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The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies


Grether, Anna; Ivanovski, Ivan; Russo, Martina; Begemann, Anaïs; Steindl, Katharina; Abela, Lucia; Papik, Michael; Zweier, Markus; Oneda, Beatrice; Joset, Pascal; Rauch, Anita (2023). The current benefit of genome sequencing compared to exome sequencing in patients with developmental or epileptic encephalopathies. Molecular Genetics & Genomic Medicine, 11(5):e2148.

Abstract

Background: As the technology of next generation sequencing rapidly develops and costs are constantly reduced, the clinical availability of whole genome sequencing (WGS) increases. Thereby, it remains unclear what exact advantage WGS offers in comparison to whole exome sequencing (WES) for the diagnosis of genetic diseases using current technologies.

Methods: Trio-WGS was conducted for 20 patients with developmental or epileptic encephalopathies who remained undiagnosed after WES and chromosomal microarray analysis.

Results: A diagnosis was reached for four patients (20%). However, retrospectively all pathogenic variants could have been detected in a WES analysis conducted with today's methods and knowledge.

Conclusion: The additional diagnostic yield of WGS versus WES is currently largely explained by new scientific insights and the general technological progress. Nevertheless, it is noteworthy that whole genome sequencing has greater potential for the analysis of small copy number and copy number neutral variants not seen with WES as well as variants in noncoding regions, especially as potentially more knowledge of the function of noncoding regions arises. We, therefore, conclude that even though today the added value of WGS versus WES seems to be limited, it may increase substantially in the future.

Abstract

Background: As the technology of next generation sequencing rapidly develops and costs are constantly reduced, the clinical availability of whole genome sequencing (WGS) increases. Thereby, it remains unclear what exact advantage WGS offers in comparison to whole exome sequencing (WES) for the diagnosis of genetic diseases using current technologies.

Methods: Trio-WGS was conducted for 20 patients with developmental or epileptic encephalopathies who remained undiagnosed after WES and chromosomal microarray analysis.

Results: A diagnosis was reached for four patients (20%). However, retrospectively all pathogenic variants could have been detected in a WES analysis conducted with today's methods and knowledge.

Conclusion: The additional diagnostic yield of WGS versus WES is currently largely explained by new scientific insights and the general technological progress. Nevertheless, it is noteworthy that whole genome sequencing has greater potential for the analysis of small copy number and copy number neutral variants not seen with WES as well as variants in noncoding regions, especially as potentially more knowledge of the function of noncoding regions arises. We, therefore, conclude that even though today the added value of WGS versus WES seems to be limited, it may increase substantially in the future.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > Institute of Medical Genetics
08 Research Priority Programs > Adaptive Brain Circuits in Development and Learning (AdaBD)
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Uncontrolled Keywords:Genetics (clinical), Genetics, Molecular Biology, diagnostic yield, epileptic encephalopathy, whole exome sequencing, whole genome sequencing
Language:English
Date:1 May 2023
Deposited On:15 Feb 2023 14:41
Last Modified:28 Apr 2024 01:50
Publisher:Wiley Open Access
ISSN:2324-9269
Additional Information:ETHICAL COMPLIANCE The study was approved by the ethical committee of the Kanton of Zurich (StV 11/09 and PB_2016-02520) and informed consent of the participating individuals or their legal guardians was obtained. DATA AVAILABILITY STATEMENT Raw data or samples are not publically available due to consent restrictions.
OA Status:Gold
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1002/mgg3.2148
Related URLs:https://doi.org/10.1002/mgg3.2199
PubMed ID:36785910
Project Information:
  • : FunderSNSF
  • : Grant ID179547
  • : Project TitleGenetic causes and molecular mechanisms in severe intellectual disability
  • : Project Websitehttps://data.snf.ch/grants/grant/179547
  • : FunderUZH
  • : Grant IDCRPP praeclare
  • : Project TitleClarification of genetic variants for personalized prenatal and reproductive medicine
  • : Project Websitehttps://www.praeclare.uzh.ch/
  • : FunderUZH
  • : Grant IDURPP AdaBD
  • : Project TitleAdaptive Brain Circuits in Development and Learning (AdaBD)
  • : Project Websitehttps://www.adabd.uzh.ch/
  • : FunderUZH
  • : Grant IDURPP ITINERARE
  • : Project TitleInnovative Therapies in Rare Diseases
  • : Project Websitehttps://www.itinerare.uzh.ch/
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)