Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.
OBJECTIVE
The targeted genetic screening of Sudden Arrhythmic Death Syndrome (SADS) probands in a molecular autopsy has a diagnostic yield of up to 35%. Exome sequencing has the potential to improve this yield. The primary aim of this study is to examine the feasibility and diagnostic utility of targeted exome screening in SADS victims, utilizing familial clinical screening whenever possible.


RESULTS
To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isolated from 59 SADS victims (mean age 25 years, range 1-51 years). Targeted exome sequencing of 135 genes associated with cardiomyopathies and ion channelopathies was performed on the Illumina HiSeq2000 platform. Non-synonymous, loss-of-function, and splice-site variants with a minor allele frequency <0.02% in the NHLBI exome sequencing project and an internal set of control exomes were prioritized for analysis followed by <0.5% frequency threshold secondary analysis. First-degree relatives were offered clinical screening for inherited cardiac conditions. Seven probands (12%) carried very rare (<0.02%) or novel non-sense candidate mutations and 10 probands (17%) had previously published rare (0.02-0.5%) candidate mutations-a total yield of 29%. Co-segregation fully confirmed two private SCN5A Na channel mutations. Variants of unknown significance were detected in a further 34% of probands.


CONCLUSIONS
Molecular autopsy using targeted exome sequencing has a relatively low diagnostic yield of very rare potentially disease causing mutations. Candidate pathogenic variants with a higher frequency in control populations are relatively common and should be interpreted with caution.
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Laurence M
LM
Nunn
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Luis R
LR
Lopes
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Petros
P
Syrris
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Cian
C
Murphy
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Vincent
V
Plagnol
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Eileen
E
Firman
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Chrysoula
C
Dalageorgou
Unit for Inherited Heart Diseases and Sudden Cardiac Death, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Esther
E
Zorio
Unit for Inherited Heart Diseases and Sudden Cardiac Death, Cardiology Department, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
Diana
D
Domingo
West of Scotland Clinical Genetics, Laboratory Medicine, Southern General Hospital, Edinburgh, UK.
Victoria
V
Murday
West of Scotland Clinical Genetics, Laboratory Medicine, Southern General Hospital, Edinburgh, UK.
Iain
I
Findlay
West of Scotland Clinical Genetics, Laboratory Medicine, Southern General Hospital, Edinburgh, UK.
Alexis
A
Duncan
St Thomas' Hospital, London, UK.
Gerry
G
Carr-White
St Thomas' Hospital, London, UK.
Leema
L
Robert
St Thomas' Hospital, London, UK.
Teofila
T
Bueser
St Thomas' Hospital, London, UK.
Caroline
C
Langman
Papworth Hospital, Cambridge, UK.
Simon P
SP
Fynn
Papworth Hospital, Cambridge, UK.
Martin
M
Goddard
Papworth Hospital, Cambridge, UK.
Anne
A
White
Unit for Inherited Heart Diseases, The Heart Centre, National University Hospital, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
Henning
H
Bundgaard
Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Laura
L
Ferrero-Miliani
South Yorkshire Regional Inherited Cardiac Conditions Service, South Yorkshire Cardiothoracic Centre, Sheffield, UK.
Nigel
N
Wheeldon
South Yorkshire Regional Inherited Cardiac Conditions Service, South Yorkshire Cardiothoracic Centre, Sheffield, UK.
Simon K
SK
Suvarna
South Yorkshire Regional Inherited Cardiac Conditions Service, South Yorkshire Cardiothoracic Centre, Sheffield, UK.
Aliceson
A
O'Beirne
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Martin D
MD
Lowe
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
William J
WJ
McKenna
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Perry M
PM
Elliott
Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK d.lambiase@ucl.ac.uk.
Pier D
PD
Lambiase
D000293:Adolescent; D000328:Adult; D001344:Autopsy; D053840:Brugada Syndrome / Q000175:diagnosis* / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D016757:Death, Sudden, Cardiac / Q000517:prevention & control; D059472:Exome / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D007223:Infant; D008133:Long QT Syndrome / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D010375:Pedigree; D017422:Sequence Analysis, DNA; D006113:United Kingdom; D055815:Young Adult
D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human
Brugada syndrome; Exome sequencing; Long QT syndrome; Molecular autopsy; SADS; Sudden cardiac death