Implications of age and sex on the diagnostic yield of sudden arrhythmic death syndrome

Abstract Introduction Sudden arrhythmic death syndrome (SADS) refers to an unexplained sudden death with a negative autopsy. An inherited cardiac condition (ICC) may be diagnosed through familial clinical evaluation (FE) or post-mortem genetic testing (molecular autopsy [MA]) or both. We aimed to investigate the impact of age and sex of SADS decedents on the diagnostic yield and aetiology to facilitate a targeted approach to management. Methods Consecutive referrals to a single centre for FE only, MA only or both, following a SADS death were included. First-degree family members underwent comprehensive FE. A panel of 36 cardiac genes was sequenced for MA. A post-mortem diagnosis could be obtained by either FE, MA or both. A Bayesian framework for analysis was performed to identify associations. Results Seven-hundred-and-sixty SADS decedents (66% male; mean age 31±12 years) were investigated. The overall diagnostic yield for an ICC was 37% (32-42%) and 9% (6-12%) for FE and MA cohorts, respectively. In a subset where both MA and FE were performed the diagnostic yield was 45% (38-61%). For each year increase in age, the relative risk of an FE diagnosis of long QT syndrome (LQTS) or Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) versus remaining unexplained declined by 5.6% (RR 0.94 [0.91-0.98]) and by 11% (RR 0.89 [0.81-0.97]), respectively. Females were more likely to have a diagnosis compared with males by both FE (40% [34-45%] vs 36% [31-41%]) and MA (15% [10-21%] vs 6% [3-8%]). Females (8.1% [4.1-13.4%)], were more likely to be diagnosed with LQTS than males (1.2% [0.2-2.7%]) in the MA cohort. Conclusions After a SADS death, the diagnostic yield of comprehensive FE, MA or both in an expert setting can be up to 45%. Younger age of death is associated with greater likelihood of LQTS and CPVT diagnosis with the highest yield in children and adolescents. Female sex in SADS decedents is associated with a higher yield of LQTS in MA. These data highlight the relative utility of FE and MA depending on age and sex for determining underlying diagnoses following SADS deaths.