Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

EP Europace, Jun 2016

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.

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Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

Europace Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing Laurence M. Nunn 2 Luis R. Lopes 2 Petros Syrris 2 Cian Murphy 2 Vincent Plagnol 2 Eileen Firman 2 Chrysoula Dalageorgou 2 Esther Zorio 1 Diana Domingo 1 Victoria Murday 0 Iain Findlay 0 Alexis Duncan 0 Gerry Carr-White 6 Leema Robert 6 Teofila Bueser 6 Caroline Langman 6 Simon P Fynn 5 Martin Goddard 5 Anne White 5 Henning Bundgaard 4 Laura Ferrero-Miliani 3 Nigel Wheeldon 7 Simon K. Suvarna 7 Aliceson O'Beirne 7 Martin D. Lowe 2 William J. McKenna 2 Perry M. Elliott 2 Pier D. Lambiase 2 0 West of Scotland Clinical Genetics, Laboratory Medicine, Southern General Hospital , Edinburgh , UK 1 Unit for Inherited Heart Diseases and Sudden Cardiac Death, Cardiology Department, Hospital Universitario y Polite ́cnico La Fe , Valencia , Spain 2 Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL , West Smithfield, London EC1A 7BE , UK 3 Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen , Copenhagen , Denmark 4 Unit for Inherited Heart Diseases, The Heart Centre, National University Hospital , Rigshospitalet , University of Copenhagen , Copenhagen , Denmark 5 Papworth Hospital , Cambridge , UK 6 St Thomas' Hospital , London , UK 7 South Yorkshire Regional Inherited Cardiac Conditions Service, South Yorkshire Cardiothoracic Centre , Sheffield , UK Aims 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Methods To determine the feasibility and diagnostic yield of targeted exome sequencing deoxyribonucleic acid (DNA) was isoand results lated 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. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion 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. - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - What’s new? † Molecular autopsy of Sudden Arrhythmic Death Syndrome victims is best undertaken in the context of a multidisciplinary assessment involving detailed clinical screening of firstdegree relatives so that genetic results are interpreted in the context of the relatives’ phenotype. † Molecular autopsy utilizing targeted exome sequencing results in a high frequency of candidate pathogenic variants that require further evaluation to determine their clinical importance and should be interpreted with caution. Introduction Sudden Arrhythmic Death Syndrome (SADS) causes 500 deaths in England and Wales every year.1 International guidelines recommend clinical assessment of the surviving first-degree relatives of (...truncated)


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Nunn, Laurence M., Lopes, Luis R., Syrris, Petros, Murphy, Cian, Plagnol, Vincent, Firman, Eileen, Dalageorgou, Chrysoula, Zorio, Esther, Domingo, Diana, Murday, Victoria, Findlay, Iain, Duncan, Alexis, Carr-White, Gerry, Robert, Leema, Bueser, Teofila, Langman, Caroline, Fynn, Simon P, Goddard, Martin, White, Anne, Bundgaard, Henning, Ferrero-Miliani, Laura, Wheeldon, Nigel, Suvarna, Simon K., O'Beirne, Aliceson, Lowe, Martin D., McKenna, William J., Elliott, Perry M., Lambiase, Pier D.. Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing, EP Europace, 2016, pp. 888-896, Volume 18, Issue 6, DOI: 10.1093/europace/euv285