Richard D Bagnall1, Jipin Das K1, Johan Duflou2, Christopher Semsarian3. 1. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia. 2. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Department of Forensic Medicine, Sydney, Australia. 3. Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, Australia; Sydney Medical School, University of Sydney, Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia. Electronic address: c.semsarian@centenary.org.au.
Abstract
BACKGROUND: Postmortem genetic testing (molecular autopsy) for the common long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) genes reveals a pathogenic mutation in up to 30% of sudden unexplained death (SUD). The role of additional cardiac arrhythmia and cardiomyopathy genes in SUD is largely unknown. OBJECTIVE: The purpose of this study was to investigate the feasibility and outcomes of performing exome sequencing-based molecular autopsies in a cohort of consecutive SUD cases. METHODS: Autopsies performed from 2005 to 2009 were reviewed for SUD. Postmortem blood was collected, DNA was isolated, and whole exome sequencing was performed. Rare sequence variants in cardiac arrhythmia and cardiomyopathy genes were sought. RESULTS: There were 50 SUD cases aged 1 to 40 years (mean 21.7 ± 12 years) in the 5-year period, with a male predominance of 1.9:1. The most common event at death was "sleep" (48%). Exome sequencing in a subgroup of 28 SUD cases revealed 3 rare variations in 3 SUD cases (10%; 2 from exome sequencing and 1 from previous Sanger sequencing) in the common LQTS genes: a splice site variation and a single base deletion in KCNH2, and a missense variation in KCNQ1. Six rare variations in an additional 25 common genes of cardiac arrhythmias and cardiomyopathies were identified in 6 SUD (21%). CONCLUSION: Exome sequencing-based molecular autopsy is a useful strategy as part of the investigation of SUD cases. The findings further expand the role of the molecular autopsy in both identifying a cause of death in the decedent and evaluating at-risk family relatives.
BACKGROUND: Postmortem genetic testing (molecular autopsy) for the common long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT) genes reveals a pathogenic mutation in up to 30% of sudden unexplained death (SUD). The role of additional cardiac arrhythmia and cardiomyopathy genes in SUD is largely unknown. OBJECTIVE: The purpose of this study was to investigate the feasibility and outcomes of performing exome sequencing-based molecular autopsies in a cohort of consecutive SUD cases. METHODS: Autopsies performed from 2005 to 2009 were reviewed for SUD. Postmortem blood was collected, DNA was isolated, and whole exome sequencing was performed. Rare sequence variants in cardiac arrhythmia and cardiomyopathy genes were sought. RESULTS: There were 50 SUD cases aged 1 to 40 years (mean 21.7 ± 12 years) in the 5-year period, with a male predominance of 1.9:1. The most common event at death was "sleep" (48%). Exome sequencing in a subgroup of 28 SUD cases revealed 3 rare variations in 3 SUD cases (10%; 2 from exome sequencing and 1 from previous Sanger sequencing) in the common LQTS genes: a splice site variation and a single base deletion in KCNH2, and a missense variation in KCNQ1. Six rare variations in an additional 25 common genes of cardiac arrhythmias and cardiomyopathies were identified in 6 SUD (21%). CONCLUSION: Exome sequencing-based molecular autopsy is a useful strategy as part of the investigation of SUD cases. The findings further expand the role of the molecular autopsy in both identifying a cause of death in the decedent and evaluating at-risk family relatives.
Authors: Belinda Gray; Richard D Bagnall; Lien Lam; Jodie Ingles; Christian Turner; Eric Haan; Andrew Davis; Pei-Chi Yang; Colleen E Clancy; Raymond W Sy; Christopher Semsarian Journal: Heart Rhythm Date: 2016-05-05 Impact factor: 6.343
Authors: Georgia Sarquella-Brugada; Oscar Campuzano; Sergi Cesar; Anna Iglesias; Anna Fernandez; Josep Brugada; Ramon Brugada Journal: Int J Legal Med Date: 2016-02-12 Impact factor: 2.686
Authors: Oscar Campuzano; Olallo Sanchez-Molero; Anna Fernandez; Irene Mademont-Soler; Monica Coll; Alexandra Perez-Serra; Jesus Mates; Bernat Del Olmo; Ferran Pico; Laia Nogue-Navarro; Georgia Sarquella-Brugada; Anna Iglesias; Sergi Cesar; Esther Carro; Juan Carlos Borondo; Josep Brugada; Josep Castellà; Jordi Medallo; Ramon Brugada Journal: Sports Med Date: 2017-10 Impact factor: 11.136
Authors: C L Hertz; S L Christiansen; L Ferrero-Miliani; M Dahl; P E Weeke; G L Ottesen; R Frank-Hansen; H Bundgaard; N Morling Journal: Int J Legal Med Date: 2015-09-17 Impact factor: 2.686
Authors: Alica M Goldman; Elijah R Behr; Christopher Semsarian; Richard D Bagnall; Sanjay Sisodiya; Paul N Cooper Journal: Epilepsia Date: 2016-01 Impact factor: 5.864