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

195 Citations (Web of Science)

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
Pages (from-to)2413-2421
Number of pages9
JournalGenetics in Medicine
Volume21
Issue number11
DOIs
Publication statusPublished - 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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