Paget Disease of Bone via the SQSTM1 Gene

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 inherited or 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, the 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. Variants in SQSTM1 have been reported to account for 20–50% of familial cases and 5–20% of sporadic cases (Eekhoff et al. Arthritis Rheum 50:1650–1654, 2004; Laurin et al. Am J Hum Genet 70: 1582–1588, 2002; Hocking et al. Hum Mol Genet 11:2735–2739, 2002; Beyens et al. Calcif Tissue Int 75:144–152, 2004; Cundy et al. Calcif Tissue Int 2011 July 7 epub). Although different types of variants have been reported, including missense, nonsense, splice site, and frameshift variants, loss of ubiquitin binding is the unifying mechanism by which SQSTM1 variants cause this disease (Cavey et al. Calcif Tissue Int 78:271-277, 2006; Daroszewska et al. Hum Mol Genet 20:2734–2744, 2011). Patients with SQSTM1 variants have severe PDB and a high degree of penetrance with increasing age (Ralston et al. 2008). A minority of PDB cases are caused by variant in the TNFRSF11A gene, which encodes the receptor activator of NFκB (RANK), a protein essential in osteoclast formation (see Test #854 for more information).

This test is predicted to detect disease variants in 20–50% of familial cases and 5–20% of sporadic cases with PDB (Eekhoff et al. 2004; Laurin et al. 2002; Hocking et al. 2002; Beyens et al. 2004; Cundy et al. 2011).

This test provides full coverage of all coding exons of the SQSTM1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.