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

the NDD Exome Scoping Review Work Group

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 languageEnglish (US)
JournalGenetics in Medicine
DOIs
StatePublished - Jan 1 2019

Fingerprint

Exome
Routine Diagnostic Tests
Meta-Analysis
Consensus
Consensus Development Conferences
Molecular Pathology
Neurodevelopmental Disorders
PubMed
Intellectual Disability

Keywords

  • autism
  • consensus development conference
  • diagnostic yield
  • genetic testing
  • intellectual disability

ASJC Scopus subject areas

  • Genetics(clinical)

Cite this

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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",
author = "{the NDD Exome Scoping Review Work Group} and Siddharth Srivastava and Love-Nichols, {Jamie A.} and Dies, {Kira A.} and Ledbetter, {David H.} and Martin, {Christa L.} and Chung, {Wendy K.} and Firth, {Helen V.} 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.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1038/s41436-019-0554-6",
language = "English (US)",
journal = "Genetics in Medicine",
issn = "1098-3600",
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T1 - Meta-analysis and multidisciplinary consensus statement

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

AU - the NDD Exome Scoping Review Work Group

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 V.

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.

PY - 2019/1/1

Y1 - 2019/1/1

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.

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