Journal
GENETICS IN MEDICINE
Volume 20, Issue 4, Pages 435-443Publisher
ELSEVIER SCIENCE INC
DOI: 10.1038/gim.2017.119
Keywords
copy number variation; next-generation sequencing; noncoding; diagnostics; whole-genome sequencing
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Funding
- Centre for Genetic Medicine
- Centre for Applied Genomics
- Hospital for Sick Children
- University of Toronto McLaughlin Centre
- CREMS Research Scholarship from the Faculty of Medicine
- McLaughlin Centre at the University of Toronto
- Canadian Institutes for Health Research (CIHR) GlaxoSmithKline Endowed Chair in Genome Sciences at The Hospital for Sick Children
- University of Toronto
- Genome Canada
- Women's Auxiliary Chair in Clinical and Metabolic Genetics at The Hospital for Sick Children
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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.& para;& para;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.& para;& para;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 x +/- 8 x (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.& para;& para;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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