@article{3341051,
    title = "FOXI3 pathogenic variants cause one form of craniofacial microsomia",
    author = "Mao, K. and Borel, C. and Ansar, M. and Jolly, A. and Makrythanasis, P. and Froehlich, C. and Iwaszkiewicz, J. and Wang, B. and Xu, X. and Li, Q. and Blanc, X. and Zhu, H. and Chen, Q. and Jin, F. and Ankamreddy, H. and Singh, S. and Zhang, H. and Wang, X. and Chen, P. and Ranza, E. and Paracha, S.A. and Shah, S.F. and Guida, V. and Piceci-Sparascio, F. and Melis, D. and Dallapiccola, B. and Digilio, M.C. and Novelli, A. and Magliozzi, M. and Fadda, M.T. and Streff, H. and Machol, K. and Lewis, R.A. and Zoete, V. and Squeo, G.M. and Prontera, P. and Mancano, G. and Gori, G. and Mariani, M. and Selicorni, A. and Psoni, S. and Fryssira, H. and Douzgou, S. and Marlin, S. and Biskup, S. and De Luca, A. and Merla, G. and Zhao, S. and Cox, T.C. and Groves, A.K. and Lupski, J.R. and Zhang, Q. and Zhang, Y.-B. and Antonarakis, S.E.",
    journal = "Nature Communications",
    year = "2023",
    volume = "14",
    number = "1",
    publisher = "Lithuanian Nature Research Centre",
    issn = "2041-1723",
    doi = "10.1038/s41467-023-37703-6",
    keywords = "allele;  ancestry;  biochemistry;  etiology;  gene expression;  morphology;  phenotype;  phenotypic plasticity, adult;  allele;  animal experiment;  article;  autosomal dominant inheritance;  autosomal recessive inheritance;  cellular distribution;  controlled study;  gene frequency;  genetic transcription;  human;  male;  mouse;  nonhuman;  pedigree;  penetrance;  protein expression;  animal;  face asymmetry;  Goldenhar syndrome;  pathology, forkhead transcription factor;  Foxi3 protein, mouse, Animals;  Facial Asymmetry;  Forkhead Transcription Factors;  Goldenhar Syndrome;  Mice;  Pedigree",
    abstract = "Craniofacial microsomia (CFM; also known as Goldenhar syndrome), is a craniofacial developmental disorder of variable expressivity and severity with a recognizable set of abnormalities. These birth defects are associated with structures derived from the first and second pharyngeal arches, can occur unilaterally and include ear dysplasia, microtia, preauricular tags and pits, facial asymmetry and other malformations. The inheritance pattern is controversial, and the molecular etiology of this syndrome is largely unknown. A total of 670 patients belonging to unrelated pedigrees with European and Chinese ancestry with CFM, are investigated. We identify 18 likely pathogenic variants in 21 probands (3.1%) in FOXI3. Biochemical experiments on transcriptional activity and subcellular localization of the likely pathogenic FOXI3 variants, and knock-in mouse studies strongly support the involvement of FOXI3 in CFM. Our findings indicate autosomal dominant inheritance with reduced penetrance, and/or autosomal recessive inheritance. The phenotypic expression of the FOXI3 variants is variable. The penetrance of the likely pathogenic variants in the seemingly dominant form is reduced, since a considerable number of such variants in affected individuals were inherited from non-affected parents. Here we provide suggestive evidence that common variation in the FOXI3 allele in trans with the pathogenic variant could modify the phenotypic severity and accounts for the incomplete penetrance. © 2023, The Author(s)."
}