FOXI3 pathogenic variants cause one form of craniofacial microsomia

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.

Identification of potential molecular mechanism related to craniofacial dysmorphism caused by FOXI3 deficiency

“…Several copy number variations and signal nucleotide variations of genes were reported to be associated with craniofacial dysmorphism (Guida, Sparascio, et al., 2021 ; Zamariolli et al., 2019 ). In addition, several animal model studies have shown craniofacial dysmorphism in Foxi3 −/− mice (Mao et al., 2023 ; Singh et al., 2018 ; Youssoufian et al., 1986 ). In the study, we also found craniofacial dysmorphism in Foxi3 −/− mice.…”

“…For example, Qin et al (2021) found that loss-of-function variants in FOXI3 were found in patients with microtia and mandibular hypoplasia. Mao et al, 2023 identified 18 likely pathogenic variants of FOXI3 in 21 patients (3.1%) with craniofacial dysmorphism. Several animal model studies have shown abnormalities in the inner ear, jaw, outer and middle ears, heart and artery development, and thymus in Foxi3 −/− animals (Mao et al, 2023;Singh et al, 2018;Youssoufian et al, 1986).…”

“…Mao et al., 2023 identified 18 likely pathogenic variants of FOXI3 in 21 patients (3.1%) with craniofacial dysmorphism. Several animal model studies have shown abnormalities in the inner ear, jaw, outer and middle ears, heart and artery development, and thymus in Foxi3 −/− animals (Mao et al., 2023 ; Singh et al., 2018 ; Youssoufian et al., 1986 ). These findings suggest that FOXI3 is closely related to craniofacial dysmorphism and may be a susceptibility gene for HFM.…”

Dysregulation in Spatiotemporal Expression ofHMX1Coordinated by Multifaceted Enhancers Drives an Auricular Disorder

“…Our screening for causal mutations began with linkage analysis to pinpoint the suspected genomic locus for bilateral isolated constricted ear. We adhered to the quality control (QC) procedures outlined by Mao et al for pruning SNPs in strong linkage disequilibrium, removing SNPs with Mendelian errors, and verifying sex specifications 15 . Parametric multi-point linkage analysis was conducted on Pedigrees 1, 3, and 7, both individually and collectively, using MERLIN v.1.1.2 69 .…”

“…Elucidating the function of cis-regulatory elements in specific cellular and temporal settings is key to unraveling the complex mechanisms of ear development and regulatory variations that influence the external ear phenotype 12,13 . Recent research underscores CNCCs as vital in craniofacial development, including the outer ear [14][15][16] . CNCCs positional identity is determined by a complex set of signaling factors that govern a distinct hierarchy of gene expression profiles.…”