Copy number variation analysis implicates novel pathways in patients with oculo-auriculo-vertebral-spectrum and congenital heart defects.
DACH1, DACH2, congenital heart disease
Goldenhar syndrome
PAX-SIX-EYA-DACH network
copy-number-variants
oculo-auriculo-vertebral spectrum
Journal
Clinical genetics
ISSN: 1399-0004
Titre abrégé: Clin Genet
Pays: Denmark
ID NLM: 0253664
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
revised:
22
04
2021
received:
10
02
2021
accepted:
08
05
2021
pubmed:
15
5
2021
medline:
27
1
2022
entrez:
14
5
2021
Statut:
ppublish
Résumé
Oculo-auriculo-vertebral spectrum (OAVS) is a developmental disorder of craniofacial morphogenesis. Its etiology is unclear, but assumed to be complex and heterogeneous, with contribution of both genetic and environmental factors. We assessed the occurrence of copy number variants (CNVs) in a cohort of 19 unrelated OAVS individuals with congenital heart defect. Chromosomal microarray analysis identified pathogenic CNVs in 2/19 (10.5%) individuals, and CNVs classified as variants of uncertain significance in 7/19 (36.9%) individuals. Remarkably, two subjects had small intragenic CNVs involving DACH1 and DACH2, two paralogs coding for key components of the PAX-SIX-EYA-DACH network, a transcriptional regulatory pathway controlling developmental processes relevant to OAVS and causally associated with syndromes characterized by craniofacial involvement. Moreover, a third patient showed a large duplication encompassing DMBX1/OTX3, encoding a transcriptional repressor of OTX2, another transcription factor functionally connected to the DACH-EYA-PAX network. Among the other relevant CNVs, a deletion encompassing HSD17B6, a gene connected with the retinoic acid signaling pathway, whose dysregulation has been implicated in craniofacial malformations, was also identified. Our findings suggest that CNVs affecting gene dosage likely contribute to the genetic heterogeneity of OAVS, and implicate the PAX-SIX-EYA-DACH network as novel pathway involved in the etiology of this developmental trait.
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
268-279Subventions
Organisme : Italian Ministry of Health
Informations de copyright
© 2021 John Wiley & Sons A/S . Published by John Wiley & Sons Ltd.
Références
Barisic I, Odak L, Loane M, et al. Prevalence, prenatal diagnosis and clinical features of oculo-auriculo-vertebral spectrum: a registry-based study in Europe. Eur J Hum Genet. 2014;22:1026-1033.
Tasse C, Böhringer S, Fischer S, et al. Oculo-auriculo-vertebral spectrum (OAVS): clinical evaluation and severity scoring of 53 patients and proposal for a new classification. Eur J Med Genet. 2005;48:397-411.
Rooryck C, Souakri N, Cailley D, et al. Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum. Am J Med Genet A. 2010;152A:1984-1989.
Digilio MC, McDonald-McGinn DM, Heike C, et al. Three patients with oculo-auriculo-vertebral spectrum and microdeletion 22q11.2. Am J Med Genet A. 2009;149A:2860-2864.
Guida V, Sinibaldi L, Pagnoni M, et al. A de novo proximal 3q29 chromosome microduplication in a patient with oculo auriculo vertebral spectrum. Am J Med Genet A. 2015;167A:797-801.
Ou Z, Martin DM, Bedoyan JK, et al. Branchiootorenal syndrome and oculoauriculovertebral spectrum features associated with duplication of SIX1, SIX6, and OTX2 resulting from a complex chromosomal rearrangement. Am J Med Genet A. 2008;146A:2480-2489.
Ballesta-Martínez MJ, López-González V, Dulcet LA, Rodríguez-Santiago B, Garcia-Miñaúr S, Guillen-Navarro E. Autosomal dominant oculoauriculovertebral spectrum and 14q23.1 microduplication. Am J Med Genet A. 2013;161A(8):2030-2035.
Zielinski D, Markus B, Sheikh M, et al. OTX2 duplication is implicated in hemifacial microsomia. PLoS One. 2014;9:e96788.
Huang XS, Li X, Tan C, et al. Genome-wide scanning reveals complex etiology of oculo-auriculo-vertebral spectrum. Tohoku J Exp Med. 2010;222:311-318.
Kelberman D, Tyson J, Chandler DC, et al. Hemifacial microsomia: progress in understanding the genetic basis of a complex malformation syndrome. Hum Genet. 2001;109:638-645.
Lopez E, Berenguer M, Tingaud-Sequeira A, et al. Mutations in MYT1, encoding the myelin transcription factor 1, are a rare cause of OAVS. J Med Genet. 2016;53:752-760.
Rengasamy Venugopalan S, Farrow E, et al. A novel nonsense substitution identified in the AMIGO2 gene in an Occulo-Auriculo-vertebral spectrum patient. Orthod Craniofac Res. 2019;22(Suppl 1):163-167.
