Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders
Open accessAbstract
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”
From Tackling healthcare access barriers for individuals with autism from diagnosis to adulthood (2022) · cites this paper as [101]
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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- 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)
- ORCID
- Venue
- Genetics in Medicine
- Publisher
- Elsevier BV
- Published
- 2019-11
- Volume
- 21
- Issue
- 11
- Pages
- 2413-2421
- ISSN
- 1098-3600 (ISSN-L)
- PMC
- PMC6831729
- 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
- hybrid
- doi.org
- Licence
- 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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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