New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements.
Authors
Guimarães-Ramos, Sofia Ligia
Zhou, Yan
Masotti, Cibele
Ezquina, Suzana
Moreira, Danielle de Paula
Buermans, Henk
Freitas, Renato S
Den Dunnen, Johan T
Publication Date
2022-09Journal Title
J Med Genet
ISSN
0022-2593
Publisher
BMJ
Language
en
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Romanelli Tavares, V. L., Guimarães-Ramos, S. L., Zhou, Y., Masotti, C., Ezquina, S., Moreira, D. d. P., Buermans, H., et al. (2022). New locus underlying auriculocondylar syndrome (ARCND): 430 kb duplication involving TWIST1 regulatory elements.. J Med Genet https://doi.org/10.1136/jmedgenet-2021-107825
Description
Funder: VTCT Foundation Fellowship
Abstract
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.
Keywords
Novel disease loci, 1506, gene duplication, congenital, hereditary, and neonatal diseases and abnormalities, genetic variation, high-throughput nucleotide sequencing, human genetics
Sponsorship
CEPID/FAPESP (2013/08028-1)
MRC through the WIMM Strategic Alliance (G0902418, MC_UU_12025)
Project Grant (093329)
Action Medical Research (GN2483)
Wellcome (102731)
CNPq (303712/2016-3)
Identifiers
jmedgenet-2021-107825
External DOI: https://doi.org/10.1136/jmedgenet-2021-107825
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336671
Rights
Licence:
https://creativecommons.org/licenses/by/4.0/
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