FOXI3 pathogenic variants cause one form of craniofacial microsomia

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