Tingaud-Sequeira A, Trimouille A, Marlin S, et al. Functional and genetic analyses of ZYG11B provide evidences for its involvement in OAVS. Mol Genet Genomic Med. 2020;8:e1375.
Trimouille A, Tingaud-Sequeira A, Lacombe D, et al. Description of a family with X-linked OAVS associated with polyalanine tract expansion in ZIC3. Clin Genet. 2020;98:384-389.
Wessels MW, Kuchinka B, Heydanus R, et al. Polyalanine expansion in the ZIC3 gene leading to X-linked heterotaxy with VACTERL association: a new polyalanine disorder? J Med Genet. 2010;47:351-355.
Wieczorek D, Ludwig M, Boehringer S, Jongbloet PH, Gillessen-Kaesbach G, Horsthemke B. Reproduction abnormalities and twin pregnancies in parents of sporadic patients with oculo-auriculo-vertebral spectrum/Goldenhar syndrome. Hum Genet. 2007;121:369-376.
Fischer S, Lüdecke HJ, Wieczorek D, Böhringer S, Gillessen-Kaesbach G, Horsthemke B. Histone acetylation dependent allelic expression imbalance of BAPX1 in patients with the oculo-auriculo-vertebral spectrum. Hum Mol Genet. 2006;15:581-587.
Guida V, Calzari L, Fadda MT, et al. Genome-wide DNA methylation analysis of a cohort of 41 patients affected by Oculo-Auriculo-vertebral Spectrum (OAVS). Int J Mol Sci. 2021;22:1190.
Digilio MC, Calzolari F, Capolino R, et al. Congenital heart defects in patients with oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Am J Med Genet A. 2008;146A:1815-1819.
Saraclar M, Friedman S. Congenital cardiac anomalies in Goldenhar's syndrome. (Oculo-auriculo-vertebral dysplasia). Turk J Pediatr. 1974;16:124-129.
Greenwood RD, Rosenthal A, Sommer A, Wolff G, Craenen J. Cardiovascular malformations in oculoauriculovertebral dysplasia (Goldenhar syndrome). J Pediatr. 1974;85:816-818.
Rollnick BR, Kaye CI, Nagatoshi K, Hauck W, Martin AO. Oculoauriculovertebral dysplasia and variants: phenotypic characteristics of 294 patients. Am J Med Genet. 1987;26:361-375.
Morrison PJ, Mulholland HC, Craig BG, Nevin NC. Cardiovascular abnormalities in the oculo-auriculo-vertebral spectrum (Goldenhar syndrome). Am J Med Genet. 1992;44:425-428.
Kumar A, Friedman JM, Taylor GP, Patterson MW. Pattern of cardiac malformation in oculoauriculovertebral spectrum. Am J Med Genet. 1993;46:423-426.
Maat-Kievit JA, Baraitser M, Winter RM. Total situs inversus associated with the oculo-auriculo-vertebral spectrum. Clin Dysmorphol. 1994;3:82-86.
Görgü M, Aslan G, Erdoöan B, Karaca C, Aköz T. Goldenhar syndrome with situs inversus totalis. Int J Oral Maxillofac Surg. 1998;27:404.
Pierpont ME, Moller JH, Gorlin RJ, Edwards JE. Congenital cardiac, pulmonary, and vascular malformations in Oculoauriculovertebral dysplasia. Pediatr Cardiol. 1982;2:297-302.
McCarthy VP, Zimo DA, Lucas MA. Airway in the oculo-auriculo-vertebral spectrum: two cases and a review of the literature. Pediatr Pulmonol. 2001;32:250-256.
Beleza-Meireles A, Hart R, Clayton-Smith J, et al. Oculo-auriculo-vertebral spectrum: clinical and molecular analysis of 51 patients. Eur J Med Genet. 2015;58:455-465.
Silversides CK, Lionel AC, Costain G, et al. Rare copy number variations in adults with tetralogy of Fallot implicate novel risk gene pathways. PLoS Genet. 2012;8(8):e1002843.
Greenway SC, Pereira AC, Lin JC, et al. De novo copy number variants identify new genes and loci in isolated sporadic tetralogy of Fallot. Nat Genet. 2009;41:931-935.
Clark EB. Mechanisms in the pathogenesis of congenital heart defects. In: Pierpont ME, Moller J, eds. The Genetics of Cardiovascular Disease. Boston, MA: Martinus-Nijoff; 1986:3-11.
Carbone A, Bernardini L, Valenzano F, et al. Array-based comparative genomic hybridization in early-stage mycosis fungoides: recurrent deletion of tumor suppressor genes BCL7A, SMAC/DIABLO, and RHOF. Genes Chromosomes Cancer. 2008;47:1067-1075.
Riggs ER, Andersen EF, Cherry AM, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the clinical genome resource (ClinGen). Genet Med. 2020;22:245-257.
Spineli-Silva S, Sgardioli IC, Dos Santos AP, et al. Genomic imbalances in craniofacial microsomia. Am J Med Genet C Semin Med Genet. 2020;184:970-985.
