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New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements.

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cam.issuedOnline2021-11-08
dc.contributor.authorRomanelli Tavares, Vanessa Luiza
dc.contributor.authorGuimarães-Ramos, Sofia Ligia
dc.contributor.authorZhou, Yan
dc.contributor.authorMasotti, Cibele
dc.contributor.authorEzquina, Suzana
dc.contributor.authorMoreira, Danielle de Paula
dc.contributor.authorBuermans, Henk
dc.contributor.authorFreitas, Renato S
dc.contributor.authorDen Dunnen, Johan T
dc.contributor.authorTwigg, Stephen RF
dc.contributor.authorPassos-Bueno, Maria Rita
dc.contributor.orcidRomanelli Tavares, Vanessa Luiza [0000-0002-8845-5952]
dc.contributor.orcidTwigg, Stephen RF [0000-0001-5024-049X]
dc.contributor.orcidPassos-Bueno, Maria Rita [0000-0002-9248-3008]
dc.date.accessioned2021-11-12T16:47:37Z
dc.date.available2021-11-12T16:47:37Z
dc.date.issued2021-11-08
dc.date.submitted2021-03-03
dc.date.updated2021-11-12T16:47:36Z
dc.descriptionFunder: VTCT Foundation Fellowship
dc.description.abstractBACKGROUND: 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.
dc.identifier.doi10.17863/CAM.78030
dc.identifier.eissn1468-6244
dc.identifier.issn0022-2593
dc.identifier.otherjmedgenet-2021-107825
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/330586
dc.languageen
dc.publisherBMJ
dc.rightsEmbargo: ends 2021-11-07
dc.subjectNovel disease loci
dc.subject1506
dc.subjectgene duplication
dc.subjectcongenital
dc.subjecthereditary
dc.subjectand neonatal diseases and abnormalities
dc.subjectgenetic variation
dc.subjecthigh-throughput nucleotide sequencing
dc.subjecthuman genetics
dc.titleNew locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements.
dc.typeArticle
dcterms.dateAccepted2021-09-29
prism.publicationNameJ Med Genet
pubs.funder-project-idCEPID/FAPESP (2013/08028-1)
pubs.funder-project-idMRC through the WIMM Strategic Alliance (G0902418, MC_UU_12025)
pubs.funder-project-idProject Grant (093329)
pubs.funder-project-idAction Medical Research (GN2483)
pubs.funder-project-idWellcome (102731)
pubs.funder-project-idCNPq (303712/2016-3)
rioxxterms.licenseref.startdate2021-11-07
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0/
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1136/jmedgenet-2021-107825

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