FOXI3 pathogenic variants cause one form of craniofacial microsomia

Ke Mao, Christelle Borel, Muhammad Ansar, Angad Jolly, Periklis Makrythanasis, Christine Froehlich, Justyna Iwaszkiewicz, Bingqing Wang, Xiaopeng Xu, Qiang Li, Xavier Blanc, Hao Zhu, Qi Chen, Fujun Jin, Harinarayana Ankamreddy, Sunita Singh, Hongyuan Zhang, Xiaogang Wang, Peiwei Chen, Emmanuelle Ranza, Sohail Aziz Paracha, Syed Fahim Shah, Valentina Guida, Francesca Piceci-Sparascio, Daniela Melis, Bruno Dallapiccola, Maria Cristina Digilio, Antonio Novelli, Monia Magliozzi, Maria Teresa Fadda, Haley Streff, Keren Machol, Richard A. Lewis, Vincent Zoete, Gabriella Maria Squeo, Paolo Prontera, Giorgia Mancano, Giulia Gori, Milena Mariani, Angelo Selicorni, Stavroula Psoni, Helen Fryssira, Sofia Douzgou, Sandrine Marlin, Saskia Biskup, Alessandro Luca, Giuseppe Merla, Shouqin Zhao, Timothy C. Cox, Andrew K. Groves, James R. Lupski, Qingguo Zhang (), Yong-Biao Zhang () and Stylianos E. Antonarakis ()
Additional contact information
Ke Mao: Beihang University
Christelle Borel: University of Geneva Medical Faculty
Muhammad Ansar: University of Geneva Medical Faculty
Angad Jolly: Baylor College of Medicine
Periklis Makrythanasis: University of Geneva Medical Faculty
Christine Froehlich: CeGaT GmbH and Praxis für Humangenetik Tuebingen
Justyna Iwaszkiewicz: Molecular Modeling Group, Swiss Institute of Bioinformatics
Bingqing Wang: Plastic Surgery Hospital, Chinese Academy of Medical Sciences
Xiaopeng Xu: Beihang University
Qiang Li: Affiliated Hospital of Xuzhou Medical University
Xavier Blanc: Medigenome, Swiss Institute of Genomic Medicine
Hao Zhu: Beihang University
Qi Chen: Plastic Surgery Hospital, Chinese Academy of Medical Sciences
Fujun Jin: Beihang University
Harinarayana Ankamreddy: School of Bioengineering, SRMIST
Sunita Singh: Baylor College of Medicine
Hongyuan Zhang: Baylor College of Medicine
Xiaogang Wang: Beihang University
Peiwei Chen: Beijing Tongren Hospital, Capital Medical University
Emmanuelle Ranza: Medigenome, Swiss Institute of Genomic Medicine
Sohail Aziz Paracha: Khyber Medical University Institute of Medical Sciences (KIMS)
Syed Fahim Shah: KMU Institute of Medical Sciences (KIMS), DHQ Hospital KDA
Valentina Guida: Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza
Francesca Piceci-Sparascio: Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza
Daniela Melis: Università University degli of Studi di Salerno
Bruno Dallapiccola: Pediatric Cardiology, Medical Genetics Laboratory, Neuropsychiatry, Scientific Rectorate, Bambino Gesù Children Hospital, IRCCS
Maria Cristina Digilio: Sezione di Genetica Medica, Ospedale ‘Bambino Gesù’
Antonio Novelli: Sezione di Genetica Medica, Ospedale ‘Bambino Gesù’
Monia Magliozzi: Sezione di Genetica Medica, Ospedale ‘Bambino Gesù’
Maria Teresa Fadda: Policlinico Umberto I
Haley Streff: Baylor College of Medicine
Keren Machol: Baylor College of Medicine
Richard A. Lewis: Baylor College of Medicine
Vincent Zoete: Molecular Modeling Group, Swiss Institute of Bioinformatics
Gabriella Maria Squeo: Fondazione IRCCS Casa Sollievo della Sofferenza
Paolo Prontera: Hospital Santa Maria della Misericordia
Giorgia Mancano: University of Perugia Hospital SM della Misericordia
Giulia Gori: Meyer Children’s University Hospital
Milena Mariani: ASST Lariana, Santa Anna General Hospital
Angelo Selicorni: ASST Lariana, Santa Anna General Hospital
Stavroula Psoni: University of Athens
Helen Fryssira: University of Athens
Sofia Douzgou: University of Manchester
Sandrine Marlin: Centre de Référence Surdités Génétiques, Hôpital Necker, Institut Imagine
Saskia Biskup: CeGaT GmbH and Praxis für Humangenetik Tuebingen
Alessandro Luca: Medical Genetics Division, Fondazione IRCCS Casa Sollievo della Sofferenza
Giuseppe Merla: Fondazione IRCCS Casa Sollievo della Sofferenza
Shouqin Zhao: Beijing Tongren Hospital, Capital Medical University
Timothy C. Cox: University of Missouri-Kansas City
Andrew K. Groves: Baylor College of Medicine
James R. Lupski: Baylor College of Medicine
Qingguo Zhang: Plastic Surgery Hospital, Chinese Academy of Medical Sciences
Yong-Biao Zhang: Beihang University
Stylianos E. Antonarakis: University of Geneva Medical Faculty

Nature Communications, 2023, vol. 14, issue 1, 1-16

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37703-6

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