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  • Enhancing clinical decision-making for CNVs of uncertain significance in neurodevelopmental disorders: the relevance (or uselessness) of scoring and segregating

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Copy-number variation
Short report
Enhancing clinical decision-making for CNVs of uncertain significance in neurodevelopmental disorders: the relevance (or uselessness) of scoring and segregating
  1. Jorge Diogo Da Silva1,2,3,4,5,6,
  2. Nuno Maia4,5,7,
  3. Paula Jorge4,5,8,
  4. Vanessa Sousa4,5,8,
  5. Nataliya Tkachenko1,4,5,
  6. Ana Rita Soares1,4,5,6
  1. 1 Medical Genetics Centre Dr. Jacinto Magalhães, Santo António University Hospital Center, Porto, Portugal
  2. 2 Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal
  3. 3 ICVS/3B’s - PT Government Associate Laboratory, Braga/Guimarães, Portugal
  4. 4 UMIB - Unit for Multidisciplinary Research in Biomedicine, Institute of Biomedical Sciences Abel Salazar, University of Porto, Porto, Portugal
  5. 5 ITR-Laboratory for Integrative and Translational Research in Population Health, Porto, Portugal
  6. 6 Genetyca-ICM, Atrys, Porto, Portugal
  7. 7 School of Health, Polytechnic of Porto, Porto, Portugal
  8. 8 Cytogenetics Laboratory, Department of Microscopy, ICBAS - Institute of Biomedical Sciences Abel Salazar, UPorto - University of Porto, Porto, Portugal
  1. Correspondence to Prof. Jorge Diogo Da Silva; jorge.dcr.silva{at}gmail.com

Abstract

Background Clinicians often deal with copy-number variants of unknown significance (CNVUS) when managing neurodevelopmental disorders (NDDs). Variant classification is often complemented with textual comments, while the American College of Medical Genetics and Genomics (ACMG)/Clinical Genome Resource (ClinGen) numerical scores are rarely reported. Our aim was to determine if the application of ACMG/ClinGen scoring and inheritance/segregation studies are relevant for the reclassification of CNVUS.

Methods We retrieved 167 CNVUS (112 duplications, 55 heterozygous deletions) from test reports of 141 patients with NDD in a 5-year period. None of those testing reports included ACMG/ClinGen scoring information for the CNVUS. One clinical and one laboratorial geneticist independently applied the ACMG/ClinGen scoring system for CNVs. Final scores/categories were assessed for potential modification when adding inheritance/segregation criteria.

Results 138 (83%) of the CNVUS retained the VUS classification, 14 (8%) changed to benign and 15 (9%) to (likely) pathogenic. Variants deemed benign (11 duplications, 3 deletions) mostly overlapped with ClinGen-established benign regions or were common in the general population; variants deemed (likely) pathogenic (all deletions) were either associated with unrelated autosomal recessive/later-onset autosomal dominant (AD) conditions, or with an AD NDD phenotype in a single case. Inheritance studies were available for 20 (12%) variants (17 inherited, 3 de novo), and none led to a change in classification. A simulation showed that adding inheritance information would also not change the classification of any other variant.

Conclusion Application of the ACMG/ClinGen scoring system led by itself to reclassification of 17% of VUS, despite a very low increase in diagnostic yield (1/141, 0.7%). Additionally, segregation/inheritance studies in CNVUS were mostly irrelevant in most NDD cases, challenging their routine broad application in clinical practice.

  • Genetic Variation
  • Genetics, Medical
  • Human Genetics

https://doi.org/10.1136/jmg-2024-110144

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    Footnotes

    • JDDS and NM are joint first authors.

    • Contributors Conceptualisation: JDDS, NT, ARS. Formal analysis: JDDS, NM, ARS. Investigation: JDDS, NM, PJ, VS, NT, ARS. Supervision: ARS. Visualization: JDDS, NM. Writing – original draft: JDDS. Writing – review and editing: JDDS, NM, PJ, VS, NT, ARS. Guarantor: PJ.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.