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Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Lookup NU author(s): Dr Aneta Mikulasova

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

© The Author(s) 2024. Background: Neurodevelopmental disorders (NDDs) and/or associated multiple congenital abnormalities (MCAs) represent a genetically heterogeneous group of conditions with an adverse prognosis for the quality of intellectual and social abilities and common daily functioning. The rapid development of exome sequencing (ES) techniques, together with trio-based analysis, nowadays leads to up to 50% diagnostic yield. Therefore, it is considered as the state-of-the-art approach in these diagnoses. Results: In our study, we present the results of ES in a cohort of 85 families with 90 children with severe NDDs and MCAs. The interconnection of the in-house bioinformatic pipeline and a unique algorithm for variant prioritization resulted in a diagnostic yield of up to 48.9% (44/90), including rare and novel causative variants (41/90) and intragenic copy-number variations (CNVs) (3/90). Of the total number of 47 causative variants, 53.2% (25/47) were novel, highlighting the clinical benefit of ES for unexplained NDDs. Moreover, trio-based ES was verified as a reliable tool for the detection of rare CNVs, ranging from intragenic exon deletions (GRIN2A, ZC4H2 genes) to a 6-Mb duplication. The functional analysis using PANTHER Gene Ontology confirmed the involvement of genes with causative variants in a wide spectrum of developmental processes and molecular pathways, which form essential structural and functional components of the central nervous system. Conclusion: Taken together, we present one of the first ES studies of this scale from the central European region. Based on the high diagnostic yield for paediatric NDDs in this study, 48.9%, we confirm trio-based ES as an effective and reliable first-tier diagnostic test in the genetic evaluation of children with NDDs.


Publication metadata

Author(s): Wayhelova M, Vallova V, Broz P, Mikulasova A, Smetana J, Dynkova Filkova H, Machackova D, Handzusova K, Gaillyova R, Kuglik P

Publication type: Article

Publication status: Published

Journal: Orphanet Journal of Rare Diseases

Year: 2024

Volume: 19

Online publication date: 06/02/2024

Acceptance date: 29/01/2024

Date deposited: 20/02/2024

ISSN (electronic): 1750-1172

Publisher: BioMed Central Ltd

URL: https://doi.org/10.1186/s13023-024-03056-6

DOI: 10.1186/s13023-024-03056-6

Data Access Statement: The datasets generated and analysed during the study are not publicly available to protect personal data privacy but are available from the corresponding author on reasonable request. All novel causative and candidate sequence variants were submitted to the Global Variome shared LOVD v.3.0—Leiden Open Variation Database (https://www.lovd.nl/) (see Additional file 5 for their IDs). The detailed outputs from the STRING Interaction Network and PANTHER™ Classification system (Functional analysis and Overrepresentation analysis) for interaction networks including candidate genes GRIN3B and ASAP1 are available on the Figshare Online Repository, doi: https://doi.org/10.6084/m9.figshare.22300378.

PubMed id: 38321498


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Funding

Funder referenceFunder name
Ministry of Health of the Czech Republic
NU20-07-00145

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