Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders

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Authors

WAYHELOVÁ Markéta VALLOVÁ Vladimíra BROŽ Petr MIKULASOVA Aneta SMETANA Jan DYNKOVA FILKOVA Hana MACHÁČKOVÁ Dominika HANDZUŠOVÁ Kristína GAILLYOVA Renata KUGLÍK Petr

Year of publication 2024
Type Article in Periodical
Magazine / Source Orphanet Journal of Rare Diseases
MU Faculty or unit

Faculty of Science

Citation
Web https://ojrd.biomedcentral.com/articles/10.1186/s13023-024-03056-6
Doi http://dx.doi.org/10.1186/s13023-024-03056-6
Keywords Exome sequencing; Neurodevelopmental disorders; Sequence variant; Copy-number variation
Attached files
Description 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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