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Open Access 01-12-2024 | Research

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Authors: Marketa Wayhelova, Vladimira Vallova, Petr Broz, Aneta Mikulasova, Jan Smetana, Hana Dynkova Filkova, Dominika Machackova, Kristina Handzusova, Renata Gaillyova, Petr Kuglik

Published in: Orphanet Journal of Rare Diseases | Issue 1/2024

Abstract

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.

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Title: Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders
Authors: Marketa Wayhelova
Vladimira Vallova
Petr Broz
Aneta Mikulasova
Jan Smetana
Hana Dynkova Filkova
Dominika Machackova
Kristina Handzusova
Renata Gaillyova
Petr Kuglik
Publication date: 01-12-2024
Publisher: BioMed Central
Published in: Orphanet Journal of Rare Diseases / Issue 1/2024
Electronic ISSN: 1750-1172
DOI: https://doi.org/10.1186/s13023-024-03056-6

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

Abstract

Background

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Results

Conclusion

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