Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

doi:10.1038/s41431-018-0114-6

. 2018 May;26(5):740-744.

doi: 10.1038/s41431-018-0114-6. Epub 2018 Feb 16.

Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

Gregory Costain¹, Rebekah Jobling^{1

2}, Susan Walker^{3

4}, Miriam S Reuter^{3

4}, Meaghan Snell¹, Sarah Bowdin^{1

5

6}, Ronald D Cohn^{1

4

5

6}, Lucie Dupuis¹, Stacy Hewson¹, Saadet Mercimek-Andrews^{1

4

6}, Cheryl Shuman^{1

7}, Neal Sondheimer^{1

4

6}, Rosanna Weksberg^{1

4

6}, Grace Yoon^{1

6

8}, M Stephen Meyn^{1

5

6

7}, Dimitri J Stavropoulos^{2

9}, Stephen W Scherer^{3

4

5

7}, Roberto Mendoza-Londono^{1

5

6}, Christian R Marshall^{10

11

12

13}

Affiliations

¹ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
² Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁸ Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁰ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. crm@sickkids.ca.
¹¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada. crm@sickkids.ca.
¹² Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada. crm@sickkids.ca.
¹³ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. crm@sickkids.ca.

PMID: 29453418
PMCID: PMC5945683
DOI: 10.1038/s41431-018-0114-6

Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

Gregory Costain et al. Eur J Hum Genet. 2018 May.

. 2018 May;26(5):740-744.

doi: 10.1038/s41431-018-0114-6. Epub 2018 Feb 16.

Authors

Affiliations

¹ Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, ON, Canada.
² Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
³ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada.
⁴ Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, ON, Canada.
⁵ Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada.
⁶ Department of Paediatrics, University of Toronto, Toronto, ON, Canada.
⁷ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
⁸ Division of Neurology, The Hospital for Sick Children, Toronto, ON, Canada.
⁹ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
¹⁰ Genome Diagnostics, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, ON, Canada. crm@sickkids.ca.
¹¹ The Centre for Applied Genomics, The Hospital for Sick Children, Toronto, ON, Canada. crm@sickkids.ca.
¹² Centre for Genetic Medicine, The Hospital for Sick Children, Toronto, ON, Canada. crm@sickkids.ca.
¹³ Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. crm@sickkids.ca.

PMID: 29453418
PMCID: PMC5945683
DOI: 10.1038/s41431-018-0114-6

Abstract

Whole-genome sequencing (WGS) as a first-tier diagnostic test could transform medical genetic assessments, but there are limited data regarding its clinical use. We previously showed that WGS could feasibly be deployed as a single molecular test capable of a higher diagnostic rate than current practices, in a prospectively recruited cohort of 100 children meeting criteria for chromosomal microarray analysis. In this study, we report on the added diagnostic yield with re-annotation and reanalysis of these WGS data ~2 years later. Explanatory variants have been discovered in seven (10.9%) of 64 previously undiagnosed cases, in emerging disease genes like HMGA2. No new genetic diagnoses were made by any other method in the interval period as part of ongoing clinical care. The results increase the cumulative diagnostic yield of WGS in the study cohort to 41%. This represents a greater than 5-fold increase over the chromosomal microarrays, and a greater than 3-fold increase over all the clinical genetic testing ordered in practice. These findings highlight periodic reanalysis as yet another advantage of genomic sequencing in heterogeneous disorders. We recommend reanalysis of an individual's genome-wide sequencing data every 1-2 years until diagnosis, or sooner if their phenotype evolves.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

**Fig. 1**
Diagnostic yield in a prospective cohort study after systematic reanalysis of whole-genome sequencing data. Bar plot showing percentage of study participants (n = 100) with molecular diagnoses via chromosomal microarray analysis (CMA), all clinical genetic testing performed in this cohort (CMA+), and whole-genome sequencing (WGS). The CMA and CMA+ diagnostic yields are significantly different (p < 0.0001) from the WGS diagnostic yield using a chi-square proportion test. Lighter blue colouring represents the new diagnoses made upon reanalysis of the WGS data

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References

1. Stavropoulos DJ, Merico D, Jobling R, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012. doi: 10.1038/npjgenmed.2015.12. - DOI - PMC - PubMed
1. Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. E-published 2017 Aug 3. doi: 10.1038/gim.2017.119. - PMC - PubMed
1. Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7. doi: 10.1038/nature13394. - DOI - PubMed
1. Taylor JC, Martin HC, Lise S, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015;47:717–26. doi: 10.1038/ng.3304. - DOI - PMC - PubMed
1. Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3:377–87. doi: 10.1016/S2213-2600(15)00139-3. - DOI - PMC - PubMed

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[1] Stavropoulos DJ, Merico D, Jobling R, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012. doi: 10.1038/npjgenmed.2015.12. - DOI - PMC - PubMed

[2] Stavropoulos DJ, Merico D, Jobling R, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012. doi: 10.1038/npjgenmed.2015.12. - DOI - PMC - PubMed

[3] Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. E-published 2017 Aug 3. doi: 10.1038/gim.2017.119. - PMC - PubMed

[4] Lionel AC, Costain G, Monfared N, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. E-published 2017 Aug 3. doi: 10.1038/gim.2017.119. - PMC - PubMed

[5] Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7. doi: 10.1038/nature13394. - DOI - PubMed

[6] Gilissen C, Hehir-Kwa JY, Thung DT, et al. Genome sequencing identifies major causes of severe intellectual disability. Nature. 2014;511:344–7. doi: 10.1038/nature13394. - DOI - PubMed

[7] Taylor JC, Martin HC, Lise S, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015;47:717–26. doi: 10.1038/ng.3304. - DOI - PMC - PubMed

[8] Taylor JC, Martin HC, Lise S, et al. Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet. 2015;47:717–26. doi: 10.1038/ng.3304. - DOI - PMC - PubMed

[9] Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3:377–87. doi: 10.1016/S2213-2600(15)00139-3. - DOI - PMC - PubMed

[10] Willig LK, Petrikin JE, Smith LD, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3:377–87. doi: 10.1016/S2213-2600(15)00139-3. - DOI - PMC - PubMed

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Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

Affiliations

Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

Authors

Affiliations

Abstract

Conflict of interest statement

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