P354: Vosoritide as a targeted therapy for FGFR3-related thanatophoric dysplasia

Introduction: Non-syndromic tooth agenesis (NSTA) is characterized by the absence of 1 permanent teeth, with at least 6 teeth missing in the oligodontia subtype.To date, more than 10 genes have been implicated in NSTA, including WNT10A.The present study describes the detection and characterization of a WNT10A causal variant for oligodontia in a family with autosomal dominant inheritance.Methods: Exome and Sanger sequences were used to analyze the family.To localize the mutated amino acid in a 3D model, the AlphaFold protein structure prediction method was applied.Results: Exome sequencing of the index case revealed a rare heterozygous novel WNT10A missense variant c.929T>A;p.(Leu310Gln).Sanger sequencing of three additional family members demonstrated that this variant co-segregated with the phenotype.Moreover, in silico analyses supported variant pathogenicity.The AlphaFold protein structure model showed that the mutant amino acid is located on the surface of the WNT10A protein, at a position opposite the Frizzled-8 and Wntless interaction sites.Conclusion: Our analysis renders a phenotype in the canonical Wnt/beta-catenin signaling pathway possible.