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Eur J Hum Genet. 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.

Author information

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.

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.

PMID:
29453418
PMCID:
PMC5945683
[Available on 2019-05-01]
DOI:
10.1038/s41431-018-0114-6
[Indexed for MEDLINE]

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