Skeletal disease in a father and daughter with a novel monoallelic WNT1 mutation

Abstract Context Most heritable causes of low bone mass in children occur due to mutations affecting type 1 collagen. We describe two related patients with low bone mass and fracture without mutations in the type 1 collagen genes. Case description We describe the index case of a 10-year-old girl with low-impact fractures in childhood and her 59-year-old father with traumatic fractures in adulthood, both with low bone mineral density. They were found to have the same heterozygous missense mutation in the WNT1 gene (p.Gly222Arg), occurring in a highly conserved WNT motif in close proximity to the Frizzled binding site. Conclusions The WNT-ligand WNT1, signaling through the canonical WNT-β­catenin pathway, plays a critical role in skeletal development, adult skeletal homeostasis, and bone remodeling. Biallelic mutations have been described and are associated with moderate to severe osteogenesis imperfecta, in some cases with extra-skeletal manifestations. Patients with monoallelic mutations, as in our case, seem to present with low bone mineral density and less severe disease. The phenotypic difference between biallelic and monoallelic mutations highlights that the aberrant protein in monoallelic mutations may exert a dominant negative effect on the wild type protein as heterozygous carriers in families with biallelic disease are usually asymptomatic. With better understanding of disorders associated with WNT1 mutations, therapies targeting this signaling pathway may offer therapeutic benefit.