Congenital aural atresia associated with agenesis of internal carotid artery in a girl with a FOXI3 deletion

Abstract

We report on the molecular characterization of a microdeletion of approximately 2.5Mb at 2p11.2 in a female baby with left congenital aural atresia, microtia, and ipsilateral internal carotid artery agenesis. The deletion was characterized by fluorescence in situ hybridization, array comparative genomic hybridization, and whole genome re-sequencing. Among the genes present in the deleted region, we focused our attention on the FOXI3 gene. Foxi3 is a member of the Foxi class of Forkhead transcription factors. In mouse, chicken and zebrafish Foxi3 homologues are expressed in the ectoderm and endoderm giving rise to elements of the jaw as well as external, middle and inner ear. Homozygous Foxi3−/− mice have recently been generated and show a complete absence of the inner, middle, and external ears as well as severe defects in the jaw and palate. Recently, a 7-bp duplication within exon 1 of FOXI3 that produces a frameshift and a premature stop codon was found in hairless dogs. Mild malformations of the outer auditory canal (closed ear canal) and ear lobe have also been noted in a fraction of FOXI3 heterozygote Peruvian hairless dogs. Based on the phenotypes of Foxi3 mutant animals, we propose that FOXI3 may be responsible for the phenotypic features of our patient. Further characterization of the genomic region and the analysis of similar patients may help to demonstrate this point.

The bald and the beautiful: hairlessness in domestic dog breeds

“…In addition to hairlessness, the dogs with FOXI3 mutations often have problems with dentition, such as missing teeth, and less commonly, malformations of the ear. This latter, secondary phenotype led to the identification of a rare human mutation involving the deletion of the FOXI3 gene in a child with microtia, an underdeveloped outer ear [42]. This remains an interesting case where a naturally occurring mutation has been under strong selection to retain only one part of the phenotype in dogs, yet can improve our knowledge of the role of the gene in development as well as contribute to our understanding of rare human disorders.…”

The development of the mammalian outer and middle ear

“…Another gene important for EAM development is the transcription factor Foxi3 ; in FOXI3 +/− dogs and the single reported human foxi3+/− patient, the ear canal is completely absent and the outer ear is hypoplastic (Tassano et al. ). However, the middle ear appears normal.…”

“…The mechanisms and molecules involved with this guidance process remain elusive; however, the above studies indicate targets of goosecoid transcription would be likely candidates. Another gene important for EAM development is the transcription factor Foxi3; in FOXI3+/À dogs and the single reported human foxi3+/À patient, the ear canal is completely absent and the outer ear is hypoplastic (Tassano et al 2015). However, the middle ear appears normal.…”

The Role of Foxi Family Transcription Factors in the Development of the Ear and Jaw

“…The mutation, a seven-base pair duplication introduces a premature stop codon prior to the DNA binding domain and is presumed to create a null allele. In addition to a striking lack of hair, possibly related to a role for FOXI3 in regulating the mammalian ectodysplasin pathway (Shirokova et al, 2013), heterozygous dogs have malformed and missing teeth and occasional malformations in the outer ear (Drogemuller et al, 2008; Tassano, 2014). A human patient with a deletion in one copy of chromosome 2 encompassing seven genes including Foxi3 has also been identified.…”

“…A human patient with a deletion in one copy of chromosome 2 encompassing seven genes including Foxi3 has also been identified. The patient was found to have mandibular asymmetry and unilateral malformation of the outer ear (Tassano, 2014). …”