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Cited by 557Genomics and Rare DiseasesPrenatal Screening and DiagnosticsConnective tissue disorders research

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

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Lionel, Anath C., Costain, Gregory, Monfared, Nasim, Walker, Susan, Reuter, Miriam S., Hosseini, S. Mohsen, Thiruvahindrapuram, Bhooma, Merico, Daniele +47 more·2018·Genetics in Medicine
DOI 10.1038/gim.2017.119PMC PMC5895460
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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.

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  • NGS genetic testing, including gene panel testing, WES, or WGS, is the most successful approach for diagnosing rare diseases with the highest diagnostic yield.

    “NGS genetic testing, including gene panel testing, WES, or whole genome sequencing (WGS), is the most successful approach for diagnosing rare diseases with the highest diagnostic yield [7,37].”

    From Identification of a Novel Non-Canonical Splice-Site Variant in ABCD1 (2023) · cites this paper as [37]

    The Introduction says WES has increased diagnostic yield, and the Results report that WGS diagnosed 41% of this pediatric cohort versus 24% with conventional testing. The paper supports a diagnostic advantage for WGS, but not the broader claim that NGS testing—including gene panels, WES, and WGS collectively—is the highest-yield approach for rare diseases generally. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Lionel, A. C., Costain, G., Monfared, N., Walker, S., Reuter, M. S., Hosseini, S. M., Thiruvahindrapuram, B., Merico, D., Jobling, R., Nalpathamkalam, T., Pellecchia, G., Sung, W. W. L., Wang, Z., Bikangaga, P., Boelman, C., Carter, M. T., Cordeiro, D., Cytrynbaum, C., Dell, S. D., Dhir, P., Dowling, J. J., Heon, E., Hewson, S., Hiraki, L., Inbar-Feigenberg, M., Klatt, R., Kronick, J., Laxer, R. M., Licht, C., MacDonald, H., Mercimek-Andrews, S., Mendoza-Londono, R., Piscione, T., Schneider, R., Schulze, A., Silverman, E., Siriwardena, K., Snead, O. C., Sondheimer, N., Sutherland, J., Vincent, A., Wasserman, J. D., Weksberg, R., Shuman, C., Carew, C., Szego, M. J., Hayeems, R. Z., Basran, R., Stavropoulos, D. J., Ray, P. N., Bowdin, S., Meyn, M. S., Cohn, R. D., Scherer, S. W., & Marshall, C. R.
Affiliations
  • Hospital for Sick Children (CA)
  • BC Children's Hospital (CA)
  • Children's Hospital of Eastern Ontario (CA)
  • University of Toronto (CA)
  • University of Alberta (CA)
Corresponding author
Marshall, Christian R.
ORCID
Venue
Genetics in Medicine
Publisher
Elsevier BV
Published
2018-04
Volume
20
Issue
4
Pages
435-443
ISSN
1098-3600 (ISSN-L)
DOI
10.1038/gim.2017.119
PMC
PMC5895460
OpenAlex
W2745065704
Cited by
557
References
2
Citations by year
2026: 36 · 2025: 55 · 2024: 65 · 2023: 71 · 2022: 81 · 2021: 69 · 2020: 70 · 2019: 52 · 2018: 51 · 2017: 5 · 2013: 1
FWCI
32.31
Type
journal article
Language
en
Open access
Licence
Locations
  • Genetics in Medicine (publishedVersion, cc-by-nc-sa)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion, cc-by-nc-sa)
  • PubMed (publishedVersion)
Funders
  • GlaxoSmithKline
  • Genome Canada
  • University of Toronto
  • Hospital for Sick Children
  • Canadian Institutes of Health Research
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Prenatal Screening and Diagnostics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Connective tissue disorders research
Keywords
whole genome sequencing, diagnostic yield, pediatric genetic testing, chromosomal microarray analysis, structural variants, trios, UNC13A
MeSH terms
Whole Genome Sequencing, Exome Sequencing, Female, Genetic Testing, Humans, Male, Phenotype, Genetic Variation, Sequence Analysis, DNA, Computational Biology, Genetic Predisposition to Disease, Genetic Diseases, Inborn, Genetic Association Studies, DNA Copy Number Variations, Molecular Sequence Annotation, Exome

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