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New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements
BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411924/ https://www.ncbi.nlm.nih.gov/pubmed/34750192 http://dx.doi.org/10.1136/jmedgenet-2021-107825 |
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author | Romanelli Tavares, Vanessa Luiza Guimarães-Ramos, Sofia Ligia Zhou, Yan Masotti, Cibele Ezquina, Suzana Moreira, Danielle de Paula Buermans, Henk Freitas, Renato S Den Dunnen, Johan T Twigg, Stephen R F Passos-Bueno, Maria Rita |
author_facet | Romanelli Tavares, Vanessa Luiza Guimarães-Ramos, Sofia Ligia Zhou, Yan Masotti, Cibele Ezquina, Suzana Moreira, Danielle de Paula Buermans, Henk Freitas, Renato S Den Dunnen, Johan T Twigg, Stephen R F Passos-Bueno, Maria Rita |
author_sort | Romanelli Tavares, Vanessa Luiza |
collection | PubMed |
description | BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family. METHODS: We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells. RESULTS: This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells. CONCLUSION: Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype. |
format | Online Article Text |
id | pubmed-9411924 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-94119242022-09-12 New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements Romanelli Tavares, Vanessa Luiza Guimarães-Ramos, Sofia Ligia Zhou, Yan Masotti, Cibele Ezquina, Suzana Moreira, Danielle de Paula Buermans, Henk Freitas, Renato S Den Dunnen, Johan T Twigg, Stephen R F Passos-Bueno, Maria Rita J Med Genet Novel Disease Loci BACKGROUND: Auriculocondylar syndrome (ARCND) is a rare genetic disease that affects structures derived from the first and second pharyngeal arches, mainly resulting in micrognathia and auricular malformations. To date, pathogenic variants have been identified in three genes involved in the EDN1-DLX5/6 pathway (PLCB4, GNAI3 and EDN1) and some cases remain unsolved. Here we studied a large unsolved four-generation family. METHODS: We performed linkage analysis, resequencing and Capture-C to investigate the causative variant of this family. To test the pathogenicity of the CNV found, we modelled the disease in patient craniofacial progenitor cells, including induced pluripotent cell (iPSC)-derived neural crest and mesenchymal cells. RESULTS: This study highlights a fourth locus causative of ARCND, represented by a tandem duplication of 430 kb in a candidate region on chromosome 7 defined by linkage analysis. This duplication segregates with the disease in the family (LOD score=2.88) and includes HDAC9, which is located over 200 kb telomeric to the top candidate gene TWIST1. Notably, Capture-C analysis revealed multiple cis interactions between the TWIST1 promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of HDAC9 and its neighbouring gene, TWIST1, in neural crest cells. We also identified decreased migration of iPSC-derived neural crest cells together with dysregulation of osteogenic differentiation in iPSC-affected mesenchymal stem cells. CONCLUSION: Our findings support the hypothesis that the 430 kb duplication is causative of the ARCND phenotype in this family and that deregulation of TWIST1 expression during craniofacial development can contribute to the phenotype. BMJ Publishing Group 2022-09 2021-11-08 /pmc/articles/PMC9411924/ /pubmed/34750192 http://dx.doi.org/10.1136/jmedgenet-2021-107825 Text en © Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Novel Disease Loci Romanelli Tavares, Vanessa Luiza Guimarães-Ramos, Sofia Ligia Zhou, Yan Masotti, Cibele Ezquina, Suzana Moreira, Danielle de Paula Buermans, Henk Freitas, Renato S Den Dunnen, Johan T Twigg, Stephen R F Passos-Bueno, Maria Rita New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements |
title | New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements |
title_full | New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements |
title_fullStr | New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements |
title_full_unstemmed | New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements |
title_short | New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements |
title_sort | new locus underlying auriculocondylar syndrome (arcnd): 430 kb duplication involving twist1 regulatory elements |
topic | Novel Disease Loci |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9411924/ https://www.ncbi.nlm.nih.gov/pubmed/34750192 http://dx.doi.org/10.1136/jmedgenet-2021-107825 |
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