Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

Siddharth Srivastava; Jamie A. Love-Nichols; Kira A. Dies; David H. Ledbetter; Christa L. Martin; Wendy K. Chung; Helen Firth; Thomas Frazier; Robin L. Hansen; Lisa Prock; Han Brunner; Ny Hoang; Stephen W. Scherer; Mustafa Sahin; David T. Miller; Bibiana Restrepo; Suma Shankar; Erin Rooney Riggs; Pete Constantinou; Anne Reed-Weston; R. Spencer Tong; Jennifer Howe; Janet Buchanan; Rachel Fisher; Sonal Mahida; NDD Exome Scoping Review Work Group

doi:10.1038/s41436-019-0554-6

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

Siddharth Srivastava, Jamie A. Love-Nichols, Kira A. Dies, David H. Ledbetter, Christa L. Martin, Wendy K. Chung, Helen Firth, Thomas Frazier, Robin L. Hansen, Lisa Prock, Han Brunner, Ny Hoang, Stephen W. Scherer, Mustafa Sahin^*, David T. Miller, Bibiana Restrepo, Suma Shankar, Erin Rooney Riggs, Pete Constantinou, Anne Reed-WestonR. Spencer Tong, Jennifer Howe, Janet Buchanan, Rachel Fisher, Sonal Mahida, NDD Exome Scoping Review Work Group

^*Corresponding author for this work

Research output: Contribution to journal › (Systematic) Review article › peer-review

Abstract

Purpose: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs.

Methods: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians.

Results: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%).

Conclusion: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

Original language	English
Pages (from-to)	2413-2421
Number of pages	9
Journal	Genetics in Medicine
Volume	21
Issue number	11
DOIs	https://doi.org/10.1038/s41436-019-0554-6
Publication status	Published - Nov 2019

Keywords

autism
consensus development conference
diagnostic yield
genetic testing
intellectual disability
AUTISM SPECTRUM DISORDERS
CHROMOSOMAL MICROARRAY
INTELLECTUAL DISABILITY
MEDICAL GENETICS
AMERICAN-COLLEGE
UTILITY
IMPACT
IDENTIFICATION
GUIDELINES
MANAGEMENT

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10.1038/s41436-019-0554-6Licence: CC BY-NC-ND

1 Erratum / corrigendum / retractions

Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders
Srivastava, S., Love-Nichols, J. A., Dies, K. A., Ledbetter, D. H., Martin, C. L., Chung, W. K., Firth, H. V., Frazier, T., Hansen, R. L., Prock, L., Brunner, H., Hoang, N., Scherer, S. W., Sahin, M., Miller, D. T. & NDD Exome Scoping Review Work Group, Oct 2020, In: Genetics in Medicine. 22, 10, p. 1731-1732 2 p.
Research output: Contribution to journal › Erratum / corrigendum / retractions › Academic

Open Access

Cite this

Srivastava, S., Love-Nichols, J. A., Dies, K. A., Ledbetter, D. H., Martin, C. L., Chung, W. K., Firth, H., Frazier, T., Hansen, R. L., Prock, L., Brunner, H., Hoang, N., Scherer, S. W., Sahin, M., Miller, D. T., Restrepo, B., Shankar, S., Riggs, E. R., Constantinou, P., ... NDD Exome Scoping Review Work Group (2019). Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. Genetics in Medicine, 21(11), 2413-2421. https://doi.org/10.1038/s41436-019-0554-6

@article{d43a26b7d2644d1583c54a8333165e4a,

title = "Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders",

abstract = "Purpose: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs.Methods: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians.Results: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%).Conclusion: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.",

keywords = "autism, consensus development conference, diagnostic yield, genetic testing, intellectual disability, AUTISM SPECTRUM DISORDERS, CHROMOSOMAL MICROARRAY, INTELLECTUAL DISABILITY, MEDICAL GENETICS, AMERICAN-COLLEGE, UTILITY, IMPACT, IDENTIFICATION, GUIDELINES, MANAGEMENT",

