Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients

Mohamed Z Alimohamed; LennartF Johansson; Anna Posafalvi; Ludolf G Boven; Krista K van Dijk; Lisa Walters; Yvonne J Vos; Helga Westers; Yvonne M Hoedemaekers; Richard J Sinke; Rolf H Sijmons; Birgit Sikkema-Raddatz; Jan D H Jongbloed; Paul A van der Zwaag

doi:10.1016/j.ijcard.2021.02.069

Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients

Mohamed Z Alimohamed^*, LennartF Johansson, Anna Posafalvi, Ludolf G Boven, Krista K van Dijk, Lisa Walters, Yvonne J Vos, Helga Westers, Yvonne M Hoedemaekers, Richard J Sinke, Rolf H Sijmons, Birgit Sikkema-Raddatz, Jan D H Jongbloed^*, Paul A van der Zwaag

^*Corresponding author for this work

Cardiovascular Centre (CVC)

Research output: Contribution to journal › Article › Academic › peer-review

11 Citations (Scopus)

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Abstract

Background: Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield.

Objectives: Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs on diagnostic yield.

Methods: Patients (N = 2002) referred for clinical genetic analysis underwent diagnostic testing of 55-61 genes associated with cardiomyopathies. Samples were analyzed and evaluated for single nucleotide variants (SNVs), indels and CNVs. CNVs identified in the NGS data and suspected of being pathogenic based on type, size and location were confirmed by additional molecular tests.

Results: A (likely) pathogenic (L)P variant was detected in 22.7% of patients, including 3 with CNVs and 25 where a variant was identified in a gene currently not associated with the patient's cardiomyopathy subtype. Only 15 out of 2002 patients (0.8%) were found to carry two (L)P variants.

Conclusion: The yield of routine clinical diagnostics of cardiomyopathies was relatively low when compared to literature. This is likely due to the fact that our study reports the outcome of patients in daily routine diagnostics, therefore also including patients not fully fulfilling (subtype specific) cardiomyopathy criteria. This may also explain why (L)P variants were identified in genes not associated with the reported subtype. The added value of CNV analysis was shown to be limited but not negligible. (C) 2021 The Authors. Published by Elsevier B.V.

Original language	English
Pages (from-to)	99-104
Number of pages	6
Journal	International Journal of Cardiology
Volume	332
Early online date	2021
DOIs	https://doi.org/10.1016/j.ijcard.2021.02.069
Publication status	Published - 1-Jun-2021

Keywords

Cardiomyopathy
NGS gene panel
Diagnostic yield
CNV
DILATED CARDIOMYOPATHY
MOLECULAR-GENETICS
FOUNDER MUTATIONS
PHENOTYPE
CLASSIFICATION
LANDSCAPE
VARIANTS
GENOTYPE

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Alimohamed, M. Z., Johansson, L., Posafalvi, A., Boven, L. G., van Dijk, K. K., Walters, L., Vos, Y. J., Westers, H., Hoedemaekers, Y. M., Sinke, R. J., Sijmons, R. H., Sikkema-Raddatz, B., Jongbloed, J. D. H., & van der Zwaag, P. A. (2021). Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients. International Journal of Cardiology, 332, 99-104. https://doi.org/10.1016/j.ijcard.2021.02.069

@article{9e13f76fc3974e6fba0a078ae9fa0d23,

title = "Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients",

abstract = "Background: Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield.Objectives: Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs on diagnostic yield.Methods: Patients (N = 2002) referred for clinical genetic analysis underwent diagnostic testing of 55-61 genes associated with cardiomyopathies. Samples were analyzed and evaluated for single nucleotide variants (SNVs), indels and CNVs. CNVs identified in the NGS data and suspected of being pathogenic based on type, size and location were confirmed by additional molecular tests.Results: A (likely) pathogenic (L)P variant was detected in 22.7% of patients, including 3 with CNVs and 25 where a variant was identified in a gene currently not associated with the patient's cardiomyopathy subtype. Only 15 out of 2002 patients (0.8%) were found to carry two (L)P variants.Conclusion: The yield of routine clinical diagnostics of cardiomyopathies was relatively low when compared to literature. This is likely due to the fact that our study reports the outcome of patients in daily routine diagnostics, therefore also including patients not fully fulfilling (subtype specific) cardiomyopathy criteria. This may also explain why (L)P variants were identified in genes not associated with the reported subtype. The added value of CNV analysis was shown to be limited but not negligible. (C) 2021 The Authors. Published by Elsevier B.V.",

keywords = "Cardiomyopathy, NGS gene panel, Diagnostic yield, CNV, DILATED CARDIOMYOPATHY, MOLECULAR-GENETICS, FOUNDER MUTATIONS, PHENOTYPE, CLASSIFICATION, LANDSCAPE, VARIANTS, GENOTYPE",

author = "Alimohamed, {Mohamed Z} and LennartF Johansson and Anna Posafalvi and Boven, {Ludolf G} and {van Dijk}, {Krista K} and Lisa Walters and Vos, {Yvonne J} and Helga Westers and Hoedemaekers, {Yvonne M} and Sinke, {Richard J} and Sijmons, {Rolf H} and Birgit Sikkema-Raddatz and Jongbloed, {Jan D H} and {van der Zwaag}, {Paul A}",

