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

https://doi.org/10.1016/j.jacc.2017.02.046Get rights and content
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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.

Key Words

cardiomyopathy
channelopathy
molecular autopsy
next-generation sequencing
unexplained sudden death

Abbreviations and Acronyms

ACM
arrhythmogenic cardiomyopathy
ACMG
American College of Medical Genetics
BrS
Brugada syndrome
CPVT
catecholaminergic polymorphic ventricular tachycardia
LQTS
long QT syndrome
MAF
minor allele frequency
SADS
sudden arrhythmic death syndrome
SCD
sudden cardiac death
VUS
variant of unknown significance

Cited by (0)

This study was funded in part by Cardiac Risk in the Young (to Drs. Raju, Papadakis, Mellor, Sharma, Sheppard, and Behr); the British Heart Foundation (to Drs. Raju, Cook, and Behr) including BHF Clinical Research Training Fellowship FS/11/71/28918: Future diagnostic role and novel genetic loci in SADS; NMRC Singapore (to Dr. Cook); Leducq Foundation (to Dr. Cook); MRC UK (to Drs. Ware and Cook); Tanoto Foundation (to Dr. Cook); SingHealth/Duke-NUS Precision Medicine Institute (PRISM) (to Dr. Cook); Cure Kids (New Zealand) (to Drs. Skinner, Crawford, and Love); NIHR Royal Brompton Cardiovascular Biomedical Research Unit (to Dr. Ware); Wellcome Trust (to Dr. Ware) and the Dutch Heart Foundation CVON-PREDICT project (CVON2012-10) (to Drs. Lahrouchi, Lodder, Wilde, and Bezzina). Dr. Wilde has consulted for Sorin. Dr. Behr has received unrestricted research funds from Biotronik and St. Jude Medical. Dr. Cook is a consultant for Illumina.

Listen to this manuscript's audio summary by JACC Editor-in-Chief Dr. Valentin Fuster.