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. 2021 Sep 1;6(9):1013-1022.
doi: 10.1001/jamacardio.2021.1573.

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

Liang Guo  1   2 , Sho Torii  1   3 , Raquel Fernandez  1 , Ryan E Braumann  1 , Daniela T Fuller  1 , Ka-Hyun Paek  1 , Neel V Gadhoke  1 , Kristin A Maloney  4 , Kathryn Harris  4 , Christina M Mayhew  1 , Roya Zarpak  1 , Laura M Stevens  5 , Brady J Gaynor  4 , Hiroyuki Jinnouchi  1 , Atsushi Sakamoto  1 , Yu Sato  1 , Hiroyoshi Mori  1   6 , Matthew D Kutyna  1 , Parker J Lee  1   4 , Leah M Weinstein  1 , Carlos J Collado-Rivera  1 , Bakr B Ali  1 , Dheeraj R Atmakuri  1 , Roma Dhingra  1 , Emma L B Finn  1 , Mack W Bell  1   4 , Megan Lynch  4 , Anne Cornelissen  1 , Salome H Kuntz  1 , Joo-Hyung Park  1 , Robert Kutys  1 , Ji-Eun Park  4 , Libin Wang  4 , Susie N Hong  4 , Anuj Gupta  4 , Jennifer L Hall  5 , Frank D Kolodgie  1 , Maria E Romero  1 , Linda J B Jeng  7 , Braxton D Mitchell  4 , Dipti Surve  1 , David R Fowler  8 , Charles C Hong  4 , Renu Virmani  1 , Aloke V Finn  1   4
Affiliations

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

Liang Guo et al. JAMA Cardiol. .

Erratum in

  • Error in Affiliations.
    [No authors listed] [No authors listed] JAMA Cardiol. 2021 Sep 1;6(9):1098. doi: 10.1001/jamacardio.2021.2394. JAMA Cardiol. 2021. PMID: 34160560 Free PMC article. No abstract available.

Abstract

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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Conflict of interest statement

Conflict of Interest Disclosures: Dr Guo reported receiving grants from the Leducq Foundation outside the submitted work. Dr Jeng reported being employed by the US Food and Drug Administration during the conduct of the study. Drs Virmani and Finn reported receiving institutional research support from the National Institutes of Health, the Leducq Foundation, 480 Biomedical, 4C Medical Technologies, 4Tech, Abbott Laboratories, AccuMedical, Amgen, Biosensors International, Boston Scientific, Cardiac Implants, Celonova BioSciences, Claret Medical, Concept Medical, Cook Medical, Cardiovascular Systems Inc, DuNing, Edwards LifeSciences, Emboline, Endotronix, Envision Scientific, Lutonix/Bard, Life Tech, LimFlow, MedAlliance, Medtronic, Mercator, Meril Life, Microport Medical, MicroVention, Mitralign, North American Science Associates, Nanova, Neovasc, Nipro, NovoGate, Occulotech, OrbusNeich Medical, phenox, Profusa, Protembis, Recor, Senseonics, Shockwave Medical, Sinomed, Spectranetics, Surmodics, Symic Bio, Vesper, W.L. Gore & Associates, and Xeltis outside the submitted work. Dr Finn reported receiving honoraria from Abbott Vascular, Biosensors, Boston Scientific, Celonova BioSciences, Cook Medical, Cardiovascular Systems Inc, Lutonix/Bard, Sinomed, and Terumo Corporation and serving as a consultant to Amgen, Abbott Vascular, Boston Scientific, Celonova BioSciences, Cook Medical, Lutonix/Bard, and Sinomed outside the submitted work. Dr Virmani reported receiving honoraria from Abbott Vascular, Biosensors International, Boston Scientific, Celonova BioSciences, Cook Medical, Cordis, Cardiovascular Systems Inc, Lutonix/Bard, Medtronic, OrbusNeich Medical, Sinomed, Recor, Terumo Corporation, W. L. Gore & Associates, and Spectranetics and serving as a consultant to Abbott Vascular, Boston Scientific, Celonova BioSciences, Cook Medical, Cordis, Cardiovascular Systems Inc, Edwards LifeSciences, Lutonix/Bard, Medtronic, OrbusNeich Medical, Recor, Sinomed, Spectranetics, Surmodics, Terumo Corporation, W. L. Gore & Associates, and Xeltis outside the submitted work. Dr Torii reported receiving research grants from Sunrise Laboratories outside the submitted work. Dr Cornelissen reported receiving grants from University Hospital Rheinisch-Westfälische Technische Hochschule Aachen outside the submitted work. No other disclosures reported.

Figures

Figure 1.
Figure 1.. Study Flow and Variant Filtering Schematic Diagrams
A, Noncardiac death included intracranial hemorrhage or drug overdose. Lack of sufficient information indicates missing data (eg, cause of death, heart dimensions); sudden coronary death, acute coronary syndrome, 75% or greater stenosis in any epicardial coronary arteries, or poststent implantation or bypass graft; sudden cardiac death, cardiomyopathy, valvular heart disease, congenital heart disease, myocarditis, pericarditis, or infective carditis, severe hypertrophy in myocardium, and severe fibrosis in myocardium. ACMG/AMP indicates American College of Medical Genetics and Genomics and the Association for Molecular Pathology; OCME-MD, Office of the Chief Medical Examiner of the State of Maryland; and UTR, untranslated region.
Figure 2.
Figure 2.. Genetic Testing for Cardiomyopathy and Arrhythmia Genes in Decedents With Unexplained Sudden Cardiac Death
ARVC indicates arrhythmogenic right ventricular cardiomyopathy; BS, Brugada syndrome; CPVT, catecholaminergic polymorphic ventricular tachycardia; DCM, dilated cardiomyopathy; HCM, hypertrophic cardiomyopathy; LQTS, long QT syndrome; P/LP, pathogenic or likely pathogenic.
Figure 3.
Figure 3.. Frequency and Characteristics of Decedents With Unexplained Sudden Cardiac Death Carrying Pathogenic or Likely Pathogenic (P/LP) Gene Variants
HCM indicates hypertrophic cardiomyopathy; MAF, minor allele frequency.
Figure 4.
Figure 4.. Differences in Pathogenic or Likely Pathogenic (P/LP) Gene Variants Between African American and White Individuals
See this image and copyright information in PMC

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