Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome

Abstract

Background: Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology.

Objectives: This study investigated the clinical utility and combined yield of post-mortem genetic testing (molecular autopsy) in cases of SADS and comprehensive clinical evaluation of surviving relatives.

Methods: We evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65% males) who underwent next-generation sequencing using an extended panel of 77 primary electrical disorder and cardiomyopathy genes. Pathogenic and likely pathogenic variants were classified using American College of Medical Genetics (ACMG) consensus guidelines. The yield of combined molecular autopsy and clinical evaluation in 82 surviving families was evaluated. A gene-level rare variant association analysis was conducted in SADS cases versus controls.

Results: A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13%). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6%] and 11 [4%], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p = 5 × 10^-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26% to 39%.

Conclusions: Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. Our data highlighted the predominant role of catecholaminergic polymorphic ventricular tachycardia and long QT syndrome, especially the RYR2 gene, as well as the minimal yield from other genes. Furthermore, we showed the enhanced utility of combined clinical and genetic evaluation.

Keywords: cardiomyopathy; channelopathy; molecular autopsy; next-generation sequencing; unexplained sudden death.

Graphical abstract

Figure 1

SADS: Demographic and Clinical Characterization Sudden arrhythmic death syndrome (SADS) (A) more often affected males and individuals 35 years and younger; (B) 72% of SADS deaths occurred during sleep or rest. (C) Whereas three-quarters exhibited no symptoms before death, 13% had a history of seizures.

Figure 2

ACMG Classification of Variants A significantly higher prevalence of variants of unknown significance (VUS) was found in cardiomyopathy genes compared to primary electrical disease genes, and there was a highly unfavorable ratio of VUS to pathogenic and likely pathogenic variants in the cardiomyopathy genes (28:1) per the American College of Medical Genetics (ACMG) classification of 288 variants in 170 cases. P = pathogenic; LP = likely pathogenic.

Central Illustration

Sudden Arrhythmic Death Syndrome: Genetic Testing and Clinical Screening (A to E) Genetic testing via next-generation sequencing in 302 sudden arrhythmic death syndrome (SADS) cases identified pathogenic and likely pathogenic variants in 13% of cases. Clinical screening of relatives in 82 families found 35 relatives from 21 families with a clinical diagnosis of a primary electrical disease: Brugada syndrome (BrS); catecholaminergic polymorphic ventricular tachycardia (CPVT); and long-QT syndrome (LQTS); there was overlap between molecular and clinical diagnosis in 7 families. Combining molecular autopsy with clinical evaluation increased diagnostic yield in surviving families to 39%. VUS = variant of unknown significance.