Goldenhar syndrome or oculo-auriculo-vertebral spectrum (OAVS) is a complex developmental disorder characterized by asymmetric ear anomalies, hemifacial microsomia, ocular and vertebral defects. We aimed at identifying and characterizing a new gene associated with OAVS. Two affected brothers with OAVS were analyzed by exome sequencing that revealed a missense variant (p.(Asn358Ser)) in the EYA3 gene. EYA3 screening was then performed in 122 OAVS patients that identified the same variant in one individual from an unrelated family. Segregation assessment in both families showed incomplete penetrance and variable expressivity. We investigated this variant in cellular models to determine its pathogenicity and demonstrated an increased half-life of the mutated protein without impact on its ability to dephosphorylate H2AFX following DNA repair pathway induction. Proteomics performed on this cellular model revealed four significantly predicted upstream regulators which are PPARGC1B, YAP1, NFE2L2 and MYC. Moreover, eya3 knocked-down zebrafish embryos developed specific craniofacial abnormalities corroborating previous animal models and supporting its involvement in the OAVS. Additionally, EYA3 gene expression was deregulated in vitro by retinoic acid exposure. EYA3 is the second recurrent gene identified to be associated with OAVS. Moreover, based on protein interactions and related diseases, we suggest the DNA repair as a key molecular pathway involved in craniofacial development.
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The authors warmly thank the patients and their families. They thank the clinician geneticists for providing patients.
This work was supported by the ANR (Agence Nationale pour la Recherche, ANR-12-JVS1-0002).
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The authors declare no conflict of interest.
The local ethics committee (Comité de Protection des Personnes: DC2012/76) approved this study.
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Tingaud-Sequeira, A., Trimouille, A., Salaria, M. et al. A recurrent missense variant in EYA3 gene is associated with oculo-auriculo-vertebral spectrum. Hum Genet (2021). https://doi.org/10.1007/s00439-021-02255-6