author = "Siddharth Srivastava and Love-Nichols, {Jamie A.} and Dies, {Kira A.} and Ledbetter, {David H.} and Martin, {Christa L.} and Chung, {Wendy K.} and Helen Firth and Thomas Frazier and Hansen, {Robin L.} and Lisa Prock and Han Brunner and Ny Hoang and Scherer, {Stephen W.} and Mustafa Sahin and Miller, {David T.} and Bibiana Restrepo and Suma Shankar and Riggs, {Erin Rooney} and Pete Constantinou and Anne Reed-Weston and Tong, {R. Spencer} and Jennifer Howe and Janet Buchanan and Rachel Fisher and Sonal Mahida and {NDD Exome Scoping Review Work Group}",

note = "Funding Information: All authors completed the International Committee of Medical Journal Editors conflict of interest disclosure forms, which were reviewed by the senior authors. H.V.F. reports personal fees from UpToDate, outside the submitted work. T.F. has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker's honorarium from the Cole Family Research Fund, Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Kugona LLC, Shire Development, Bristol-Myers Squibb, Roche Pharma, National Institutes of Health, and the Brain and Behavior Research Foundation, all unrelated to this project. S.W.S. is on the Scientific Advisory Committees of Population Bio and Deep Genomics, and intellectual property from his research held at the Hospital for Sick Children is licensed to Athena Diagnostics, and separately Lineagen. These relationships did not influence data interpretation or presentation during this study, but are being disclosed for potential future considerations. M.S. reports grant support from Novartis, Roche, Pfizer, Ipsen, LAM Therapeutics and Quadrant Biosciences, and he has served on Scientific Advisory Boards for Sage, Roche, Celgene, and Takeda, all unrelated to this project. The other authors declare no conflicts of interest. Funding Information: The authors acknowledge members of the Exome Scoping Review Work Group participating in the literature scoping review: Bibiana Restrepo and Suma Shankar (MIND Institute, Department of Pediatrics, University of California Davis), Erin Rooney Riggs (Autism & Developmental Medicine Institute, Geisinger), Pete Constantinou (West of Scotland Regional Genetics Service, Glasgow, UK), Anne Reed-Weston (Columbia University College of Physicians & Surgeons), R. Spencer Tong (The Hospital for Sick Children), Jennifer Howe and Janet Buchanan (The Hospital for Sick Children), Rachel Fisher (University of Michigan), and Sonal Mahida (Epilepsy Genetics, Boston Children{\textquoteright}s Hospital [BCH]). We also acknowledge the Wade Family Foundation for their financial support of the consensus conference, Caterina Stamoulis (Departments of Medicine and Neurology, BCH) for review of statistical methodology, and librarian Meaghan Muir (BCH) for PubMed and scoping review methodology guidance. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = nov,

doi = "10.1038/s41436-019-0554-6",

language = "English",

volume = "21",

pages = "2413--2421",

journal = "Genetics in Medicine",

issn = "1098-3600",

publisher = "Nature Publishing Group",

number = "11",

}

Srivastava, S, Love-Nichols, JA, Dies, KA, Ledbetter, DH, Martin, CL, Chung, WK, Firth, H, Frazier, T, Hansen, RL, Prock, L, Brunner, H, Hoang, N, Scherer, SW, Sahin, M, Miller, DT, Restrepo, B, Shankar, S, Riggs, ER, Constantinou, P, Reed-Weston, A, Tong, RS, Howe, J, Buchanan, J, Fisher, R, Mahida, S & NDD Exome Scoping Review Work Group 2019, 'Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders', Genetics in Medicine, vol. 21, no. 11, pp. 2413-2421. https://doi.org/10.1038/s41436-019-0554-6

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders. / Srivastava, Siddharth; Love-Nichols, Jamie A.; Dies, Kira A. et al.
In: Genetics in Medicine, Vol. 21, No. 11, 11.2019, p. 2413-2421.

Research output: Contribution to journal › (Systematic) Review article › peer-review

TY - JOUR

T1 - Meta-analysis and multidisciplinary consensus statement

T2 - exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

AU - Srivastava, Siddharth

AU - Love-Nichols, Jamie A.

