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

Genet Med. 2019 Nov;21(11):2413-2421. doi: 10.1038/s41436-019-0554-6. Epub 2019 Jun 11.


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.

Publication types

  • Meta-Analysis
  • Research Support, Non-U.S. Gov't
  • Systematic Review

MeSH terms

  • Autism Spectrum Disorder / genetics
  • Developmental Disabilities / genetics
  • Diagnostic Tests, Routine / methods
  • Exome / genetics
  • Exome Sequencing / methods
  • Genetic Testing / methods
  • Humans
  • Intellectual Disability / genetics
  • Neurodevelopmental Disorders / diagnosis*
  • Neurodevelopmental Disorders / etiology*
  • Neurodevelopmental Disorders / genetics*