413 individuals had DNA of acceptable quality for genetic sequencing. Data were collected from January 1995 to December 2015. A total of 30 CM genes and 38 arrhythmia genes were sequenced, and variants in these genes, curated as P/LP, were examined to study their frequency. Data analysis was performed from June 2018 to March 2021.

Main Outcomes and Measures  The frequency of P/LP variants for CM or arrhythmia in individuals with unexplained SCD.

Results  The median (interquartile range) age at death of the 413 included individuals was 41 (29-48) years, 259 (62.7%) were men, and 208 (50.4%) were African American adults. A total of 76 patients (18.4%) with unexplained SCD carried variants considered P/LP for CM and arrhythmia genes. In total, 52 patients (12.6%) had 49 P/LP variants for CM, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both CM and arrhythmia. Overall, 41 P/LP variants for hypertrophic CM were found in 45 patients (10.9%), 9 P/LP variants for dilated CM were found in 11 patients (2.7%), and 10 P/LP variants for long QT syndrome were found in 11 patients (2.7%). No significant difference was found in clinical and heart characteristics between individuals with or without P/LP variants. African American and White patients were equally likely to harbor P/LP variants.

Conclusions and Relevance  In this large genetic association study of community cases of unexplained SCD, nearly 20% of patients carried P/LP variants, suggesting that genetics may contribute to a significant number of cases of unexplained SCD. Our findings regarding both the association of unexplained SCD with CM genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.

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    1 Comment for this article
    Ernest M Kraus, BS Pharmacy | none
    With SCD what investigation was done looking at illicit drug use?