Paget Disease of Bone, Autosomal Recessive Osteopetrosis, and Familial Expansile Osteolysis via the TNFRSF11A Gene

Paget disease of bone (PDB, OMIM#602080) is the second most common metabolic bone disorder that affects up to 2–3% of the population aged >40 years. This 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). Osteopetrosis, autosomal recessive 7 (OPTB7, OMIM#612301) is a severe osteoclast-poor form of autosomal recessive osteopetrosis associated with hypogammaglobulinemia (Guerrini et al. Am J Hum Genet 83:64-76, 2008). Familial expansile osteolysis (FEO, OMIM#174810) is a rare bone disorder characterized by focal areas of increased bone remodeling. FEO is related to PDB but occurs in younger patients, and the skeletal involvement is more severe. The osteolytic lesions, which usually develop in the long bones during early adulthood, show increased osteoblast and osteoclast activity (Hughes et al. Nature Genet 24:45-48, 2000).

Genetic heterogeneity is evident in all three of the disorders listed above. TNFRSF11A-related PDB and FEO are inherited in an autosomal dominant manner. TNFRSF11A-related OPTB7 shows an autosomal recessive pattern. TNFRSF11A encodes receptor activator of nuclear factor-kappa-B (RANK), which is a type I transmembrane protein and contains 4 extracellular cysteine-rich repeats. RANK is essential for osteoclast formation. The causal variants are known to impair cleavage of the RANK signal peptide (Hughes et al. 2000) and to cause abnormal localization of RANK within the cell. Among the few reported cases with TNFRSF11A variants, missense and nonsense changes are associated with the OPTB7 phenotype, while small insertions or duplications are related to the PEO or PDB phenotypes.

This test is predicted to detect disease variants in most individuals with a clinical diagnosis of OPTB7 (Guerrini et al. Am J Hum Genet 83:64-76, 2008). Sensitivity for PDB and FEO is currently unknown.

This test provides full coverage of all coding exons of the TNFRSF11A gene 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 full 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).