Novel variants in FOXI3 gene confirm its implication in Oculo-Auriculo-Vertebral spectrum.

Molecular bases of the clinically heterogenous Oculo-Auriculo-Vertebral Spectrum or Craniofacial Microsomia remain largely unknown. Although genetic diagnosis is established in less than 10% of the patients, variants in the FOXI3 gene are the most recurrent genetic cause. We studied a large family with 6 affected individuals on 4 generations showing an autosomal dominant transmission of Oculo-Auriculo-Vertebral Spectrum with incomplete penetrance. The genome sequencing strategy allowed the identification of a new likely pathogenic missense variant located within the Nuclear Localization Signal of FOXI3 and affecting its subcellular localization. Moreover, we described 3 additional rare FOXI3 variants identified in 3 other patients from a cohort of 251 patients with Oculo-Auriculo-Vertebral Spectrum. These variants were classified as Variants of Unknown Significance. In conclusion, this study confirms FOXI3 implication in the Oculo-Auriculo-Vertebral Spectrum and the importance of Nuclear Localization Signal integrity. Genotype-phenotype correlations and putative modifier haplotype are discussed.