New Locus Underlying Auriculocondylar Syndrome (ARCND): 430 Kb Duplication Involving Regulatory Elements

Overview

Journal J Med Genet

Specialty Genetics

Date 2021 Nov 9

PMID 34750192

Citations 1

Authors

Vanessa Luiza Romanelli Tavares

Sofia Ligia Guimaraes-Ramos

Yan Zhou

Cibele Masotti

Suzana Ezquina

Danielle de Paula Moreira

Henk Buermans

Renato S Freitas

Johan T den Dunnen

Stephen R F Twigg

Maria Rita Passos-Bueno

Affiliations

Soon will be listed here.

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 (, and ) 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 , which is located over 200 kb telomeric to the top candidate gene . Notably, Capture-C analysis revealed multiple cis interactions between the promoter and possible regulatory elements within the duplicated region. Modelling of the disease revealed an increased expression of and its neighbouring gene, , 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 expression during craniofacial development can contribute to the phenotype.

Citing Articles

Genomic Complexity and Complex Chromosomal Rearrangements in Genetic Diagnosis: Two Illustrative Cases on Chromosome 7.

Villa N, Redaelli S, Farina S, Conconi D, Sala E, Crosti F Genes (Basel). 2023; 14(9).

PMID: 37761840 PMC: 10530880. DOI: 10.3390/genes14091700.

References

Firth H, Richards S, Bevan A, Clayton S, Corpas M, Rajan D . DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans Using Ensembl Resources. Am J Hum Genet. 2009; 84(4):524-33. PMC: 2667985. DOI: 10.1016/j.ajhg.2009.03.010. View

Stankiewicz P, Thiele H, Baldermann C, Kruger A, Giannakudis I, Dorr S . Phenotypic findings due to trisomy 7p15.3-pter including the TWIST locus. Am J Med Genet. 2001; 103(1):56-62. DOI: 10.1002/ajmg.1512. View

Okita K, Yamakawa T, Matsumura Y, Sato Y, Amano N, Watanabe A . An efficient nonviral method to generate integration-free human-induced pluripotent stem cells from cord blood and peripheral blood cells. Stem Cells. 2012; 31(3):458-66. DOI: 10.1002/stem.1293. View

Hoffmann K, Lindner T . easyLINKAGE-Plus--automated linkage analyses using large-scale SNP data. Bioinformatics. 2005; 21(17):3565-7. DOI: 10.1093/bioinformatics/bti571. View

Rimmer A, Phan H, Mathieson I, Iqbal Z, Twigg S, Wilkie A . Integrating mapping-, assembly- and haplotype-based approaches for calling variants in clinical sequencing applications. Nat Genet. 2014; 46(8):912-918. PMC: 4753679. DOI: 10.1038/ng.3036. View

Wang K, Li M, Hakonarson H . ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010; 38(16):e164. PMC: 2938201. DOI: 10.1093/nar/gkq603. View

Green S, Simoes-Costa M, Bronner M . Evolution of vertebrates as viewed from the crest. Nature. 2015; 520(7548):474-482. PMC: 5100666. DOI: 10.1038/nature14436. View

Davies J, Telenius J, McGowan S, Roberts N, Taylor S, Higgs D . Multiplexed analysis of chromosome conformation at vastly improved sensitivity. Nat Methods. 2015; 13(1):74-80. PMC: 4724891. DOI: 10.1038/nmeth.3664. View

Li H, Durbin R . Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009; 25(14):1754-60. PMC: 2705234. DOI: 10.1093/bioinformatics/btp324. View

10.

De Marco P, Raso A, Beri S, Gimelli S, Merello E, Mascelli S . A de novo balanced translocation t(7;12)(p21.2;p12.3) in a patient with Saethre-Chotzen-like phenotype downregulates TWIST and an osteoclastic protein-tyrosine phosphatase, PTP-oc. Eur J Med Genet. 2011; 54(5):e478-83. DOI: 10.1016/j.ejmg.2011.05.007. View

11.

Kobayashi G, Manso Musso C, Moreira D, Pontillo-Guimaraes G, Hsia G, Caires-Junior L . Recapitulation of Neural Crest Specification and EMT via Induction from Neural Plate Border-like Cells. Stem Cell Reports. 2020; 15(3):776-788. PMC: 7486307. DOI: 10.1016/j.stemcr.2020.07.023. View

12.

Rabadan-Diehl C, Nathanielsz P . From Mice to Men: research models of developmental programming. J Dev Orig Health Dis. 2013; 4(1):3-9. PMC: 3605751. DOI: 10.1017/S2040174412000487. View

13.

de Ruijter A, van Gennip A, Caron H, Kemp S, van Kuilenburg A . Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J. 2002; 370(Pt 3):737-49. PMC: 1223209. DOI: 10.1042/BJ20021321. View

14.

Romanelli Tavares V, Gordon C, Zechi-Ceide R, Kokitsu-Nakata N, Voisin N, Tan T . Novel variants in GNAI3 associated with auriculocondylar syndrome strengthen a common dominant negative effect. Eur J Hum Genet. 2014; 23(4):481-5. PMC: 4666574. DOI: 10.1038/ejhg.2014.132. View

15.

Firulli B, Krawchuk D, Centonze V, Vargesson N, Virshup D, Conway S . Altered Twist1 and Hand2 dimerization is associated with Saethre-Chotzen syndrome and limb abnormalities. Nat Genet. 2005; 37(4):373-81. PMC: 2568820. DOI: 10.1038/ng1525. View

16.

McKenna A, Hanna M, Banks E, Sivachenko A, Cibulskis K, Kernytsky A . The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010; 20(9):1297-303. PMC: 2928508. DOI: 10.1101/gr.107524.110. View

17.

Soo K, ORourke M, Khoo P, Steiner K, Wong N, Behringer R . Twist function is required for the morphogenesis of the cephalic neural tube and the differentiation of the cranial neural crest cells in the mouse embryo. Dev Biol. 2002; 247(2):251-70. DOI: 10.1006/dbio.2002.0699. View

18.

Zhang Y, Blackwell E, McKnight M, Knutsen G, Vu W, Ruest L . Specific inactivation of Twist1 in the mandibular arch neural crest cells affects the development of the ramus and reveals interactions with hand2. Dev Dyn. 2012; 241(5):924-40. PMC: 3346293. DOI: 10.1002/dvdy.23776. View

19.

El Ghouzzi V, Le Merrer M, Perrin-Schmitt F, Lajeunie E, Benit P, Renier D . Mutations of the TWIST gene in the Saethre-Chotzen syndrome. Nat Genet. 1997; 15(1):42-6. DOI: 10.1038/ng0197-42. View

20.

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View