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Cited by 97Genomics and Rare DiseasesGenetics and Neurodevelopmental DisordersGenomic variations and chromosomal abnormalities

The performance of genome sequencing as a first-tier test for neurodevelopmental disorders

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van der Sanden, Bart P. G. H., Schobers, Gaby, Corominas Galbany, Jordi, Koolen, David A., Sinnema, Margje, van Reeuwijk, Jeroen, Stumpel, Connie T. R. M., Kleefstra, Tjitske +18 more·2023·European Journal of Human Genetics
DOI 10.1038/s41431-022-01185-9PMC PMC9822884
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Abstract

Genome sequencing (GS) can identify novel diagnoses for patients who remain undiagnosed after routine diagnostic procedures. We tested whether GS is a better first-tier genetic diagnostic test than current standard of care (SOC) by assessing the technical and clinical validity of GS for patients with neurodevelopmental disorders (NDD). We performed both GS and exome sequencing in 150 consecutive NDD patient-parent trios. The primary outcome was diagnostic yield, calculated from disease-causing variants affecting exonic sequence of known NDD genes. GS (30%, n = 45) and SOC (28.7%, n = 43) had similar diagnostic yield. All 43 conclusive diagnoses obtained with SOC testing were also identified by GS. SOC, however, required integration of multiple test results to obtain these diagnoses. GS yielded two more conclusive diagnoses, and four more possible diagnoses than ES-based SOC (35 vs. 31). Interestingly, these six variants detected only by GS were copy number variants (CNVs). Our data demonstrate the technical and clinical validity of GS to serve as routine first-tier genetic test for patients with NDD. Although the additional diagnostic yield from GS is limited, GS comprehensively identified all variants in a single experiment, suggesting that GS constitutes a more efficient genetic diagnostic workflow.

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  • Among two nonsense variants and one frameshift variant, the recurrent variant p.Arg506Ter has been identified in three individuals.

    “Among two nonsense variants and one frameshift variant, the recurrent variant p.Arg506Ter has been identified in three individuals94–97.”

    From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [97]

    Table 2 in Results (SOC diagnostic yield; page unavailable) lists a de novo WASF1 p.(Arg506*) variant in one individual, supporting identification of the nonsense variant. It does not report that variant in three individuals or establish the claimed set of two nonsense variants and one frameshift variant. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
van der Sanden, B. P. G. H., Schobers, G., Corominas Galbany, J., Koolen, D. A., Sinnema, M., van Reeuwijk, J., Stumpel, C. T. R. M., Kleefstra, T., de Vries, B. B. A., Ruiterkamp-Versteeg, M., Leijsten, N., Kwint, M., Derks, R., Swinkels, H., den Ouden, A., Pfundt, R., Rinne, T., de Leeuw, N., Stegmann, A. P., Stevens, S. J., van den Wijngaard, A., Brunner, H. G., Yntema, H. G., Gilissen, C., Nelen, M. R., & Vissers, L. E. L. M.
Affiliations
  • Radboud University Nijmegen (NL)
  • Radboud University Medical Center (NL)
  • Maastricht University Medical Centre (NL)
Corresponding author
Vissers, Lisenka E. L. M.
ORCID
Venue
European Journal of Human Genetics
Publisher
Springer Science and Business Media LLC
Published
2022-09-16
Volume
31
Issue
1
Pages
81-88
ISSN
  • 1018-4813 (ISSN-L)
  • 1476-5438
DOI
10.1038/s41431-022-01185-9
PMC
PMC9822884
OpenAlex
W4296162939
Cited by
97
References
4
Citations by year
2026: 22 · 2025: 28 · 2024: 26 · 2023: 18 · 2022: 3
FWCI
11.56
Type
journal article
Language
en
Open access
Licence
Locations
  • European Journal of Human Genetics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Research Publications (Maastricht University) (publishedVersion, cc-by)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
  • Research Publications (Maastricht University) (submittedVersion, cc-by)
Funders
  • ZonMw (846002003, 015014066, 843002608)
  • EC | Horizon 2020 Framework Programme (779257)
  • Nederlandse Organisatie voor Wetenschappelijk Onderzoek (817-17-353)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
Keywords
genome sequencing, neurodevelopmental disorders, diagnostic yield, copy number variation, exome sequencing, standard of care comparison
MeSH terms
Exome Sequencing, Base Sequence, Chromosome Mapping, Genetic Testing, Humans, Neurodevelopmental Disorders

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