Refining Genotype-Phenotype Correlations for Post-Mortem Genetic Testing of Sudden Cardiac Death: From the POST SCD Study

Introduction: The POST SCD (POstmortem Systematic InvesTigation of Sudden Cardiac Death) Study is the only prospective unbiased sudden cardiac death (SCD) cohort to use comprehensive postmortem investigation to refine the SCD phenotype to true cardiac and arrhythmic causes. Most postmortem genetic testing focuses on genotypes while tolerating a SCD phenotype that is presumed cardiac. Hypothesis: We hypothesize that a comprehensive postmortem evaluation following presumed SCD will refine genotype-phenotype associations and interpretation of postmortem genetic testing. Methods: The POST SCD study prospectively identified all deaths attributed to out-of-hospital cardiac arrest between 18-90 years of age in San Francisco County between February 2011-March 2014 (20,440 deaths reviewed). Medical record review identified 525 presumed SCDs that met World Health Organization criteria. Comprehensive autopsy, toxicology, and histology ruled out non-arrhythmic causes (overdose, hemorrhage, PE) to arrive at 293 sudden arrhythmic deaths (SADs). In the first 30 SADs with high suspicion for heritable cause, a comprehensive 300-gene cardiac/arrhythmia panel was performed, then whole exome testing in cases with negative or non-contributory panel. Results: By pathologic criteria, the 30 autopsy-defined SADs (21 males [70%], median age 53 years) for genetic testing included dilated cardiomyopathy (37%), hypertrophic cardiomyopathy (HCM; 10%), hypertrophy without pathologic features of HCM (33%), primary electrical disease (10%), arrhythmogenic cardiomyopathy (3%), mitral valve prolapse (3%), or non-compaction (3%). In 3 SADs, we identified 4 pathogenic/likely pathogenic (P/LP) variants in APOB , MYBPC3 , GAA , and TTN , but 3 of 4 ( APOB, GAA , TTN ) were non-contributory to SCD. There were 61 variants of uncertain significance in 24 patients (80%). Further exome testing in 7 SADs identified no compelling variants. Conclusions: Postmortem genetic testing identified P/LP variants in 10% of autopsy-proven SADs with high suspicion for heritable cause, but detailed postmortem phenotyping excluded 75% as non-contributory to SCD. These results highlight the importance of comprehensive autopsy evaluation to refine genotype-phenotype correlations.