note = "Copyright {\textcopyright} 2021. Published by Elsevier B.V.",

year = "2021",

month = jun,

day = "1",

doi = "10.1016/j.ijcard.2021.02.069",

language = "English",

volume = "332",

pages = "99--104",

journal = "International Journal of Cardiology",

issn = "0167-5273",

publisher = "ELSEVIER IRELAND LTD",

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Alimohamed, MZ, Johansson, L, Posafalvi, A, Boven, LG , van Dijk, KK , Walters, L, Vos, YJ, Westers, H, Hoedemaekers, YM, Sinke, RJ, Sijmons, RH, Sikkema-Raddatz, B , Jongbloed, JDH & van der Zwaag, PA 2021, 'Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients', International Journal of Cardiology, vol. 332, pp. 99-104. https://doi.org/10.1016/j.ijcard.2021.02.069

TY - JOUR

T1 - Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients

AU - Alimohamed, Mohamed Z

AU - Johansson, LennartF

AU - Posafalvi, Anna

AU - Boven, Ludolf G

AU - van Dijk, Krista K

AU - Walters, Lisa

AU - Vos, Yvonne J

AU - Westers, Helga

AU - Hoedemaekers, Yvonne M

AU - Sinke, Richard J

AU - Sijmons, Rolf H

AU - Sikkema-Raddatz, Birgit

AU - Jongbloed, Jan D H

AU - van der Zwaag, Paul A

PY - 2021/6/1

Y1 - 2021/6/1

N2 - Background: Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield.Objectives: Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs on diagnostic yield.Methods: Patients (N = 2002) referred for clinical genetic analysis underwent diagnostic testing of 55-61 genes associated with cardiomyopathies. Samples were analyzed and evaluated for single nucleotide variants (SNVs), indels and CNVs. CNVs identified in the NGS data and suspected of being pathogenic based on type, size and location were confirmed by additional molecular tests.Results: A (likely) pathogenic (L)P variant was detected in 22.7% of patients, including 3 with CNVs and 25 where a variant was identified in a gene currently not associated with the patient's cardiomyopathy subtype. Only 15 out of 2002 patients (0.8%) were found to carry two (L)P variants.Conclusion: The yield of routine clinical diagnostics of cardiomyopathies was relatively low when compared to literature. This is likely due to the fact that our study reports the outcome of patients in daily routine diagnostics, therefore also including patients not fully fulfilling (subtype specific) cardiomyopathy criteria. This may also explain why (L)P variants were identified in genes not associated with the reported subtype. The added value of CNV analysis was shown to be limited but not negligible. (C) 2021 The Authors. Published by Elsevier B.V.

AB - Background: Next-generation sequencing (NGS) is increasingly used for clinical evaluation of cardiomyopathy patients as it allows for simultaneous screening of multiple cardiomyopathy-associated genes. Adding copy number variant (CNV) analysis of NGS data is not routine yet and may contribute to the diagnostic yield.Objectives: Determine the diagnostic yield of our targeted NGS gene panel in routine clinical diagnostics of Dutch cardiomyopathy patients and explore the impact of exon CNVs on diagnostic yield.Methods: Patients (N = 2002) referred for clinical genetic analysis underwent diagnostic testing of 55-61 genes associated with cardiomyopathies. Samples were analyzed and evaluated for single nucleotide variants (SNVs), indels and CNVs. CNVs identified in the NGS data and suspected of being pathogenic based on type, size and location were confirmed by additional molecular tests.Results: A (likely) pathogenic (L)P variant was detected in 22.7% of patients, including 3 with CNVs and 25 where a variant was identified in a gene currently not associated with the patient's cardiomyopathy subtype. Only 15 out of 2002 patients (0.8%) were found to carry two (L)P variants.Conclusion: The yield of routine clinical diagnostics of cardiomyopathies was relatively low when compared to literature. This is likely due to the fact that our study reports the outcome of patients in daily routine diagnostics, therefore also including patients not fully fulfilling (subtype specific) cardiomyopathy criteria. This may also explain why (L)P variants were identified in genes not associated with the reported subtype. The added value of CNV analysis was shown to be limited but not negligible. (C) 2021 The Authors. Published by Elsevier B.V.

KW - Cardiomyopathy

KW - NGS gene panel

KW - Diagnostic yield

KW - CNV

KW - DILATED CARDIOMYOPATHY

KW - MOLECULAR-GENETICS

KW - FOUNDER MUTATIONS

KW - PHENOTYPE

KW - CLASSIFICATION

KW - LANDSCAPE

KW - VARIANTS

KW - GENOTYPE

U2 - 10.1016/j.ijcard.2021.02.069

DO - 10.1016/j.ijcard.2021.02.069

M3 - Article

C2 - 33662488

SN - 0167-5273

VL - 332

SP - 99

EP - 104

JO - International Journal of Cardiology

JF - International Journal of Cardiology

ER -

Diagnostic yield of targeted next generation sequencing in 2002 Dutch cardiomyopathy patients

Abstract

Keywords

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