Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program

Katherine E. Bonini; Amanda Thomas-Wilson; Priya N. Marathe; Monisha Sebastin; Jacqueline A. Odgis; Miranda Di Biase; Nicole R. Kelly; Michelle A. Ramos; Beverly J. Insel; Laura Scarimbolo; Atteeq U. Rehman; Saurav Guha; Volkan Okur; Avinash Abhyankar; Shruti Phadke; Caroline Nava; Katie M. Gallagher; Lama Elkhoury; Lisa Edelmann; Randi E. Zinberg; Noura S. Abul-Husn; George A. Diaz; John M. Greally; Sabrina A. Suckiel; Carol R. Horowitz; Eimear E. Kenny; Melissa Wasserstein; Bruce D. Gelb; Vaidehi Jobanputra

doi:10.1111/cge.14365

Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program

Katherine E. Bonini, Amanda Thomas-Wilson, Priya N. Marathe, Monisha Sebastin, Jacqueline A. Odgis, Miranda Di Biase, Nicole R. Kelly, Michelle A. Ramos, Beverly J. Insel, Laura Scarimbolo, Atteeq U. Rehman, Saurav Guha, Volkan Okur, Avinash Abhyankar, Shruti Phadke, Caroline Nava, Katie M. Gallagher, Lama Elkhoury, Lisa Edelmann, Randi E. ZinbergNoura S. Abul-Husn, George A. Diaz, John M. Greally, Sabrina A. Suckiel, Carol R. Horowitz, Eimear E. Kenny, Melissa Wasserstein, Bruce D. Gelb, Vaidehi Jobanputra

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

Abstract

Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0–21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.

Original language	English (US)
Pages (from-to)	210-225
Number of pages	16
Journal	Clinical Genetics
Volume	104
Issue number	2
DOIs	https://doi.org/10.1111/cge.14365
State	Published - Aug 2023
Externally published	Yes

Keywords

CNV
clinical genomics
copy number variation
diagnostic testing
diverse populations
genome sequencing
pediatric genomics

ASJC Scopus subject areas

Genetics
Genetics(clinical)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1111/cge.14365

Cite this

Bonini, K. E., Thomas-Wilson, A., Marathe, P. N., Sebastin, M., Odgis, J. A., Di Biase, M., Kelly, N. R., Ramos, M. A., Insel, B. J., Scarimbolo, L., Rehman, A. U., Guha, S., Okur, V., Abhyankar, A., Phadke, S., Nava, C., Gallagher, K. M., Elkhoury, L., Edelmann, L., ... Jobanputra, V. (2023). Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program. Clinical Genetics, 104(2), 210-225. https://doi.org/10.1111/cge.14365

Bonini, KE, Thomas-Wilson, A, Marathe, PN, Sebastin, M, Odgis, JA, Di Biase, M, Kelly, NR, Ramos, MA, Insel, BJ, Scarimbolo, L, Rehman, AU, Guha, S, Okur, V, Abhyankar, A, Phadke, S, Nava, C, Gallagher, KM, Elkhoury, L, Edelmann, L, Zinberg, RE, Abul-Husn, NS, Diaz, GA, Greally, JM, Suckiel, SA, Horowitz, CR, Kenny, EE, Wasserstein, M, Gelb, BD & Jobanputra, V 2023, 'Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program', Clinical Genetics, vol. 104, no. 2, pp. 210-225. https://doi.org/10.1111/cge.14365

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title = "Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program",

abstract = "Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0–21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.",

keywords = "CNV, clinical genomics, copy number variation, diagnostic testing, diverse populations, genome sequencing, pediatric genomics",

author = "Bonini, {Katherine E.} and Amanda Thomas-Wilson and Marathe, {Priya N.} and Monisha Sebastin and Odgis, {Jacqueline A.} and {Di Biase}, Miranda and Kelly, {Nicole R.} and Ramos, {Michelle A.} and Insel, {Beverly J.} and Laura Scarimbolo and Rehman, {Atteeq U.} and Saurav Guha and Volkan Okur and Avinash Abhyankar and Shruti Phadke and Caroline Nava and Gallagher, {Katie M.} and Lama Elkhoury and Lisa Edelmann and Zinberg, {Randi E.} and Abul-Husn, {Noura S.} and Diaz, {George A.} and Greally, {John M.} and Suckiel, {Sabrina A.} and Horowitz, {Carol R.} and Kenny, {Eimear E.} and Melissa Wasserstein and Gelb, {Bruce D.} and Vaidehi Jobanputra",

note = "Publisher Copyright: {\textcopyright} 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.",

year = "2023",

month = aug,

doi = "10.1111/cge.14365",

language = "English (US)",

volume = "104",

pages = "210--225",

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T2 - Clinical experiences from the NYCKidSeq program

AU - Bonini, Katherine E.

AU - Thomas-Wilson, Amanda

AU - Marathe, Priya N.

AU - Sebastin, Monisha

AU - Odgis, Jacqueline A.

AU - Di Biase, Miranda

AU - Kelly, Nicole R.

AU - Ramos, Michelle A.

AU - Insel, Beverly J.

AU - Scarimbolo, Laura

AU - Rehman, Atteeq U.

AU - Guha, Saurav

AU - Okur, Volkan

AU - Abhyankar, Avinash

AU - Phadke, Shruti

AU - Nava, Caroline

AU - Gallagher, Katie M.

AU - Elkhoury, Lama

AU - Edelmann, Lisa

AU - Zinberg, Randi E.

AU - Abul-Husn, Noura S.

AU - Diaz, George A.

AU - Greally, John M.

AU - Suckiel, Sabrina A.

AU - Horowitz, Carol R.

AU - Kenny, Eimear E.

AU - Wasserstein, Melissa

AU - Gelb, Bruce D.

AU - Jobanputra, Vaidehi

PY - 2023/8

Y1 - 2023/8

N2 - Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0–21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.

AB - Copy number variations (CNVs) play a significant role in human disease. While chromosomal microarray has traditionally been the first-tier test for CNV detection, use of genome sequencing (GS) is increasing. We report the frequency of CNVs detected with GS in a diverse pediatric cohort from the NYCKidSeq program and highlight specific examples of its clinical impact. A total of 1052 children (0–21 years) with neurodevelopmental, cardiac, and/or immunodeficiency phenotypes received GS. Phenotype-driven analysis was used, resulting in 183 (17.4%) participants with a diagnostic result. CNVs accounted for 20.2% of participants with a diagnostic result (37/183) and ranged from 0.5 kb to 16 Mb. Of participants with a diagnostic result (n = 183) and phenotypes in more than one category, 5/17 (29.4%) were solved by a CNV finding, suggesting a high prevalence of diagnostic CNVs in participants with complex phenotypes. Thirteen participants with a diagnostic CNV (35.1%) had previously uninformative genetic testing, of which nine included a chromosomal microarray. This study demonstrates the benefits of GS for reliable detection of CNVs in a pediatric cohort with variable phenotypes.

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KW - clinical genomics

KW - copy number variation

KW - diagnostic testing

KW - diverse populations

KW - genome sequencing

KW - pediatric genomics

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JF - Clinical Genetics

IS - 2

ER -

Identification of copy number variants with genome sequencing: Clinical experiences from the NYCKidSeq program

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

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