Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders
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 developm...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Orphanet Journal of Rare Diseases |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s13023-024-03056-6 |
| _version_ | 1797273236503789568 |
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| author | Marketa Wayhelova Vladimira Vallova Petr Broz Aneta Mikulasova Jan Smetana Hana Dynkova Filkova Dominika Machackova Kristina Handzusova Renata Gaillyova Petr Kuglik |
| author_facet | Marketa Wayhelova Vladimira Vallova Petr Broz Aneta Mikulasova Jan Smetana Hana Dynkova Filkova Dominika Machackova Kristina Handzusova Renata Gaillyova Petr Kuglik |
| author_sort | Marketa Wayhelova |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T14:41:35Z |
| format | Article |
| id | doaj.art-46268ac87d8b4810be2aceadfdb01208 |
| institution | Directory Open Access Journal |
| issn | 1750-1172 |
| language | English |
| last_indexed | 2024-03-07T14:41:35Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Orphanet Journal of Rare Diseases |
| spelling | doaj.art-46268ac87d8b4810be2aceadfdb012082024-03-05T20:20:16ZengBMCOrphanet Journal of Rare Diseases1750-11722024-02-0119111210.1186/s13023-024-03056-6Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disordersMarketa Wayhelova0Vladimira Vallova1Petr Broz2Aneta Mikulasova3Jan Smetana4Hana Dynkova Filkova5Dominika Machackova6Kristina Handzusova7Renata Gaillyova8Petr Kuglik9Department of Experimental Biology, Faculty of Science, Masaryk UniversityDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityBiosciences Institute, Faculty of Medical Sciences, Newcastle UniversityDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityCentre of Molecular Biology and Genetics, University Hospital BrnoDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityDepartment of Medical Genetics and Genomics, University Hospital BrnoDepartment of Experimental Biology, Faculty of Science, Masaryk UniversityAbstract 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.https://doi.org/10.1186/s13023-024-03056-6Exome sequencingNeurodevelopmental disordersSequence variantCopy-number variation |
| spellingShingle | Marketa Wayhelova Vladimira Vallova Petr Broz Aneta Mikulasova Jan Smetana Hana Dynkova Filkova Dominika Machackova Kristina Handzusova Renata Gaillyova Petr Kuglik Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders Orphanet Journal of Rare Diseases Exome sequencing Neurodevelopmental disorders Sequence variant Copy-number variation |
| title | Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders |
| title_full | Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders |
| title_fullStr | Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders |
| title_full_unstemmed | Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders |
| title_short | Exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders |
| title_sort | exome sequencing improves the molecular diagnostics of paediatric unexplained neurodevelopmental disorders |
| topic | Exome sequencing Neurodevelopmental disorders Sequence variant Copy-number variation |
| url | https://doi.org/10.1186/s13023-024-03056-6 |
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