FOXI3 pathogenic variants cause one form of craniofacial microsomia

11. April, 2023

Ke Mao # 1Christelle Borel # 2Muhammad Ansar # 2 3Angad Jolly 4Periklis Makrythanasis 2 5 6Christine Froehlich 7Justyna Iwaszkiewicz 8Bingqing Wang 9Xiaopeng Xu 1 10Qiang Li 11Xavier Blanc 12Hao Zhu 1Qi Chen 9Fujun Jin 1 10Harinarayana Ankamreddy 13Sunita Singh 14Hongyuan Zhang 4 14Xiaogang Wang 1 10Peiwei Chen 15Emmanuelle Ranza 12Sohail Aziz Paracha 16Syed Fahim Shah 17Valentina Guida 18Francesca Piceci-Sparascio 18Daniela Melis 19Bruno Dallapiccola 20Maria Cristina Digilio 21Antonio Novelli 21Monia Magliozzi 21Maria Teresa Fadda 22Haley Streff 4Keren Machol 4Richard A Lewis 4Vincent Zoete 8 23Gabriella Maria Squeo 24Paolo Prontera 25Giorgia Mancano 26Giulia Gori 27Milena Mariani 28Angelo Selicorni 28Stavroula Psoni 5Helen Fryssira 5Sofia Douzgou 29 30Sandrine Marlin 31Saskia Biskup 7Alessandro De Luca 18Giuseppe Merla 24 32Shouqin Zhao 15Timothy C Cox 33Andrew K Groves 4 14James R Lupski 4 34 35Qingguo Zhang 36Yong-Biao Zhang 37 38Stylianos E Antonarakis 39 40 41


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.