Key result
Genetic sequencing revealed that 34.6% of adults with unexplained sudden cardiac death and normal cardiac pathology carried pathogenic or likely pathogenic variants for inherited cardiac diseases.
Why the study?
The relationship between pathogenic or likely pathogenic variants in inherited cardiomyopathies and primary electrical disorders and unexplained sudden cardiac death risk in US adults had never been systematically examined.
What is the prevalence of pathogenic or likely pathogenic variants in cardiomyopathy and arrhythmia genes among adults with unexplained sudden cardiac death?
Observational (n=413)
No
What is the prevalence of pathogenic or likely pathogenic variants in cardiomyopathy and arrhythmia genes among adults with unexplained sudden cardiac death?
Nearly one-third of adults with unexplained sudden cardiac death and no gross pathological findings carry pathogenic or likely pathogenic genetic variants for cardiomyopathies or primary electrical disorders.
May support genetic testing in unexplained SCD with normal pathology; leaves open prospective impact on family screening and prevention.
Background Unexplained-sudden cardiac death (SCD) describes SCD with no cause identified after a comprehensive autopsy and toxicologic examination. Genetic testing helps to diagnose inherited cardiac diseases in unexplained-SCD, however, the relationship between pathogenic or likely pathogenic (P/LP) variants of inherited cardiomyopathies and primary electrical disorders (PED) and risk of unexplained-SCD in adults living the United States has never been systematically examined. Methods We performed sequencing of 29 cardiomyopathy and 39 arrhythmia genes in 413 African-Americans and Caucasians (≥18 years-old) who died of unexplained-SCD (median age; 41 years-old, 37% females, 50% African-Americans) and whose hearts were found to have no gross pathological finding upon referral to our institution for pathologic consultation from the State of Maryland Medical Examiner. We examined P/LP variants in these genes to study the association between presence of these variants and unexplained-SCD. Results 143/413 (34.6%) subjects had variants considered P/LP for cardiomyopathy and/or PED (i.e. Brugada Syndrome (BrS), long QT syndrome (LQTS), and arrhythmogenic right ventricular dysplasia (ARVD)). In total, 102 (24.7%) subjects harbored 86 P/LP variants for cardiomyopathies and 60 (14.5%) subjects carried 76 P/LP variants for PED. The following pathogenic variants were identified: 68 P/LP variants for hypertrophic cardiomyopathy (HCM) in 79/413 (19.1%) subjects, 18 P/LP variants for dilated cardiomyopathy (DCM) in 22/413 subjects (5.3%), and 76 P/LP variants in 60/413 (14.5%) for PED. There were greater than 121.0- and 138.5-fold median enrichments (431.4- and 200.0-fold cumulative enrichments) in these cardiomyopathy and arrhythmia variants in victims of unexplained SCD versus the general population, respectively. Among these P/LP positive carriers, combinations of conditions were found, including 14/413 (2.4%) having both HCM and PED variants, and 5/413 (1.2%) with DCM and PED variants. African Americans (AA) and Caucasians were equally likely to harbor P/LP variants (32.7% versus 36.6%, p=0.5), but AA had a higher frequent variants of unknown significance. Conclusions This study represents the largest examination reported on the association between cardiomyopathy and arrhythmia P/LP genetic variants and unexplained-SCD in adults with no gross abnormality on rigorous pathological examination. Nearly one-third of those with unexplained-SCD were carriers of P/LP variants. Our findings with respect to both the association of unexplained SCD with cardiomyopathy genes and race-specific genetic variants suggest new avenues of study for this poorly understood entity.
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Guo et al. (2019) conducted an observational in Unexplained Sudden Cardiac Death (n=413). Genetic sequencing (29 cardiomyopathy and 39 arrhythmia genes) vs. General population databases was evaluated on Presence of pathogenic or likely pathogenic (P/LP) variants for cardiomyopathy and/or primary electrical disorders. Genetic sequencing revealed that 34.6% of adults with unexplained sudden cardiac death and normal cardiac pathology carried pathogenic or likely pathogenic variants for inherited cardiac diseases.
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