Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

Rolph Pfundt; Marisol del Rosario; Lisenka E. L. M. Vissers; Michael P. Kwint; Irene M. Janssen; Nicole de Leeuw; Helger G. Yntema; Marcel R. Nelen; Dorien Lugtenberg; Erik-Jan Kamsteeg; Nienke Wieskamp; Alexander P. A. Stegmann; Servi J. C. Stevens; Richard J. T. Rodenburg; Annet Simons; Arjen R. Mensenkamp; Tuula Rinne; Christian Gilissen; Hans Scheffer; Joris A. Veltman; Jayne Y. Hehir-Kwa

doi:10.1038/gim.2016.163

Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

Rolph Pfundt, Marisol del Rosario, Lisenka E. L. M. Vissers, Michael P. Kwint, Irene M. Janssen, Nicole de Leeuw, Helger G. Yntema, Marcel R. Nelen, Dorien Lugtenberg, Erik-Jan Kamsteeg, Nienke Wieskamp, Alexander P. A. Stegmann, Servi J. C. Stevens, Richard J. T. Rodenburg, Annet Simons, Arjen R. Mensenkamp, Tuula Rinne, Christian Gilissen, Hans Scheffer, Joris A. VeltmanJayne Y. Hehir-Kwa^*

^*Corresponding author for this work

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

Abstract

Purpose: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a firsttier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome-or genome-wide approach with a single test.

Methods: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.

Results: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of similar to 2%(ranging from 0 to -5.8% per disorder).

Conclusions: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.

Original language	English
Pages (from-to)	667-675
Number of pages	9
Journal	Genetics in Medicine
Volume	19
Issue number	6
DOIs	https://doi.org/10.1038/gim.2016.163
Publication status	Published - Jun 2017

Keywords

copy-number variants
diagnostic yield
exome sequencing
read depth
structural variation
SEVERE INTELLECTUAL DISABILITY
CONGENITAL-ANOMALIES
STRUCTURAL VARIATION
DEVELOPMENTAL DELAY
QT SYNDROME
GENOME
MODEL
MAP
POLYMORPHISM
INSERTIONS

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Cite this

Pfundt, R., del Rosario, M., Vissers, L. E. L. M., Kwint, M. P., Janssen, I. M., de Leeuw, N., Yntema, H. G., Nelen, M. R., Lugtenberg, D., Kamsteeg, E.-J., Wieskamp, N., Stegmann, A. P. A., Stevens, S. J. C., Rodenburg, R. J. T., Simons, A., Mensenkamp, A. R., Rinne, T., Gilissen, C., Scheffer, H., ... Hehir-Kwa, J. Y. (2017). Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genetics in Medicine, 19(6), 667-675. https://doi.org/10.1038/gim.2016.163

@article{ee08ace6c6db4f20b048fa50452acc52,

title = "Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders",

abstract = "Purpose: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a firsttier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome-or genome-wide approach with a single test.Methods: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.Results: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of similar to 2%(ranging from 0 to -5.8% per disorder).Conclusions: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.",

keywords = "copy-number variants, diagnostic yield, exome sequencing, read depth, structural variation, SEVERE INTELLECTUAL DISABILITY, CONGENITAL-ANOMALIES, STRUCTURAL VARIATION, DEVELOPMENTAL DELAY, QT SYNDROME, GENOME, MODEL, MAP, POLYMORPHISM, INSERTIONS",

author = "Rolph Pfundt and {del Rosario}, Marisol and Vissers, {Lisenka E. L. M.} and Kwint, {Michael P.} and Janssen, {Irene M.} and {de Leeuw}, Nicole and Yntema, {Helger G.} and Nelen, {Marcel R.} and Dorien Lugtenberg and Erik-Jan Kamsteeg and Nienke Wieskamp and Stegmann, {Alexander P. A.} and Stevens, {Servi J. C.} and Rodenburg, {Richard J. T.} and Annet Simons and Mensenkamp, {Arjen R.} and Tuula Rinne and Christian Gilissen and Hans Scheffer and Veltman, {Joris A.} and Hehir-Kwa, {Jayne Y.}",