AU - Dies, Kira A.

AU - Ledbetter, David H.

AU - Martin, Christa L.

AU - Chung, Wendy K.

AU - Firth, Helen

AU - Frazier, Thomas

AU - Hansen, Robin L.

AU - Prock, Lisa

AU - Brunner, Han

AU - Hoang, Ny

AU - Scherer, Stephen W.

AU - Sahin, Mustafa

AU - Miller, David T.

AU - Restrepo, Bibiana

AU - Shankar, Suma

AU - Riggs, Erin Rooney

AU - Constantinou, Pete

AU - Reed-Weston, Anne

AU - Tong, R. Spencer

AU - Howe, Jennifer

AU - Buchanan, Janet

AU - Fisher, Rachel

AU - Mahida, Sonal

AU - NDD Exome Scoping Review Work Group

N1 - Funding Information: All authors completed the International Committee of Medical Journal Editors conflict of interest disclosure forms, which were reviewed by the senior authors. H.V.F. reports personal fees from UpToDate, outside the submitted work. T.F. has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker's honorarium from the Cole Family Research Fund, Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Kugona LLC, Shire Development, Bristol-Myers Squibb, Roche Pharma, National Institutes of Health, and the Brain and Behavior Research Foundation, all unrelated to this project. S.W.S. is on the Scientific Advisory Committees of Population Bio and Deep Genomics, and intellectual property from his research held at the Hospital for Sick Children is licensed to Athena Diagnostics, and separately Lineagen. These relationships did not influence data interpretation or presentation during this study, but are being disclosed for potential future considerations. M.S. reports grant support from Novartis, Roche, Pfizer, Ipsen, LAM Therapeutics and Quadrant Biosciences, and he has served on Scientific Advisory Boards for Sage, Roche, Celgene, and Takeda, all unrelated to this project. The other authors declare no conflicts of interest. Funding Information: The authors acknowledge members of the Exome Scoping Review Work Group participating in the literature scoping review: Bibiana Restrepo and Suma Shankar (MIND Institute, Department of Pediatrics, University of California Davis), Erin Rooney Riggs (Autism & Developmental Medicine Institute, Geisinger), Pete Constantinou (West of Scotland Regional Genetics Service, Glasgow, UK), Anne Reed-Weston (Columbia University College of Physicians & Surgeons), R. Spencer Tong (The Hospital for Sick Children), Jennifer Howe and Janet Buchanan (The Hospital for Sick Children), Rachel Fisher (University of Michigan), and Sonal Mahida (Epilepsy Genetics, Boston Children’s Hospital [BCH]). We also acknowledge the Wade Family Foundation for their financial support of the consensus conference, Caterina Stamoulis (Departments of Medicine and Neurology, BCH) for review of statistical methodology, and librarian Meaghan Muir (BCH) for PubMed and scoping review methodology guidance. Publisher Copyright: © 2019, The Author(s).

PY - 2019/11

Y1 - 2019/11

N2 - Purpose: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs.Methods: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians.Results: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%).Conclusion: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

AB - Purpose: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs.Methods: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians.Results: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%).Conclusion: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

KW - autism

KW - consensus development conference

KW - diagnostic yield

KW - genetic testing

KW - intellectual disability

KW - AUTISM SPECTRUM DISORDERS

KW - CHROMOSOMAL MICROARRAY

KW - INTELLECTUAL DISABILITY

KW - MEDICAL GENETICS

KW - AMERICAN-COLLEGE

KW - UTILITY

KW - IMPACT

KW - IDENTIFICATION

KW - GUIDELINES

KW - MANAGEMENT

U2 - 10.1038/s41436-019-0554-6

DO - 10.1038/s41436-019-0554-6

M3 - (Systematic) Review article

SN - 1098-3600

VL - 21

SP - 2413

EP - 2421

JO - Genetics in Medicine

JF - Genetics in Medicine

IS - 11

ER -

Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

Abstract

Keywords

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Research output

Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders

Cite this