Genetics of Unexplained Sudden Cardiac Death in Adult Caucasian and African American Individuals Living in the State of Maryland
Authors: Guo Liang , Torii Sho , Fernandez Raquel , Braumann Ryan E. , Paek Ka Hyun , Fuller Daniela T. , Mayhew Christina M. , Zarpak Roya , Jinnouchi Hiroyuki , Sakamoto Atsushi , Sato Yu , Mori Hiroyoshi , Kutyna Matthew D. , Lee Parker J. , Weinstein Leah M. , Collado-Rivera Carlos J. , Gadhoke Neel V. , Ali Bakr B. , Atmakuri Dheeraj R. , Dhingra Roma , Finn Emma LB. , Bell Mack W. , Cornelissen Anne , Kuntz Salome H. , Park Joohyung , Kutys Robert , Wang Libin , Hong Susie N. , Gupta Anuj , Kolodgie Frank D. , Romero Maria E. , Mitchell Braxton D. , Surve Dipti , Fowler David R. , Hong Charles C. , Virmani Renu , Finn Aloke V. 
Published: September 2019

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.