Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels
Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a l...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2023-02-01
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| Series: | Genes |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2073-4425/14/3/615 |
| _version_ | 1797611550064771072 |
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| author | Rebecca S. Tooze Eduardo Calpena Astrid Weber Louise C. Wilson Stephen R. F. Twigg Andrew O. M. Wilkie |
| author_facet | Rebecca S. Tooze Eduardo Calpena Astrid Weber Louise C. Wilson Stephen R. F. Twigg Andrew O. M. Wilkie |
| author_sort | Rebecca S. Tooze |
| collection | DOAJ |
| description | Craniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms of craniosynostosis. |
| first_indexed | 2024-03-11T06:30:15Z |
| format | Article |
| id | doaj.art-a314a6c6bc1c4e0eac25a2b05c7cc84a |
| institution | Directory Open Access Journal |
| issn | 2073-4425 |
| language | English |
| last_indexed | 2024-03-11T06:30:15Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Genes |
| spelling | doaj.art-a314a6c6bc1c4e0eac25a2b05c7cc84a2023-11-17T11:17:02ZengMDPI AGGenes2073-44252023-02-0114361510.3390/genes14030615Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene PanelsRebecca S. Tooze0Eduardo Calpena1Astrid Weber2Louise C. Wilson3Stephen R. F. Twigg4Andrew O. M. Wilkie5Clinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKLiverpool Centre for Genomic Medicine, Liverpool Women’s NHS Foundation Trust, Liverpool L8 7SS, UKNorth East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London WC1N 3JH, UKClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKClinical Genetics Group, MRC Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UKCraniosynostosis, the premature fusion of the cranial sutures, affects ~1 in 2000 children. Although many patients with a genetically determined cause harbor a variant in one of just seven genes or have a chromosomal abnormality, over 60 genes are known to be recurrently mutated, thus comprising a long tail of rarer diagnoses. Genome sequencing for the diagnosis of rare diseases is increasingly used in clinical settings, but analysis of the data is labor intensive and involves a trade-off between achieving high sensitivity or high precision. PanelApp, a crowd-sourced disease-focused set of gene panels, was designed to enable prioritization of variants in known disease genes for a given pathology, allowing enhanced identification of true-positives. For heterogeneous disorders like craniosynostosis, these panels must be regularly updated to ensure that diagnoses are not being missed. We provide a systematic review of genetic literature on craniosynostosis over the last 5 years, including additional results from resequencing a 42-gene panel in 617 affected individuals. We identify 16 genes (representing a 25% uplift) that should be added to the list of bona fide craniosynostosis disease genes and discuss the insights that these new genes provide into pathophysiological mechanisms of craniosynostosis.https://www.mdpi.com/2073-4425/14/3/615craniosynostosisPanelAppexome/genome sequencinggene-panels |
| spellingShingle | Rebecca S. Tooze Eduardo Calpena Astrid Weber Louise C. Wilson Stephen R. F. Twigg Andrew O. M. Wilkie Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels Genes craniosynostosis PanelApp exome/genome sequencing gene-panels |
| title | Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels |
| title_full | Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels |
| title_fullStr | Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels |
| title_full_unstemmed | Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels |
| title_short | Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels |
| title_sort | review of recurrently mutated genes in craniosynostosis supports expansion of diagnostic gene panels |
| topic | craniosynostosis PanelApp exome/genome sequencing gene-panels |
| url | https://www.mdpi.com/2073-4425/14/3/615 |
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