A panel-based sequencing analysis of patients with Paget's disease of bone suggests enrichment of rare genetic variation in regulators of NF-κB signaling and supports the importance of the 7q33 locus

Paget's disease of bone (PDB) is a common bone disorder characterized by focal lesions caused by increased bone turnover. Monogenic forms of PDB and PDB-related phenotypes as well as genome-wide association studies strongly support the involvement of genetic variation in components of the NF-kappa B signaling pathway in the pathogenesis of PDB. In this study, we performed a panel-based mutation screening of 52 genes. Single variant association testing and a series of gene-based association tests were performed. The former revealed a novel association with NFKBIA and further supports an involvement of variation in NR4A1, VCP, TNFRSF11A, and NUP205. The latter indicated a trend for enrichment of rare genetic variation in GAB2 and PRKCI. Both single variant tests and gene-based tests highlighted two genes, NR4A1 and NUP205. In conclusion, our findings support the involvement of genetic variation in modulators of NF-kappa B signaling in PDB and confirm the association of previously associated genes with the pathogenesis of PDB.