Influence of age and sex on the diagnostic yield of inherited cardiac conditions in sudden arrhythmic death syndrome decedents.

Abstract

Aims: Sudden arrhythmic death syndrome (SADS) refers to a sudden death, which remains unexplained despite comprehensive post-mortem examination and a toxicological screen. We aimed to investigate the impact of age and sex on the overall diagnostic yield and underlying aetiology in decedents with SADS using a combined approach of familial evaluation (FE) and molecular autopsy (MA).

Methods and results: 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 and decedents with post-mortem DNA were sequenced with a 36 cardiac gene panel for MA. A Bayesian framework for analysis was performed to identify associations. Among 760 SADS decedents (66% male; mean age 31 ± 12 years) the overall diagnostic yield for an inherited cardiac condition was 37% (32-42%) and 9% (6-12%) for FE and MA cohorts. In a subset where both FE and MA were performed the diagnostic yield was 45% (38-61%). The relative risk of an FE diagnosis of long QT syndrome (LQTS) or Catecholaminergic polymorphic ventricular tachycardia (CPVT) vs. remaining unexplained declined by 5.6% [RR 0.94 (0.91-0.98)] and by 11% [RR 0.89 (0.81-0.97)], for each year increase in age. Females were more likely to have a diagnosis 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.

Conclusion: After a SADS death, the diagnostic yield of comprehensive FE, MA, or both in an expert setting can be up to 45% with a combined approach. Females had higher diagnostic yield than males, most notable with LQTS. CPVT and LQTS diagnoses declined with increasing age. These data highlight the relative utility of FE and MA depending on age and sex for determining underlying diagnoses following SADS deaths.