Key result
Post-mortem genetic testing identifies pathogenic variants in ~18% of adult unexplained sudden cardiac deaths.
Why the study?
The associations between pathogenic or likely pathogenic variants of inherited cardiomyopathies and arrhythmia syndromes and unexplained SCD risk had never been systematically examined in both White and African American US adults.
Observational (n=413)
No
Nearly 20% of adults who die from unexplained sudden cardiac death with a structurally normal heart harbor pathogenic or likely pathogenic genetic variants for inherited cardiomyopathies or arrhythmia syndromes.
Answers are grounded in this paper and cite their sources.
Supports considering postmortem genetic testing after unexplained SCD; leaves open effects on family screening and prevention.
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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Guo et al. (2021) conducted an observational in Unexplained sudden cardiac death (n=413). Unexplained sudden cardiac death was evaluated on Frequency of pathogenic or likely pathogenic (P/LP) genetic variants for inherited cardiomyopathies and arrhythmia syndromes. Pathogenic or likely pathogenic genetic variants for inherited cardiomyopathies and arrhythmia syndromes were identified in 18.4% of adult patients who died of unexplained sudden cardiac death.
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