The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model

Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested—whole blood, dermal fibroblasts or saliva—but is on...

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Autores principales:	Katherine C. MacKenzie, Rhiana Garritsen, Rajendra K. Chauhan, Yunia Sribudiani, Bianca M. de Graaf, Tim Rugenbrink, Rutger Brouwer, Wilfred F. J. van Ijcken, Ivo de Blaauw, Alice S. Brooks, Cornelius E. J. Sloots, Conny J. H. M. Meeuwsen, René M. Wijnen, Donald F. Newgreen, Alan J. Burns, Robert M. W. Hofstra, Maria M. Alves, Erwin Brosens
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	Enteric Nervous System somatic mutation Hirschsprung disease missing heritability gastrointestinal disease motility disorder Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/f7f6764065824070b5f3079e8362a7e4
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spelling	oai:doaj.org-article:f7f6764065824070b5f3079e8362a7e42021-11-25T17:55:39ZThe Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model10.3390/ijms2222123541422-00671661-6596https://doaj.org/article/f7f6764065824070b5f3079e8362a7e42021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/22/12354https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested—whole blood, dermal fibroblasts or saliva—but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to ‘missing heritability’ in developmental defects.Katherine C. MacKenzieRhiana GarritsenRajendra K. ChauhanYunia SribudianiBianca M. de GraafTim RugenbrinkRutger BrouwerWilfred F. J. van IjckenIvo de BlaauwAlice S. BrooksCornelius E. J. SlootsConny J. H. M. MeeuwsenRené M. WijnenDonald F. NewgreenAlan J. BurnsRobert M. W. HofstraMaria M. AlvesErwin BrosensMDPI AGarticleEnteric Nervous Systemsomatic mutationHirschsprung diseasemissing heritabilitygastrointestinal diseasemotility disorderBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 12354, p 12354 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Enteric Nervous System somatic mutation Hirschsprung disease missing heritability gastrointestinal disease motility disorder Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	Enteric Nervous System somatic mutation Hirschsprung disease missing heritability gastrointestinal disease motility disorder Biology (General) QH301-705.5 Chemistry QD1-999 Katherine C. MacKenzie Rhiana Garritsen Rajendra K. Chauhan Yunia Sribudiani Bianca M. de Graaf Tim Rugenbrink Rutger Brouwer Wilfred F. J. van Ijcken Ivo de Blaauw Alice S. Brooks Cornelius E. J. Sloots Conny J. H. M. Meeuwsen René M. Wijnen Donald F. Newgreen Alan J. Burns Robert M. W. Hofstra Maria M. Alves Erwin Brosens The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
description	Patients with Hirschsprung disease (HSCR) do not always receive a genetic diagnosis after routine screening in clinical practice. One of the reasons for this could be that the causal mutation is not present in the cell types that are usually tested—whole blood, dermal fibroblasts or saliva—but is only in the affected tissue. Such mutations are called somatic, and can occur in a given cell at any stage of development after conception. They will then be present in all subsequent daughter cells. Here, we investigated the presence of somatic mutations in HSCR patients. For this, whole-exome sequencing and copy number analysis were performed in DNA isolated from purified enteric neural crest cells (ENCCs) and blood or fibroblasts of the same patient. Variants identified were subsequently validated by Sanger sequencing. Several somatic variants were identified in all patients, but causative mutations for HSCR were not specifically identified in the ENCCs of these patients. Larger copy number variants were also not found to be specific to ENCCs. Therefore, we believe that somatic mutations are unlikely to be identified, if causative for HSCR. Here, we postulate various modes of development following the occurrence of a somatic mutation, to describe the challenges in detecting such mutations, and hypothesize how somatic mutations may contribute to ‘missing heritability’ in developmental defects.
format	article
author	Katherine C. MacKenzie Rhiana Garritsen Rajendra K. Chauhan Yunia Sribudiani Bianca M. de Graaf Tim Rugenbrink Rutger Brouwer Wilfred F. J. van Ijcken Ivo de Blaauw Alice S. Brooks Cornelius E. J. Sloots Conny J. H. M. Meeuwsen René M. Wijnen Donald F. Newgreen Alan J. Burns Robert M. W. Hofstra Maria M. Alves Erwin Brosens
author_facet	Katherine C. MacKenzie Rhiana Garritsen Rajendra K. Chauhan Yunia Sribudiani Bianca M. de Graaf Tim Rugenbrink Rutger Brouwer Wilfred F. J. van Ijcken Ivo de Blaauw Alice S. Brooks Cornelius E. J. Sloots Conny J. H. M. Meeuwsen René M. Wijnen Donald F. Newgreen Alan J. Burns Robert M. W. Hofstra Maria M. Alves Erwin Brosens
author_sort	Katherine C. MacKenzie
title	The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
title_short	The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
title_full	The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
title_fullStr	The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
title_full_unstemmed	The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model
title_sort	somatic mutation paradigm in congenital malformations: hirschsprung disease as a model
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/f7f6764065824070b5f3079e8362a7e4
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The Somatic Mutation Paradigm in Congenital Malformations: Hirschsprung Disease as a Model

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