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

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Abstract

Purpose

Genetic 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.

Methods

We 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.

Results

WGS 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.

Conclusion

WGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.

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Most cited references 16

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Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.

Jennifer E. Posey, Tamar Harel, Pengfei Liu … (2017)

Background Whole-exome sequencing can provide insight into the relationship between observed clinical phenotypes and underlying genotypes. Methods We conducted a retrospective analysis of data from a series of 7374 consecutive unrelated patients who had been referred to a clinical diagnostic laboratory for whole-exome sequencing; our goal was to determine the frequency and clinical characteristics of patients for whom more than one molecular diagnosis was reported. The phenotypic similarity between molecularly diagnosed pairs of diseases was calculated with the use of terms from the Human Phenotype Ontology. Results A molecular diagnosis was rendered for 2076 of 7374 patients (28.2%); among these patients, 101 (4.9%) had diagnoses that involved two or more disease loci. We also analyzed parental samples, when available, and found that de novo variants accounted for 67.8% (61 of 90) of pathogenic variants in autosomal dominant disease genes and 51.7% (15 of 29) of pathogenic variants in X-linked disease genes; both variants were de novo in 44.7% (17 of 38) of patients with two monoallelic variants. Causal copy-number variants were found in 12 patients (11.9%) with multiple diagnoses. Phenotypic similarity scores were significantly lower among patients in whom the phenotype resulted from two distinct mendelian disorders that affected different organ systems (50 patients) than among patients with disorders that had overlapping phenotypic features (30 patients) (median score, 0.21 vs. 0.36; P=1.77×10(-7)). Conclusions In our study, we found multiple molecular diagnoses in 4.9% of cases in which whole-exome sequencing was informative. Our results show that structured clinical ontologies can be used to determine the degree of overlap between two mendelian diseases in the same patient; the diseases can be distinct or overlapping. Distinct disease phenotypes affect different organ systems, whereas overlapping disease phenotypes are more likely to be caused by two genes encoding proteins that interact within the same pathway. (Funded by the National Institutes of Health and the Ting Tsung and Wei Fong Chao Foundation.).

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Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

Dimitri J Stavropoulos, Daniele Merico, Rebekah Jobling … (2016)

The standard of care for first-tier clinical investigation of the aetiology 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 utilised 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 fourfold increase in diagnostic rate over CMA (8%; P value=1.42E−05) alone and more than twofold 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 harbouring a pathogenic CNV and SNV. When considering medically actionable secondary findings in addition to primary WGS findings, 38% of patients would benefit from genetic counselling. 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.

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Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.

Mark Consugar, Daniel Navarro-Gomez, Emily Place … (2015)

Next-generation sequencing-based methods are being adopted broadly for genetic diagnostic testing, but the performance characteristics of these techniques with regard to test accuracy and reproducibility have not been fully defined. We developed a targeted enrichment and next-generation sequencing approach for genetic diagnostic testing of patients with inherited eye disorders, including inherited retinal degenerations, optic atrophy, and glaucoma. In preparation for providing this genetic eye disease (GEDi) test on a CLIA-certified basis, we performed experiments to measure the sensitivity, specificity, and reproducibility, as well as the clinical sensitivity, of the test. The GEDi test is highly reproducible and accurate, with sensitivity and specificity of 97.9 and 100%, respectively, for single-nucleotide variant detection. The sensitivity for variant detection was notably better than the 88.3% achieved by whole-exome sequencing using the same metrics, because of better coverage of targeted genes in the GEDi test as compared with a commercially available exome capture set. Prospective testing of 192 patients with inherited retinal degenerations indicated that the clinical sensitivity of the GEDi test is high, with a diagnostic rate of 51%. Based on quantified performance metrics, the data suggest that selective targeted enrichment is preferable to whole-exome sequencing for genetic diagnostic testing.

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Author and article information

Journal

Journal ID (nlm-ta): Genet Med

Journal ID (iso-abbrev): Genet. Med

Title: Genetics in Medicine

Publisher: Nature Publishing Group

ISSN (Print): 1098-3600

ISSN (Electronic): 1530-0366

Publication date (Print): April 2018

Publication date (Electronic): 03 August 2017

Volume: 20

Issue: 4

Pages: 435-443

Affiliations

[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

Author notes

[* ]( crm@ 123456sickkids.ca )

Article

Publisher Item ID: gim2017119

DOI: 10.1038/gim.2017.119

PMC ID: 5895460

PubMed ID: 28771251

SO-VID: aca442e2-5b2d-403e-b0f3-4229b67db9e7

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This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/

History

Date received : 18 March 2017

Date accepted : 09 June 2017

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

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Abstract

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Most cited references 16

Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation.

Whole-genome sequencing expands diagnostic utility and improves clinical management in paediatric medicine

Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible, and more sensitive for variant detection, than exome sequencing.

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