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NPJ Genom Med. 2016 Jan 13;1. pii: 15012. doi: 10.1038/npjgenmed.2015.12.

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

Author information

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.

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

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.

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