Cited by 695Genomics and Rare DiseasesGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

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

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Srivastava, Siddharth, Love-Nichols, Jamie A., Dies, Kira A., Ledbetter, David H., Martin, Christa L., Chung, Wendy K., Firth, Helen V., Frazier, Thomas +7 more·2019·Genetics in Medicine

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.

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  • Exome sequencing with copy number variation analysis can be used to inform patient management in individuals with ASD.

    “can be used to inform patient management”
  • The set of genes included in gene panel testing requires continual revision as new associations are discovered, and reanalysis is limited to the genes originally included in the panel.

    “the set of genes included requires continual revision as new associations are discovered, and reanalysis is limited to the genes originally included in the panel.44”

    From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [44]

  • Exome sequencing has been recommended as a first-tier clinical test for individuals with unexplained NDDs by a multidisciplinary expert group following completion of scoping review and meta-analysis of diagnostic yield.

    “Recently, exome sequencing has been recommended as a first-tier clinical test for individuals with unexplained NDDs by a multidisciplinary expert group following completion of scoping review and meta-analysis of diagnostic yield.44”

    From Insufficient Evidence for “Autism-Specific” Genes (2020) · cites this paper as [44]

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Research works printed but not linked: 1

  1. [50]Nolan D Carlson M Whole exome sequencing in pediatric neurology patients: clinical implications and estimated cost analysis J Child Neurol 2016 31 887 894 26863999

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Authors
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.
Affiliations
  • Boston Children's Hospital (US)
  • Geisinger Medical Center (US)
  • Simons Foundation (US)
  • Cambridge University Hospitals NHS Foundation Trust (GB)
  • Autism Speaks (US)
  • University of California Davis Medical Center (US)
  • Radboud University Nijmegen (NL)
  • University of Toronto (CA)
Venue
Genetics in Medicine
Publisher
Elsevier BV
Published
2019-11
Volume
21
Issue
11
Pages
2413-2421
ISSN
1098-3600 (ISSN-L)
OpenAlex
W2953369183
Cited by
695
References
63
Citations by year
2026: 75 · 2025: 105 · 2024: 132 · 2023: 106 · 2022: 100 · 2021: 107 · 2020: 58 · 2019: 11
FWCI
9.51
Type
journal article
Language
en
Update notices
erratum (2020-10-01)
Open access
Locations
  • Genetics in Medicine (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion)
  • Apollo (University of Cambridge) (submittedVersion, cc-by-nc-nd)
  • Research Publications (Maastricht University) (submittedVersion, other-oa)
  • Apollo
Funders
Wade Family Foundation (N/A)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
exome sequencing, neurodevelopmental disorders, diagnostic yield, chromosomal microarray analysis, diagnostic algorithm, autism spectrum disorder, intellectual disability, global developmental delay, genetic diagnosis, diagnostic odyssey
MeSH terms
Autism Spectrum Disorder, Exome Sequencing, Developmental Disabilities, Consensus Statements as Topic, Diagnostic Tests, Routine, Genetic Testing, Humans, Intellectual Disability, Exome, Neurodevelopmental Disorders

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