year = "2017",

month = jun,

doi = "10.1038/gim.2016.163",

language = "English",

volume = "19",

pages = "667--675",

journal = "Genetics in Medicine",

issn = "1098-3600",

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Pfundt, R, del Rosario, M, Vissers, LELM, Kwint, MP, Janssen, IM, de Leeuw, N, Yntema, HG, Nelen, MR, Lugtenberg, D, Kamsteeg, E-J, Wieskamp, N, Stegmann, APA , Stevens, SJC, Rodenburg, RJT, Simons, A, Mensenkamp, AR, Rinne, T, Gilissen, C, Scheffer, H, Veltman, JA & Hehir-Kwa, JY 2017, 'Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders', Genetics in Medicine, vol. 19, no. 6, pp. 667-675. https://doi.org/10.1038/gim.2016.163

TY - JOUR

T1 - Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders

AU - Pfundt, Rolph

AU - del Rosario, Marisol

AU - Vissers, Lisenka E. L. M.

AU - Kwint, Michael P.

AU - Janssen, Irene M.

AU - de Leeuw, Nicole

AU - Yntema, Helger G.

AU - Nelen, Marcel R.

AU - Lugtenberg, Dorien

AU - Kamsteeg, Erik-Jan

AU - Wieskamp, Nienke

AU - Stegmann, Alexander P. A.

AU - Stevens, Servi J. C.

AU - Rodenburg, Richard J. T.

AU - Simons, Annet

AU - Mensenkamp, Arjen R.

AU - Rinne, Tuula

AU - Gilissen, Christian

AU - Scheffer, Hans

AU - Veltman, Joris A.

AU - Hehir-Kwa, Jayne Y.

PY - 2017/6

Y1 - 2017/6

N2 - Purpose: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a firsttier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome-or genome-wide approach with a single test.Methods: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.Results: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of similar to 2%(ranging from 0 to -5.8% per disorder).Conclusions: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.

AB - Purpose: Copy-number variation is a common source of genomic variation and an important genetic cause of disease. Microarray-based analysis of copy-number variants (CNVs) has become a firsttier diagnostic test for patients with neurodevelopmental disorders, with a diagnostic yield of 10-20%. However, for most other genetic disorders, the role of CNVs is less clear and most diagnostic genetic studies are generally limited to the study of single-nucleotide variants (SNVs) and other small variants. With the introduction of exome and genome sequencing, it is now possible to detect both SNVs and CNVs using an exome-or genome-wide approach with a single test.Methods: We performed exome-based read-depth CNV screening on data from 2,603 patients affected by a range of genetic disorders for which exome sequencing was performed in a diagnostic setting.Results: In total, 123 clinically relevant CNVs ranging in size from 727 bp to 15.3 Mb were detected, which resulted in 51 conclusive diagnoses and an overall increase in diagnostic yield of similar to 2%(ranging from 0 to -5.8% per disorder).Conclusions: This study shows that CNVs play an important role in a broad range of genetic disorders and that detection via exome-based CNV profiling results in an increase in the diagnostic yield without additional testing, bringing us closer to single-test genomics.

KW - copy-number variants

KW - diagnostic yield

KW - exome sequencing

KW - read depth

KW - structural variation

KW - SEVERE INTELLECTUAL DISABILITY

KW - CONGENITAL-ANOMALIES

KW - STRUCTURAL VARIATION

KW - DEVELOPMENTAL DELAY

KW - QT SYNDROME

KW - GENOME

KW - MODEL

KW - MAP

KW - POLYMORPHISM

KW - INSERTIONS

U2 - 10.1038/gim.2016.163

DO - 10.1038/gim.2016.163

M3 - Article

C2 - 28574513

SN - 1098-3600

VL - 19

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JO - Genetics in Medicine

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