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Genet Med. 2018 Apr;20(4):435-443. doi: 10.1038/gim.2017.119. Epub 2017 Aug 3.

Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.

Author information

1
The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, Ontario, Canada.
2
Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
3
Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.
4
Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
5
Cardiac Genome Clinic, Ted Rogers Centre for Heart Research, The Hospital for Sick Children, Toronto, Ontario, Canada.
6
Deep Genomics Inc., Toronto, Ontario, Canada.
7
Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
8
William Osler Health Centre, Brampton, Ontario, Canada.
9
Division of Respiratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
10
Division of Neurology, BC Children's Hospital, Vancouver, British Columbia, Canada.
11
Regional Genetics Program, The Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
12
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
13
Child Health Evaluative Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
14
Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada.
15
Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada.
16
Department of Ophthalmology and Vision Sciences, The Hospital for Sick Children, Toronto, Ontario, Canada.
17
Division of Rheumatology, The Hospital for Sick Children, Toronto, Ontario, Canada.
18
Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada.
19
Program in Cell Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
20
Program Physiology & Experimental Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.
21
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
22
Division of Endocrinology, The Hospital for Sick Children, Toronto, Ontario, Canada.
23
Centre for Clinical Ethics, St. Joseph's Health Centre, Toronto, Ontario, Canada.
24
Joint Centre for Bioethics, University of Toronto, Toronto, Ontario, Canada.
25
Department of Family and Community Medicine and Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
26
Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada.
27
Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.

Abstract

PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; P = 0.01). Genes clinically sequenced in the cohort (n = 1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

PMID:
28771251
PMCID:
PMC5895460
DOI:
10.1038/gim.2017.119
[Indexed for MEDLINE]
Free PMC Article

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