TY - JOUR
T1 - Utility of post-mortem genetic testing in cases of sudden arrhythmic death syndrome
AU - Lahrouchi, Najim
AU - Raju, Hariharan
AU - Lodder, Elisabeth M.
AU - Papatheodorou, Efstathios
AU - Ware, James S.
AU - Papadakis, Michael
AU - Tadros, Rafik
AU - Cole, Della
AU - Skinner, Jonathan R.
AU - Crawford, Jackie
AU - Love, Donald R.
AU - Pua, Chee J.
AU - Soh, Bee Y.
AU - Bhalshankar, Jaydutt D.
AU - Govind, Risha
AU - Tfelt-Hansen, Jacob
AU - Winkel, Bo G.
AU - van der Werf, Christian
AU - Wijeyeratne, Yanushi D.
AU - Mellor, Greg
AU - Till, Jan
AU - Cohen, Marta C.
AU - Tome-Esteban, Maria
AU - Sharma, Sanjay
AU - Wilde, Arthur A.M.
AU - Cook, Stuart A.
AU - Bezzina, Connie R.
AU - Sheppard, Mary N.
AU - Behr, Elijah R.
N1 - Copyright the Author(s) 2017. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.
PY - 2017/5/2
Y1 - 2017/5/2
N2 - 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.
AB - 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.
KW - cardiomyopathy
KW - channelopathy
KW - molecular autopsy
KW - next-generation sequencing
KW - unexplained sudden death
UR - http://www.scopus.com/inward/record.url?scp=85018680507&partnerID=8YFLogxK
U2 - 10.1016/j.jacc.2017.02.046
DO - 10.1016/j.jacc.2017.02.046
M3 - Article
C2 - 28449774
AN - SCOPUS:85018680507
SN - 0735-1097
VL - 69
SP - 2134
EP - 2145
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 17
ER -