Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Tooze, Rebecca S., Calpena, Eduardo, Weber, Astrid, Wilson, Louise C., Twigg, Stephen R. F., Wilkie, Andrew O. M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048212/
https://www.ncbi.nlm.nih.gov/pubmed/36980886
http://dx.doi.org/10.3390/genes14030615
_version_ 1785014127233597440
author Tooze, Rebecca S.
Calpena, Eduardo
Weber, Astrid
Wilson, Louise C.
Twigg, Stephen R. F.
Wilkie, Andrew O. M.
author_facet Tooze, Rebecca S.
Calpena, Eduardo
Weber, Astrid
Wilson, Louise C.
Twigg, Stephen R. F.
Wilkie, Andrew O. M.
author_sort Tooze, Rebecca S.
collection PubMed
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.
format Online
Article
Text
id pubmed-10048212
institution National Center for Biotechnology Information
language English
publishDate 2023
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-100482122023-03-29 Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic Gene Panels Tooze, Rebecca S. Calpena, Eduardo Weber, Astrid Wilson, Louise C. Twigg, Stephen R. F. Wilkie, Andrew O. M. Genes (Basel) Article 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. MDPI 2023-02-28 /pmc/articles/PMC10048212/ /pubmed/36980886 http://dx.doi.org/10.3390/genes14030615 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Tooze, Rebecca S.
Calpena, Eduardo
Weber, Astrid
Wilson, Louise C.
Twigg, Stephen R. F.
Wilkie, Andrew O. M.
Review of Recurrently Mutated Genes in Craniosynostosis Supports Expansion of Diagnostic 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 Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10048212/
https://www.ncbi.nlm.nih.gov/pubmed/36980886
http://dx.doi.org/10.3390/genes14030615
work_keys_str_mv AT toozerebeccas reviewofrecurrentlymutatedgenesincraniosynostosissupportsexpansionofdiagnosticgenepanels
AT calpenaeduardo reviewofrecurrentlymutatedgenesincraniosynostosissupportsexpansionofdiagnosticgenepanels
AT weberastrid reviewofrecurrentlymutatedgenesincraniosynostosissupportsexpansionofdiagnosticgenepanels
AT wilsonlouisec reviewofrecurrentlymutatedgenesincraniosynostosissupportsexpansionofdiagnosticgenepanels
AT twiggstephenrf reviewofrecurrentlymutatedgenesincraniosynostosissupportsexpansionofdiagnosticgenepanels
AT wilkieandrewom reviewofrecurrentlymutatedgenesincraniosynostosissupportsexpansionofdiagnosticgenepanels