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

doi:10.1038/s41436-019-0554-6

Meta-Analysis

. 2019 Nov;21(11):2413-2421.

doi: 10.1038/s41436-019-0554-6. Epub 2019 Jun 11.

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

Siddharth Srivastava^#¹, Jamie A Love-Nichols^#¹, Kira A Dies¹, David H Ledbetter², Christa L Martin², Wendy K Chung^{3

4}, Helen V Firth^{5

6}, Thomas Frazier⁷, Robin L Hansen⁸, Lisa Prock^{1

9}, Han Brunner^{10

11

12}, Ny Hoang^{13

14

15}, Stephen W Scherer^{14

15

16

17}, Mustafa Sahin¹⁸, David T Miller¹⁹; NDD Exome Scoping Review Work Group

Affiliations

¹ Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA.
³ Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA.
⁴ SFARI, Simons Foundation, New York, NY, USA.
⁵ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
⁶ East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
⁷ Autism Speaks, Cleveland, OH, USA.
⁸ MIND Institute, Department of Pediatrics, University of California Davis, Sacramento, CA, USA.
⁹ Developmental Medicine Center, Boston Children's Hospital, Boston, MA, USA.
¹⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
¹² The Netherlands; Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
¹³ Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁴ Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁶ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁷ McLaughlin Centre and Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁸ Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. mustafa.sahin@childrens.harvard.edu.
¹⁹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

^# Contributed equally.

PMID: 31182824
PMCID: PMC6831729
DOI: 10.1038/s41436-019-0554-6

Meta-Analysis

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

Siddharth Srivastava et al. Genet Med. 2019 Nov.

. 2019 Nov;21(11):2413-2421.

doi: 10.1038/s41436-019-0554-6. Epub 2019 Jun 11.

Authors

Affiliations

¹ Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
² Autism & Developmental Medicine Institute, Geisinger, Danville, PA, USA.
³ Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA.
⁴ SFARI, Simons Foundation, New York, NY, USA.
⁵ Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
⁶ East Anglian Medical Genetics Service, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Cambridge, UK.
⁷ Autism Speaks, Cleveland, OH, USA.
⁸ MIND Institute, Department of Pediatrics, University of California Davis, Sacramento, CA, USA.
⁹ Developmental Medicine Center, Boston Children's Hospital, Boston, MA, USA.
¹⁰ Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands.
¹¹ Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
¹² The Netherlands; Department of Clinical Genetics and GROW-School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, The Netherlands.
¹³ Department of Genetic Counselling, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁴ Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁶ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
¹⁷ McLaughlin Centre and Department of Molecular Genetics, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
¹⁸ Translational Neuroscience Center, Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. mustafa.sahin@childrens.harvard.edu.
¹⁹ Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.

^# Contributed equally.

PMID: 31182824
PMCID: PMC6831729
DOI: 10.1038/s41436-019-0554-6

Erratum in

Correction: Meta-analysis and multidisciplinary consensus statement: exome sequencing is a first-tier clinical diagnostic test for individuals with neurodevelopmental disorders.
Srivastava S, Love-Nichols JA, Dies KA, Ledbetter DH, Martin CL, Chung WK, Firth HV, Frazier T, Hansen RL, Prock L, Brunner H, Hoang N, Scherer SW, Sahin M, Miller DT; NDD Exome Scoping Review Work Group. Srivastava S, et al. Genet Med. 2020 Oct;22(10):1731-1732. doi: 10.1038/s41436-020-0913-3. Genet Med. 2020. PMID: 32728138 Free PMC article.

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.

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Conflict of interest statement

All authors completed the International Committee of Medical Journal Editors conflict of interest disclosure forms, which were reviewed by the senior authors. H.V.F. reports personal fees from UpToDate, outside the submitted work. T.F. has received federal funding or research support from, acted as a consultant to, received travel support from, and/or received a speaker's honorarium from the Cole Family Research Fund, Simons Foundation, Ingalls Foundation, Forest Laboratories, Ecoeos, IntegraGen, Kugona LLC, Shire Development, Bristol-Myers Squibb, Roche Pharma, National Institutes of Health, and the Brain and Behavior Research Foundation, all unrelated to this project. S.W.S. is on the Scientific Advisory Committees of Population Bio and Deep Genomics, and intellectual property from his research held at the Hospital for Sick Children is licensed to Athena Diagnostics, and separately Lineagen. These relationships did not influence data interpretation or presentation during this study, but are being disclosed for potential future considerations. M.S. reports grant support from Novartis, Roche, Pfizer, Ipsen, LAM Therapeutics and Quadrant Biosciences, and he has served on Scientific Advisory Boards for Sage, Roche, Celgene, and Takeda, all unrelated to this project. The other authors declare no conflicts of interest.

Figures

**Fig. 1**
**Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of scoping review article inclusion.** ^aRecords identified through iterative review were reviewed by one reviewer at the screening stage.ES exome sequencing,*NDD* neurodevelopmental disorder.

**Fig. 2**
**Forest plot of meta-analysis subcategorized as neurodevelopmental disorder (NDD) and NDD plus associated conditions.**CI confidence interval.

**Fig. 3**
Diagnostic algorithm incorporating exome sequencing (ES) in the clinical evaluation of individuals with unexplained neurodevelopmental disorders (NDDs) (global developmental delay/intellectual disability [GDD/ID] and/or autism spectrum disorder [ASD]). An incomplete diagnosis represents a diagnosis that explains only part of an individual’s phenotype. Factors such as the turnaround time of test, availability of tests, and availability of genetic counseling may be considerations in application of this algorithm in clinical use. ^aOr technology that supersedes ES such as genome sequencing. *CMA* chromosomal microarray, *CNV* copy-number variant.

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References

1. Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704. - PubMed
1. Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399–407. - PubMed
1. Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742–745. - PMC - PubMed
1. Vissers LELM, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17:9–18. - PubMed
1. Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–764. - PMC - PubMed

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[1] Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704. - PubMed

[2] Retterer K, Juusola J, Cho MT, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18:696–704. - PubMed

[3] Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399–407. - PubMed

[4] Schaefer GB, Mendelsohn NJ, Professional Practice and Guidelines Committee. Clinical genetics evaluation in identifying the etiology of autism spectrum disorders: 2013 guideline revisions. Genet Med. 2013;15:399–407. - PubMed

[5] Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742–745. - PMC - PubMed

[6] Manning M, Hudgins L, Professional Practice and Guidelines Committee. Array-based technology and recommendations for utilization in medical genetics practice for detection of chromosomal abnormalities. Genet Med. 2010;12:742–745. - PMC - PubMed

[7] Vissers LELM, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17:9–18. - PubMed

[8] Vissers LELM, Gilissen C, Veltman JA. Genetic studies in intellectual disability and related disorders. Nat Rev Genet. 2016;17:9–18. - PubMed

[9] Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–764. - PMC - PubMed

[10] Miller DT, Adam MP, Aradhya S, et al. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86:749–764. - PMC - PubMed

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

Affiliations

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

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Conflict of interest statement

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