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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...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2022
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.
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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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