Paget Disease of Bone (PDB) Panel

Paget disease of bone (PDB, OMIM#602080) is the second most common metabolic bone disorder affecting ~2% of the population aged >40 years. The disorder is characterized by focal areas of increased and disorganized bone turnover, leading to bone pain, deformity, pathological fracture, neurological complications, and an increased risk of osteosarcoma (Laurin et al. Am J Hum Genet 70:1582-1588, 2002). The axial skeleton is preferentially affected. Common sites of involvement include the pelvis (70% of cases), femur (55%), lumbar spine (53%), skull (42%), and tibia (32%) (Ralston et al. The Lancet 372:155-163, 2008). PDB can be both inherited and sporadic, with the inherited form accounting for about one-third of patients with PDB (Michou et al. Joint Bone Spine 73:243-248, 2006).

The familial form of PDB is inherited in an autosomal dominant manner with ~80% penetrance (Michou et al. Joint Bone Spine 73:243-248, 2006). At least 8 loci have been described in familial PDB cases by linkage studies, suggesting extensive genetic heterogeneity; however disease-causing genes within most of these loci have not yet been discovered. The most important gene underlying PDB is SQSTM1, which encodes a scaffold protein (Sequestosome 1) in the nuclear factor κB (NFκB) signaling pathway. Mutations in SQSTM1 have been reported to account for 20–50% of familial cases and 5–20% of sporadic cases (Ralston et al. The Lancet 372:155-163, 2008). A minority of PDB cases are caused by mutation in the TNFRSF11A gene, which encodes the receptor activator of NFκB (RANK), a protein essential in osteoclast formation.

Mutations in SQSTM1 have been reported to account for 20–50% of familial cases and 5–20% of sporadic cases with PDB (Ralston et al. 2008). Sensitivity in familial PDB cases that are caused by TNFRSF11A mutations is currently unknown.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This panel provides 100% coverage of all coding exons of the genes plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).