Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test

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 D Dell, Priya Dhir, James J Dowling, Elise Heon, Stacy Hewson, Linda Hiraki, Michal Inbar-Feigenberg, Regan Klatt, Jonathan Kronick, Ronald M Laxer, Christoph Licht, Heather MacDonald, Saadet Mercimek-Andrews, Roberto Mendoza-Londono, Tino Piscione, Rayfel Schneider, Andreas Schulze, Earl 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, 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 D Dell, Priya Dhir, James J Dowling, Elise Heon, Stacy Hewson, Linda Hiraki, Michal Inbar-Feigenberg, Regan Klatt, Jonathan Kronick, Ronald M Laxer, Christoph Licht, Heather MacDonald, Saadet Mercimek-Andrews, Roberto Mendoza-Londono, Tino Piscione, Rayfel Schneider, Andreas Schulze, Earl 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

Abstract

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.

Conflict of interest statement

The authors declare no conflict of interest.

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Source: PubMed

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