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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

2017; Elsevier BV; Volume: 20; Issue: 4 Linguagem: Inglês

10.1038/gim.2017.119

1530-0366

Anath C. Lionel, Gregory Costain, Nasim Monfared, Susan Walker, Miriam S. Reuter, S. Mohsen Hosseini, Bhooma Thiruvahindrapuram, Daniele Merico, Rebekah Jobling, Thomas Nalpathamkalam, Giovanna Pellecchia, Wilson W. L. Sung, Zhuozhi Wang, Peter Bikangaga, Cyrus Boelman, Melissa T. Carter, Dawn Cordeiro, Cheryl Cytrynbaum, Sharon Dell, Priya Dhir, James J. Dowling, Elise Héon, Stacy Hewson, Linda T. Hiraki, Michal Inbar‐Feigenberg, Regan Klatt, Jonathan B. Kronick, Ronald M. Laxer, Christoph Licht, H. Robson MacDonald, Saadet Mercimek‐Andrews, Roberto Mendoza‐Londono, Tino D. Piscione, Rayfel Schneider, Andreas Schulze, Earl D. Silverman, Komudi Siriwardena, O. Carter Snead, Neal Sondheimer, Joanne Sutherland, Ajoy Vincent, Jonathan D. Wasserman, Rosanna Weksberg, Cheryl Shuman, Chris Carew, Michael J. Szego, Robin Z. Hayeems, Raveen Basran, Dimitri J. Stavropoulos, Peter N. Ray, Sarah Bowdin, M. Stephen Meyn, Ronald D. Cohn, Stephen W. Scherer, Christian R. Marshall,

Genetics and Neurodevelopmental Disorders

PurposeGenetic 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.MethodsWe 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.ResultsWGS 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.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.