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

Published version
Peer-reviewed

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Authors

Romanelli Tavares, Vanessa Luiza  ORCID logo  https://orcid.org/0000-0002-8845-5952
Guimarães-Ramos, Sofia Ligia 
Zhou, Yan 
Masotti, Cibele 
Ezquina, Suzana 

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.

Description

Funder: VTCT Foundation Fellowship

Keywords

Novel disease loci, 1506, gene duplication, congenital, hereditary, and neonatal diseases and abnormalities, genetic variation, high-throughput nucleotide sequencing, human genetics

Journal Title

J Med Genet

Conference Name

Journal ISSN

0022-2593
1468-6244

Volume Title

Publisher

BMJ

Rights

Embargo: ends 2021-11-07
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)