The authors present their research study and methodology in which they explored the clinical utility and combined yield of post-mortem genetic testing of sudden arrhythmic death syndrome (SADS), including next-generation sequencing and variant filtering, classification, and analysis; they present their results along with follow-up discussion and comparison with previous next-generation sequencing molecular autopsy studies, noting observed warning symptoms before death, cardiomyopathy-associated variants in SADS, and study limitations.
Sudden arrhythmic death syndrome (SADS) describes a sudden death with negative autopsy and toxicological analysis. Cardiac genetic disease is a likely etiology. 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. The authors evaluated 302 expertly validated SADS cases with suitable DNA (median age: 24 years; 65 percent 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. A clinically actionable pathogenic or likely pathogenic variant was identified in 40 of 302 cases (13 percent). The main etiologies established were catecholaminergic polymorphic ventricular tachycardia and long QT syndrome (17 [6 percent] and 11 [4 percent], respectively). Gene-based rare variants association analysis showed enrichment of rare predicted deleterious variants in RYR2 (p ¼ 5 x 10^-5). Combining molecular autopsy with clinical evaluation in surviving families increased diagnostic yield from 26 percent to 39 percent. Molecular autopsy for electrical disorder and cardiomyopathy genes, using ACMG guidelines for variant classification, identified a modest but realistic yield in SADS. The authors’ 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, they showed the enhanced utility of combined clinical and genetic evaluation. (Publisher Abstract Provided)