The Oculo-Auriculo-Vertebral Spectrum (OAVS) or Goldenhar Syndrome is an abnormality of embryonic development of 1rst and second branchial arches, characterized by hemifacial microsomia associated with auricular, ocular and vertebral malformations. For the past 10 years, thanks to national and international collaborations, we have constituted one of the largest cohorts of OAVS described so far, with nearly 350 patients. However, the clinical and genetic heterogeneity of this spectrum with incomplete penetrance and variable expressivity, make its molecular diagnosis complex. Thus, diverse rare CNVs are associated with OAVS, and we identified the first genes associated with OAVS by exomes and genomes sequencing. MYT1 is the first and still the most “frequent” OAVS gene, with variants in less than 2% of our patients. We also identified ZYG11B gene, encoding a protein associated with ubiquitin ligase E2, having a role in the degradation of substrates by the proteasome. Knock-down experiments of zyg11 in the zebrafish model show a specific deleterious effect on the development of craniofacial cartilages, as well as a proximal wavy notochord phenotype that may correspond to the vertebral abnormalities observed in the OAVS patients. We also demonstrated abnormal alanine expansion in another gene, ZIC3, associated with unilateral microtia and hemifacial microsomia in 8 boys from a large Danish family. This gene is already known to be involved in heterotaxy and congenital heart disease, and plays a role in determining the left-right axis. This biological function could explain the unilateral nature of craniofacial involvement in this family and in the OAVS. We also identified a recurrent missense variant in the EYA3 gene in two unrelated families. We induced specific craniofacial abnormalities in zebrafish eya3 morphants, with a phenotype comparable with previous animal models. Proteomic studies on knockdown cell models on EYA3 through siRNA showed in particular a deregulation of the DNA repair pathway, the oxidative phosphorylation pathway, the protein polyubiquitination pathway and an activation of the retinoic acid pathway. Another approach through experiments of toxic in utero exposure of mouse embryos to retinoic acid, at a given stage of development, allowed us to highlight other candidate genes involved in craniofacial malformations, some of which were already known to be associated with OAVS phenocopies. Since 2020, the European Solve-RD project allowed us to perform Whole Genome Sequencing in OAVS patients having a negative exome. Different approaches combining multi-omics and environmental studies are necessary to decipher the etiological bases of this complex disease.
Dr Caroline Rooryck [PU-PH,Full Professor]
Dr Aurélien Trimouille [MCU-PH, Associate Professor]
Angèle Tingaud-Sequeira [Engineer]
Dr Thomas Sagardoy [surgeon ORL, PhD student]
National and International Collaborations
Pr Arnaud Picard, Pr Françoise Denoyelle, Dr Sandrine Marlin, Pr Jeanne Amiel, Hôpital Necker, APHP, CRMR MAFACE et MALO, Institut IMAGINE
Pr Charles Coutton, Laboratoire génétique, CHU de Grenoble
Filière Santé Maladies Rares « Tête et cou » Dr Bénédicte Demeer, Pr Nicolas Leboulanger
Association Française pour l’Atrésie de l’œsophage (AFAO)
Dr Mileny Colovati , Maria I Melaragno, Silvia Bragagnolo, Ana B A Perez, Division of Genetics, Department of Morphology and Genetics, Universidade Federal de Sao Paulo, Sao Paulo, Brazil.
Dr Hanne Buciek Hove, Clinical Genetics, Department of Odontology, University of Copenhagen, Copenhagen, Denmark.
Dr Manju Salaria, Genetic Health Service, Monash Health, 246 Clayton Road, Clayton, VIC, 3168, Australia.
Dr Rachel Stapelton, Genetic Health Service NZ-South Island Hub, Christchurch Hospital, Christchurch, 8140, New Zealand.
Tingaud-Sequeira A, Trimouille A, Sagardoy T, Lacombe D, Rooryck C. Oculo-auriculo-vertebral spectrum: new genes and literature review on a complex disease. J Med Genet 2022 in press.
Tingaud-Sequeira A, Trimouille A, Salaria M, Stapleton R, Claverol S,Plaisant C, Bonneu M, Lopez E, Arveiler B, Lacombe D, Rooryck C. A recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebralspectrum. Hum Genet. 2021 Jun;140(6):933-944. DOI: 10.1007/s00439-021-02255-6
Tingaud-Sequeira A, Trimouille A, Marlin S, Lopez E, Berenguer M, Gherbi S, Arveiler B, Lacombe D, Rooryck C. Functional and genetic analyses of ZYG11B provide evidences for its involvement in OAVS. Mol Genet Genomic Med. 2020 Oct;8(10):e1375. DOI: 10.1002/mgg3.1375
Trimouille A, Tingaud-Sequeira A, Lacombe D, Duelund Hjortshøj T, KreiborgS, Buciek Hove H, Rooryck C. Description of a family with X-linked oculo-auriculo-vertebral spectrum associated with polyalanine tract expansion in ZIC3. Clin Genet. 2020 Oct;98(4):384-389. DOI: 10.1111/cge.13811
Berenguer M, Darnaudery M, Claverol S, Bonneu M, Lacombe D, Rooryck C. Prenatal retinoic acid exposure reveals candidate genes for craniofacialdisorders. Sci Rep. 2018 Nov 30;8(1):17492. DOI: 10.1038/s41598-018-35681-0
Berenguer M, Tingaud-Sequeira A, Colovati M, Melaragno MI, Bragagnolo S,Perez ABA, Arveiler B, Lacombe D, Rooryck C. A novel de novo mutation in MYT1, the unique OAVS gene identified so far. Eur J Hum Genet. 2017 Sep;25(9):1083-1086. DOI: 10.1038/ejhg.2017.101
Lopez E, Berenguer M, Tingaud-Sequeira A, Marlin S, Toutain A, Denoyelle F,Picard A, Charron S, Mathieu G, de Belvalet H, Arveiler B, Babin PJ, Lacombe D, Rooryck C. Mutations in MYT1, encoding the myelin transcription factor 1,are a rare cause of OAVS. J Med Genet. 2016 Nov;53(11):752-760. DOI: 10.1136/jmedgenet-2016-103774
Brun A, Cailley D, Toutain J, Bouron J, Arveiler B, Lacombe D, Goizet C, Rooryck C. 1.5 Mb microdeletion in 15q24 in a patient with mild OAVS phenotype. Eur J Med Genet. 2012 Feb;55(2):135-9. DOI : 10.1016/j.ejmg.2011.11.006
Rooryck C, Souakri N, Cailley D, Bouron J, Goizet C, Delrue MA, Marlin S,Lacombe FD, Arveiler B. Array-CGH analysis of a cohort of 86 patients with oculoauriculovertebral spectrum. Am J Med Genet A. 2010 Aug;152A(8):1984-9. DOI : 10.1002/ajmg.a.33491
Rooryck C, VuPhi Y, Souakri N, Burgelin I, Saura R, Lacombe D, Arveiler B,Taine L. Characterization of a de novo balanced translocation t(9;18)(p23;q12.2)in a patient with oculoauriculovertebral spectrum. Eur J Med Genet. 2010 Mar-Apr;53(2):104 . DOI : 10.1016/j.ejmg.2010.01.003
Rooryck C, Stef M, Burgelin I, Simon D, Souakri N, Thambo JB, Chateil JF,Lacombe D, Arveiler B. 2.3 Mb terminal deletion in 12p13.33 associated withoculoauriculovertebral spectrum and evaluation of WNT5B as a candidate gene. EurJ Med Genet. 2009 Nov-Dec;52(6):446-9. DOI : 10.1016/j.ejmg.2009.08.005