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

Laurence M Nunn; Luis R Lopes; Petros Syrris; Cian Murphy; Vincent Plagnol; Eileen Firman; Chrysoula Dalageorgou; Esther Zorio; Diana Domingo; Victoria Murday; Iain Findlay; Alexis Duncan; Gerry Carr-White; Leema Robert; Teofila Bueser; Caroline Langman; Simon P Fynn; Martin Goddard; Anne White; Henning Bundgård; Laura Ferrero-Miliani; Nigel Wheeldon; Simon K Suvarna; Aliceson O'Beirne; Martin D Lowe; William J McKenna; Perry M Elliott; Pier D Lambiase

doi:10.1093/europace/euv285

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

Laurence M Nunn, Luis R Lopes, Petros Syrris, Cian Murphy, Vincent Plagnol, Eileen Firman, Chrysoula Dalageorgou, Esther Zorio, Diana Domingo, Victoria Murday, Iain Findlay, Alexis Duncan, Gerry Carr-White, Leema Robert, Teofila Bueser, Caroline Langman, Simon P Fynn, Martin Goddard, Anne White, Henning BundgårdLaura Ferrero-Miliani, Nigel Wheeldon, Simon K Suvarna, Aliceson O'Beirne, Martin D Lowe, William J McKenna, Perry M Elliott, Pier D Lambiase

43 Citations (Scopus)

Abstract

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 and 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. 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.

Original language	English
Journal	Europace
Volume	18
Pages (from-to)	888-896
ISSN	1099-5129
DOIs	https://doi.org/10.1093/europace/euv285
Publication status	Published - Jun 2016

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Nunn, L. M., Lopes, L. R., 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, S. P., Goddard, M., White, A., ... Lambiase, P. D. (2016). Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing. Europace, 18, 888-896. https://doi.org/10.1093/europace/euv285

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, Bundgård, H, Ferrero-Miliani, L, Wheeldon, N, Suvarna, SK, O'Beirne, A, Lowe, MD, McKenna, WJ, Elliott, PM & Lambiase, PD 2016, 'Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing', Europace, vol. 18, pp. 888-896. https://doi.org/10.1093/europace/euv285

@article{bce2536587b643c4a4252aff65b42c66,

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

abstract = "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 and 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. 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.",

author = "Nunn, {Laurence M} and Lopes, {Luis R} and Petros Syrris and Cian Murphy and Vincent Plagnol and Eileen Firman and Chrysoula Dalageorgou and Esther Zorio and Diana Domingo and Victoria Murday and Iain Findlay and Alexis Duncan and Gerry Carr-White and Leema Robert and Teofila Bueser and Caroline Langman and Fynn, {Simon P} and Martin Goddard and Anne White and Henning Bundg{\aa}rd and Laura Ferrero-Miliani and Nigel Wheeldon and Suvarna, {Simon K} and Aliceson O'Beirne and Lowe, {Martin D} and McKenna, {William J} and Elliott, {Perry M} and Lambiase, {Pier D}",

year = "2016",

month = jun,

doi = "10.1093/europace/euv285",

language = "English",

volume = "18",

pages = "888--896",

journal = "Europace",

issn = "1099-5129",

publisher = "Oxford University Press",

}

TY - JOUR

T1 - Diagnostic yield of molecular autopsy in patients with sudden arrhythmic death syndrome using targeted exome sequencing

AU - Nunn, Laurence M

AU - Lopes, Luis R

AU - Syrris, Petros

AU - Murphy, Cian

AU - Plagnol, Vincent

AU - Firman, Eileen

AU - Dalageorgou, Chrysoula

AU - Zorio, Esther

AU - Domingo, Diana

AU - Murday, Victoria

AU - Findlay, Iain

AU - Duncan, Alexis

AU - Carr-White, Gerry

AU - Robert, Leema

AU - Bueser, Teofila

AU - Langman, Caroline

AU - Fynn, Simon P

AU - Goddard, Martin

AU - White, Anne

AU - Bundgård, Henning

AU - Ferrero-Miliani, Laura

AU - Wheeldon, Nigel

AU - Suvarna, Simon K

AU - O'Beirne, Aliceson

AU - Lowe, Martin D

AU - McKenna, William J

AU - Elliott, Perry M

AU - Lambiase, Pier D

PY - 2016/6

Y1 - 2016/6

N2 - 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 and 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. 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.

AB - 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 and 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. 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.

U2 - 10.1093/europace/euv285

DO - 10.1093/europace/euv285

M3 - Journal article

C2 - 26498160

SN - 1099-5129

VL - 18

SP - 888

EP - 896

JO - Europace

JF - Europace

ER -

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

Abstract

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