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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Acknowledgements
We thank the patients and families whose participation made this project possible, the many healthcare providers involved in their care, and the staff at The Centre for Applied Genomics. We also thank the Genome Aggregation Database (gnomAD) and the groups that provided exome and genome variant data to this resource. A full list of contributing groups can be found at http://gnomad.broadinstitute.org/about. This study was funded by the Centre for Genetic Medicine, The Centre for Applied Genomics, The Hospital for Sick Children, Genome Canada, and the University of Toronto McLaughlin Centre. R.D.C. holds the Women’s Auxiliary Chair in Clinical and Metabolic Genetics at The Hospital for Sick Children. S.W.S. holds the Canadian Institutes for Health Research (CIHR) GlaxoSmithKline Endowed Chair in Genome Sciences at The Hospital for Sick Children and the University of Toronto.
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Costain, G., Jobling, R., Walker, S. et al. Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing. Eur J Hum Genet 26, 740–744 (2018). https://doi.org/10.1038/s41431-018-0114-6
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DOI: https://doi.org/10.1038/s41431-018-0114-6
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