Li X, Perissi V, Liu F, Rose DW, Rosenfeld MG. Tissue-specific regulation of retinal and pituitary precursor cell proliferation. Science. 2002;297:1180-1183.
Rhinn M, Dierich A, Shawlot W, Behringer RR, Le Meur M, Ang SL. Sequential roles for Otx2 in visceral endoderm and neuroectoderm for forebrain and midbrain induction and specification. Development. 1998;125:845-856.
Chassaing N, Causse A, Vigouroux A, et al. Molecular findings and clinical data in a cohort of 150 patients with anophthalmia/microphthalmia. Clin Genet. 2014;86:326-334.
Chassaing N, Sorrentino S, Davis EE, et al. OTX2 mutations contribute to the otocephaly-dysgnathia complex. J Med Genet. 2012;49:373-379.
Beleza-Meireles A, Clayton-Smith J, Saraiva JM, Tassabehji M. Oculo-auriculo-vertebral spectrum: a review of the literature and genetic update. J Med Genet. 2014;51:635-645.
Davidsson J, Collin A, Björkhem G, Soller M. Array based characterization of a terminal deletion involving chromosome subband 15q26.2: an emerging syndrome associated with growth retardation, cardiac defects and developmental delay. BMC Med Genet. 2008;9:2.
Kantaputra PN, Pruksametanan A, Phondee N, et al. ADAMTSL1 and mandibular prognathism. Clin Genet. 2019;95:507-515.
Hendee K, Wang LW, Reis LM, Rice GM, Apte SS, Semina EV. Identification and functional analysis of an ADAMTSL1 variant associated with a complex phenotype including congenital glaucoma, craniofacial, and other systemic features in a three-generation human pedigree. Hum Mutat. 2017;38:1485-1490.
Shimizu A, Asakawa S, Sasaki T, et al. A novel giant gene CSMD3 encoding a protein with CUB and sushi multiple domains: a candidate gene for benign adult familial myoclonic epilepsy on human chromosome 8q23.3-q24.1. Biochem Biophys Res Commun. 2003;309:143-154.
Pappu KS, Mardon G. Genetic control of retinal specification and determination in drosophila. Int J Dev Biol. 2004;48:913-924.
Ferese R, Bonetti M, Consoli F, et al. Heterozygous missense mutations in NFATC1 are associated with atrioventricular septal defect. Hum Mutat. 2018;39:1428-1441.
Zhu L, Peng JL, Harutyunyan KG, Garcia MD, Justice MJ, Belmont JW. Craniofacial, skeletal, and cardiac defects associated with altered embryonic murine Zic3 expression following targeted insertion of a PGK-NEO cassette. Front Biosci. 2007;12:1680-1690.
Khadir MA, Narayana G, Ramagopal G, Nayar PG. Isolated hypoplasia of left pulmonary artery with agenesis of left lobe of thyroid: a case report. J Clin Diagn Res. 2016;10:SD04-SD05.
Christensen KL, Patrick AN, McCoy EL, Ford HL. The six family of homeobox genes in development and cancer. Adv Cancer Res. 2008;101:93-126.
Li X, Oghi KA, Zhang J, et al. Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis. Nature. 2003;426:247-254.
Smith RJH. Branchiootorenal Spectrum disorder. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. Gene Reviews. Seattle, WA: University of Washington; 1999:1993-2020.
Kimura K, Miki T, Shibasaki T, et al. Functional analysis of transcriptional repressor Otx3/Dmbx1. FEBS Lett. 2005;579:2926-2932.
Zagozewski J, Shahriary GM, Morrison LC, et al. An OTX2-PAX3 signaling axis regulates group 3 medulloblastoma cell fate. Nat Commun. 2020;11:3627.
Luo J, Liu K, Yao Y, et al. DMBX1 promotes tumor proliferation and regulates cell cycle progression via repressing OTX2-mediated transcription of p21 in lung adenocarcinoma cell. Cancer Lett. 2019;453:45-56.
Puvabanditsin S, Garrow E, Umaru S, Padilla J, Chowdawarapu S, Biswas A. Otocephaly, and pulmonary malformation association: two case reports. Genet Couns. 2006;17:167-171.
Hide T, Hatakeyama J, Kimura-Yoshida C, et al. Genetic modifiers of otocephalic phenotypes in Otx2 heterozygous mutant mice. Development. 2002;129:4347-4357.
Unolt M, Putotto C, Silvestri LM, et al. Transposition of great arteries: new insights into the pathogenesis. Front Pediatr. 2013;1:11.
Talkowski ME, Mullegama SV, Rosenfeld JA, et al. Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder. Am J Hum Genet. 2011;89:551-563.
Zapata H, Edwards JE, Titus JL. Aberrant right subclavian artery with left aortic arch: associated cardiac anomalies. Pediatr Cardiol. 1993;14:159-161.
Bragagnolo S, Colovati MES, Souza MZ, et al. Clinical and cytogenomic findings in OAV spectrum. Am J Med Genet A. 2018;176:638-648.