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

Lahrouchi, N; Raju, H; Lodder, EM; Papatheodorou, E; Ware, JS; Papadakis, M; Tadros, R; Cole, D; Skinner, JR; Crawford, J; et al. Lahrouchi, N; Raju, H; Lodder, EM; Papatheodorou, E; Ware, JS; Papadakis, M; Tadros, R; Cole, D; Skinner, JR; Crawford, J; Love, DR; Pua, CJ; Soh, BY; Bhalshankar, JD; Govind, R; Tfelt-Hansen, J; Winkel, BG; van der Werf, C; Wijeyeratne, YD; Mellor, G; Till, J; Cohen, MC; Tome-Esteban, M; Sharma, S; Wilde, AAM; Cook, SA; Bezzina, CR; Sheppard, MN; Behr, ER (2017) Utility of Post-Mortem Genetic Testing in Cases of Sudden Arrhythmic Death Syndrome. J Am Coll Cardiol, 69 (17). pp. 2134-2145. ISSN 1558-3597 https://doi.org/10.1016/j.jacc.2017.02.046
SGUL Authors: Behr, Elijah Raphael Cole, Della Sheppard, Mary Noelle

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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.

Item Type: Article
Additional Information: © 2017 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the cc by license (http://creativecommons.org/licenses/by/4.0/).
Keywords: cardiomyopathy, channelopathy, molecular autopsy, next-generation sequencing, unexplained sudden death, Cardiovascular System & Hematology, 1102 Cardiovascular Medicine And Haematology, 1117 Public Health And Health Services
SGUL Research Institute / Research Centre: Academic Structure > Molecular and Clinical Sciences Research Institute (MCS)
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) > Cardiac (INCCCA)
Journal or Publication Title: J Am Coll Cardiol
ISSN: 1558-3597
Language: eng
Dates:
DateEvent
2 May 2017Published
24 April 2017Published Online
14 February 2017Accepted
Publisher License: Creative Commons: Attribution 4.0
Projects:
Project IDFunderFunder ID
FS/11/71/28918British Heart Foundationhttp://dx.doi.org/10.13039/501100000274
UNSPECIFIEDCardiac Risk in the YoungUNSPECIFIED
PubMed ID: 28449774
Go to PubMed abstract
URI: http://openaccess.sgul.ac.uk/id/eprint/108808
Publisher's version: https://doi.org/10.1016/j.jacc.2017.02.046

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