Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine

Dimitri J Stavropoulos^{1

2}, Daniele Merico^{3

4}, Rebekah Jobling⁵, Sarah Bowdin^{5

6

7}, Nasim Monfared^{5

6}, Bhooma Thiruvahindrapuram^{3

4}, Thomas Nalpathamkalam^{3

4}, Giovanna Pellecchia^{3

4}, Ryan K C Yuen^{3

4}, Michael J Szego^{3

8

9}, Robin Z Hayeems¹⁰, Randi Zlotnik Shaul^{8

11}, Michael Brudno^{4

12

13}, Marta Girdea^{4

12}, Brendan Frey^{13

14

15}, Babak Alipanahi¹⁴, Sohnee Ahmed⁵, Riyana Babul-Hirji^{4

5

15}, Ramses Badilla Porras⁵, Melissa T Carter^{5

7}, Lauren Chad⁵, Ayeshah Chaudhry⁵, David Chitayat^{5

7

16}, Soghra Jougheh Doust⁵, Cheryl Cytrynbaum^{4

5

15}, Lucie Dupuis^{5

15}, Resham Ejaz⁵, Leona Fishman⁵, Andrea Guerin⁵, Bita Hashemi⁵, Mayada Helal⁵, Stacy Hewson^{5

15}, Michal Inbar-Feigenberg⁵, Peter Kannu^{4

5

7}, Natalya Karp⁵, Raymond Kim⁵, Jonathan Kronick⁵, Eriskay Liston¹⁷, Heather MacDonald¹⁸, Saadet Mercimek-Mahmutoglu^{4

5

7}, Roberto Mendoza-Londono^{4

5

7}, Enas Nasr⁵, Graeme Nimmo⁵, Nicole Parkinson¹⁷, Nada Quercia^{5

15}, Julian Raiman^{5

7}, Maian Roifman⁵, Andreas Schulze^{4

5

7}, Andrea Shugar^{5

15}, Cheryl Shuman^{5

15}, Pierre Sinajon⁵, Komudi Siriwardena^{5

7}, Rosanna Weksberg^{4

5

7

15}, Grace Yoon^{5

7}, Chris Carew⁶, Raith Erickson¹⁹, Richard A Leach¹⁹, Robert Klein¹⁹, Peter N Ray^{1

4

6

15}, M Stephen Meyn^{4

5

6

15}, Stephen W Scherer^{3

4

6

15}, Ronald D Cohn^{4

5

6

7}, Christian R Marshall^{1

6}

Affiliations

¹ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
² Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
⁸ Joint Centre for Bioethics, University of Toronto, Toronto, Ontario, Canada.
⁹ Department of Family and Community Medicine and Clinical Public Health Division, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Bioethics, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹² Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹³ Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Department of Electrical and Computer Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON, Canada.
¹⁷ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁸ Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁹ Complete Genomics Inc, Mountain View, California, USA.

PMID: 28567303
PMCID: PMC5447450
DOI: 10.1038/npjgenmed.2015.12

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine

Dimitri J Stavropoulos et al. NPJ Genom Med. 2016.

. 2016 Jan 13:1:15012.

doi: 10.1038/npjgenmed.2015.12.

Authors

Affiliations

¹ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
² Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁴ Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁵ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁶ Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
⁷ Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
⁸ Joint Centre for Bioethics, University of Toronto, Toronto, Ontario, Canada.
⁹ Department of Family and Community Medicine and Clinical Public Health Division, University of Toronto, Toronto, Ontario, Canada.
¹⁰ Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Department of Bioethics, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹² Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹³ Department of Computer Science, University of Toronto, Toronto, Ontario, Canada.
¹⁴ Department of Electrical and Computer Engineering and Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada.
¹⁵ Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹⁶ Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto, ON, Canada.
¹⁷ Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁸ Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada.
¹⁹ Complete Genomics Inc, Mountain View, California, USA.

PMID: 28567303
PMCID: PMC5447450
DOI: 10.1038/npjgenmed.2015.12

Abstract

The standard of care for first-tier clinical investigation of the etiology of congenital malformations and neurodevelopmental disorders is chromosome microarray analysis (CMA) for copy number variations (CNVs), often followed by gene(s)-specific sequencing searching for smaller insertion-deletions (indels) and single nucleotide variant (SNV) mutations. Whole genome sequencing (WGS) has the potential to capture all classes of genetic variation in one experiment; however, the diagnostic yield for mutation detection of WGS compared to CMA, and other tests, needs to be established. In a prospective study we utilized WGS and comprehensive medical annotation to assess 100 patients referred to a paediatric genetics service and compared the diagnostic yield versus standard genetic testing. WGS identified genetic variants meeting clinical diagnostic criteria in 34% of cases, representing a 4-fold increase in diagnostic rate over CMA (8%) (p-value = 1.42e-05) alone and >2-fold increase in CMA plus targeted gene sequencing (13%) (p-value = 0.0009). WGS identified all rare clinically significant CNVs that were detected by CMA. In 26 patients, WGS revealed indel and missense mutations presenting in a dominant (63%) or a recessive (37%) manner. We found four subjects with mutations in at least two genes associated with distinct genetic disorders, including two cases harboring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counseling. Clinical implementation of WGS as a primary test will provide a higher diagnostic yield than conventional genetic testing and potentially reduce the time required to reach a genetic diagnosis.

Keywords: Chromosomal Microarray Analysis; Diagnostic Yield; Whole Genome Sequencing.

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Conflict of interest statement

Competing Interests: DM RJ, NM, BT, TN, GP, RKCY, MS, RH, RZS, MB, MG, BF, BA, SA, MTC, LC, AC, CC, LD, RE, LF, AG, BH, MH, SH, MIF, PK, NK, RK, JK, EL, HM, SMM, RML, EN, GN, NP, NQ, JR, MR, AS, AS, CS, PS, KS, RW, GY, CC, SWS, RDC, and CRM declare no conflicts of interest. SB, DJS, PNR and MSM are scientific advisors for Gene42 Inc., which provides support services for the free (open source) PhenoTips software. RE and RK are employees of Complete Genomics. RAL was an employee of Complete Genomics at the time of the study and is currently employed by WuXi NextCODE Genomics.

Figures

**Figure 1**
Overview of study design comparing the diagnostic yield of whole-genome sequencing compared with standard of care genetic testing. CMA, chromosomal microarray analysis; SNV, single-nucleotide variant; CNV, copy-number variant; HPO, Human Phenotype Ontology; Dx, diagnostic.

See this image and copyright information in PMC

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Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine

Affiliations

Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources

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Medical