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. 2023 Jan;25(1):143-150.
doi: 10.1016/j.gim.2022.09.005. Epub 2022 Oct 19.

Damaging variants in FOXI3 cause microtia and craniofacial microsomia

Daniel Quiat  1 , Andrew T Timberlake  2 , Justin J Curran  3 , Michael L Cunningham  4 , Barbara McDonough  3 , Maria A Artunduaga  5 , Steven R DePalma  3 , Milagros M Duenas-Roque  6 , Joshua M Gorham  3 , Jonas A Gustafson  7 , Usama Hamdan  8 , Anne V Hing  4 , Paula Hurtado-Villa  9 , Yamileth Nicolau  10 , Gabriel Osorno  11 , Harry Pachajoa  12 , Gloria L Porras-Hurtado  13 , Lourdes Quintanilla-Dieck  14 , Luis Serrano  15 , Melissa Tumblin  16 , Ignacio Zarante  17 , Daniela V Luquetti  4 , Roland D Eavey  18 , Carrie L Heike  19 , Jonathan G Seidman  20 , Christine E Seidman  21
Affiliations

Damaging variants in FOXI3 cause microtia and craniofacial microsomia

Daniel Quiat et al. Genet Med. 2023 Jan.

Abstract

Purpose: Craniofacial microsomia (CFM) represents a spectrum of craniofacial malformations, ranging from isolated microtia with or without aural atresia to underdevelopment of the mandible, maxilla, orbit, facial soft tissue, and/or facial nerve. The genetic causes of CFM remain largely unknown.

Methods: We performed genome sequencing and linkage analysis in patients and families with microtia and CFM of unknown genetic etiology. The functional consequences of damaging missense variants were evaluated through expression of wild-type and mutant proteins in vitro.

Results: We studied a 5-generation kindred with microtia, identifying a missense variant in FOXI3 (p.Arg236Trp) as the cause of disease (logarithm of the odds = 3.33). We subsequently identified 6 individuals from 3 additional kindreds with microtia-CFM spectrum phenotypes harboring damaging variants in FOXI3, a regulator of ectodermal and neural crest development. Missense variants in the nuclear localization sequence were identified in cases with isolated microtia with aural atresia and found to affect subcellular localization of FOXI3. Loss of function variants were found in patients with microtia and mandibular hypoplasia (CFM), suggesting dosage sensitivity of FOXI3.

Conclusion: Damaging variants in FOXI3 are the second most frequent genetic cause of CFM, causing 1% of all cases, including 13% of familial cases in our cohort.

Keywords: Craniofacial microsomia; Ectoderm; FOXI3; Microtia; Neural crest.

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Conflict of interest statement

Conflict of Interest The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1. FOXI3 variants in pedigrees with microtia and craniofacial microsomia.
A. Pedigrees of 4 kindreds with FOXI3 missense and truncating variants. “+” denotes the WT allele and “D” denotes the missense or truncating FOXI3 variant indicated above the pedigree. Red arrows in kindred 1 indicate samples that underwent genome sequencing. B. Multiple sequence alignment of FOXI3 protein sequence from vertebrate species. “.” indicates conservation with the human protein sequence. The locations of FOXI3 variants in the nuclear localization sequence (NLS) are indicated above. The forkhead-DNA binding domain and NLS are highlighted. C. Immunocytochemistry of FLAG-FOXI3 (magenta) expressed in HEK293 cells. Cellular nuclei are counterstained with DAPI (cyan). All images are shown at 60× magnification. Scale bar = 20 μm. D. Quantification of FLAG-FOXI3 cellular localization in HEK293 cells from (C). A χ2 goodness of fit test was used to compare the distribution of each missense variant with WT. *** indicates a P value of <.001. WT, wild type.
Figure 2
Figure 2. Clinical images of individuals with FOXI3 variants.
Clinical images show the phenotypic variability in kindreds with FOXI3 variants. Individual V:3 from kindred 1 (1-V:3) presents with unilateral (L) grade III microtia with aural atresia. Kindred 4 contains 3 affected siblings with variable phenotypes. Individual 4–1 presents with bilateral grade III microtia with atresia and bilateral (left side more affected than right) mandibular hypoplasia and facial tags (removed). Individual 4–2 presents with right grade I microtia with atresia and left grade II microtia with atresia. Individual 4–3 presents with bilateral grade III microtia with atresia and left mandibular hypoplasia. ID, patient identifier; L, left; R, right.
See this image and copyright information in PMC

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