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Genetic Variants and Unexplained SCD in White and African American Individuals
Quick Takes
- Molecular autopsy via genetic testing can help diagnose inherited conditions that might explain the etiology of unexplained sudden cardiac death (SCD).
- Studies to date have largely focused on small homogenous populations in young people, and none have assessed the genetic association between African American race and SCD.
- This study investigated the frequency of genetic variants of inherited cardiomyopathies and arrhythmia syndromes in African Americans and Whites who died of unexplained SCD.
Study Questions:
What is the association between clinically significant variants for inherited cardiomyopathies and arrhythmia syndromes and risk of unexplained sudden cardiac death (SCD) in adults?
Methods:
Out of 5,262 referred subjects to the Maryland Office of the Chief Medical Examiner, 683 African American and White adults who died of unexplained SCD were included in the initial autopsy registry. Of these, 413 individuals had DNA available for sequencing to examine the frequency of 30 cardiomyopathy genes and 38 arrhythmia genes and their variants (P/LP).
Results:
The median age at death of the 413 in the study group 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 P/LP variants for cardiomyopathy and arrhythmia genes; 52 (12.6%) had 49 P/LP variants for cardiomyopathy, 22 (5.3%) carried 23 P/LP variants for arrhythmia, and 2 (0.5%) had P/LP variants for both cardiomyopathy and arrhythmia. Variants for hypertrophic cardiomyopathy (HCM) were the most common—41 P/LP variants in 45 patients (10.9%), followed by dilated cardiomyopathy—9 P/LP variants in 11 patients (2.7%), long QT syndrome—10 P/LP variants in 11 patients (2.7%), and Brugada syndrome—7 P/LP variants in 7 patients (1.7%). No significant difference in clinical or heart characteristics or race was found between individuals with or without P/LP variants.
Conclusions:
In this study of community cases of unexplained SCD, nearly 18% of subjects carried P/LP variants for cardiomyopathy or arrhythmia, highlighting the contribution of genetics to unexplained SCD.
Perspective:
This is the largest genetic autopsy study to date of unexplained SCD. It is also the first to directly compare frequency of variants between African American and White subjects. The role for race-specific genetics in SCD risk stratification requires further study. A total of 2,637 (50.1%) decedents were excluded from the cohort due a known cardiac cause of death (e.g., coronary artery disease, valvular heart disease cardiomyopathy, myocarditis). Of note, no association was found between heart dimensions, myocardial fibrosis, and presence of genetic variants. Regarding HCM, patients who are genotype positive/phenotype negative are usually considered lower risk, so it was surprising to find the relatively high frequency of HCM variants in this study. Regarding race, African Americans had similar frequency of arrhythmia gene variants compared to Whites, but fewer for cardiomyopathy; that said, KCNQ1 and RYR2 variants were more common in African Americans. Race did not account for a survival difference.
Clinical Topics: Arrhythmias and Clinical EP, Congenital Heart Disease and Pediatric Cardiology, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Implantable Devices, EP Basic Science, Genetic Arrhythmic Conditions, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Congenital Heart Disease, CHD and Pediatrics and Arrhythmias, CHD and Pediatrics and Prevention, CHD and Pediatrics and Quality Improvement, Lipid Metabolism, Acute Heart Failure
Keywords: African Americans, Arrhythmias, Cardiac, Brugada Syndrome, Cardiomyopathies, Cardiomyopathy, Dilated, Cardiomyopathy, Hypertrophic, Coronary Artery Disease, Death, Sudden, Cardiac, DNA, Fibrosis, Genetic Testing, Heart Failure, KCNQ1 Potassium Channel, Long QT Syndrome, Myocarditis, Risk Assessment, Phenotype, Ryanodine Receptor Calcium Release Channel, Secondary Prevention
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