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Publication Detail
Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Article
  • Authors:
    Nunn LM, Lopes LR, Syrris P, Murphy C, Plagnol V, Firman E, Dalageorgou C, Zorio E, Domingo D, Murday V, Findlay I, Duncan A, Carr-White G, Robert L, Bueser T, Langman C, Fynn SP, Goddard M, White A, Bundgaard H, Ferrero-Miliani L, Wheeldon N, Suvarna SK, O'Beirne A, Lowe MD, McKenna WJ, Elliott PM, Lambiase PD
  • Publication date:
    25/10/2015
  • Pagination:
    888, 896
  • Journal:
    Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology
  • Volume:
    18
  • Issue:
    6
  • Medium:
    Print-Electronic
  • Print ISSN:
    1099-5129
  • Language:
    eng
  • Addresses:
    Institute of Cardiovascular Sciences, Barts Heart Centre, St Bartholomews Hospital and Institute of Cardiovascular Sciences, UCL, West Smithfield, London EC1A 7BE, UK.
Abstract
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.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.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.
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