Genetics of Paget's Disease of Bone

Genetic factors play a central role in Paget's disease of bone (PDB). Mutations of SQSTM1 are the most common cause of familial PDB. Mutations of TNFRSF11A cause familial expansile osteolysis and related disorders, which present during childhood with deafness and adolescence with a PDB-like phenotype. Mutations of TNFRSF11B cause the recessively inherited condition of juvenile PDB. Mutations of VCP, HNRNPA2B1, and HNRNPA1 cause syndromes in which PDB is associated with myopathy and neurodegeneration. Finally, several common genetic variants have been identified at the TNFRSF11A, CSF1, OPTN, DCSTAMP, RIN3, and PML loci, which act additively to influence the occurrence and severity of developing classical PDB. Environmental influences interact with genetic background to influence susceptibility to PDB by mechanisms that are incompletely understood. Advances in PDB genetics have improved understanding of the mechanisms by which bone remodeling is regulated and have uncovered genetic markers of disease occurrence and severity that might be of clinical value.