Thomas Sagardoy: Univ. Bordeaux, INSERM, MRGM, U1211, Bordeaux, France.
Laetitia Bourgeade: CHU de Bordeaux, Service de G��n��tique M��dicale, Centre de R��f��rence Anomalies du D��veloppement et Syndromes Malformatifs, Bordeaux, France.
Didier Lacombe: Univ. Bordeaux, INSERM, MRGM, U1211, Bordeaux, France.
Elizabeth Sarrazin: Centre de R��f��rence Carib��en de Maladies Neuromusculaires Rares, CERCA, CHU de Martinique, Fort de France, France - Centre de R��f��rence des Neuropathies Amylo��des familiales et autres Neuropathies P��riph��riques Rares (NNERF), Service de Cardiologie, CHU de Martinique, Fort de France, France.
Annick Toutain: Department of Medical Genetics, Centre Hospitalier Universitaire, Tours, France.
Caroline Rooryck: Univ. Bordeaux, INSERM, MRGM, U1211, Bordeaux, France. ORCID
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.
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