Juvenile Paget Disease via the TNFRSF11B Gene

Juvenile Paget disease (JPD, OMIM#239000) is a rare osteopathy characterized by rapidly remodeling woven bone, osteopenia, fractures, and progressive skeletal deformity (Whyte et al. New Eng J Med 347:175-184, 2002). Deafness and sometimes retinopathy also occur.

Juvenile Paget disease (JPD) is inherited in an autosomal recessive manner. The only molecular defect known to cause JPD are variants in TNFRSF11B, the gene that encodes osteoprotegerin (Whyte et al. J Bone Miner Res 22:938-946, 2007). Osteoprotegerin (OPG) suppresses bone turnover by functioning as a decoy receptor for the osteoclast differentiation factor (also called RANK ligand). Most JPD patients have diminished OPG inhibition of osteoclastogenesis. Distinct genotype-phenotype relationships have been reported (Chong et al. J Bone Miner Res 18:2095-2104, 2003). Missense variants in the cysteine residues, predicted to cause major disruption to the ligand-binding region, were associated with a severe phenotype in which deformity developed before 18 months of age and caused major disability. Non-cysteine missense variants in the ligand-binding domain were associated with an intermediate phenotype, with deformity recognized around the age of 5 years and an increased rate of long bone fracture. Frameshift variants in exon 5 (last exon) were associated with the mildest phenotype.

JPD is a rare condition, and analysis of a large series of patients for this disorder has not been published. Chong et al. studied 8 patients with JPD and identified homozygous TNFRSF11B variants in 5 of them (Chong et al. J Bone Miner Res 18:2095-2104, 2003).

This test provides full coverage of all coding exons of the TNFRSF11B 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).