Novel WNT1 mutations in children with osteogenesis imperfecta: Clinical and functional characterization.

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Biallelic mutations in WNT1 can give rise to a rare form of moderate to severe OI. Here we report on 12 children (age 2 to 16 years; 5 girls) with biallelic WNT1 mutations. Genomic DNA was analyzed either by targeted next-generation sequencing or Sanger sequencing. Mutations were modeled on the WNT1 protein structure. The in vitro functional effect of WNT1 mutations on WNT signaling was assessed in HEK293 cells using the topflash reporter assay system. All patients had lower extremity deformities and vertebral compression fractures. Seven individuals had upper extremity deformities. Intellectual development appeared normal in 11 children, but was clearly impaired in a 3-year old boy. Ptosis was noted in 7 patients. Height z-scores varied widely, from -7.2 to +1.5. A total of 11 disease-causing WNT1 variants (7 missense mutations, 4 mutations leading to premature termination codons) were identified, of which 9 were novel. Three-dimensional protein modeling suggested that each of the missense mutations led to structural modifications. Functional in vitro studies revealed that all observed missense mutations led to decreased ability of WNT1 to induce WNT signaling via the canonical WNT pathway. The reported biallelic WNT1 variants cause loss of WNT1 function and lead to a severe bone fragility phenotype with conspicuous involvement of the spine.