Osteopetrosis via the TNFSF11 Gene

Osteopetrosis (also called Marble bone disease) is a disorder of increased bone density and bone mass caused by malfunction of bone resorption. Affected patients are at high risk of frequent bone fractures, delayed healing, hip osteoarthritis and osteomyelitis. Some patients may have vision loss, hearing loss, and paralysis of facial muscles and bone marrow abnormalities caused by abnormal dense bone structure. Other features include short stature, development delay, dental abnormalities, hepatosplenomegaly, intellectual disability, and epilepsy (Tolar et al. 2004; Del Fattore et al. 2008; Sobacchi et al. 2013). Osteopetrosis is currently known to be caused by pathogenic variants in the following genes: CLCN7, LRP5, TCIRG1, TNFSF11, CA2, OSTM1, PLEKHM1, SNX10 and TNFRSF11A.

Pathogenic variants in the TNFSF11 gene (also called RANKL) cause autosomal recessive osteopetrosis. The TNFSF11 (tumor necrosis factor ligand superfamily member 11) protein coded by the TNFSF11 gene belongs to a member of the tumor necrosis factor cytokine family and plays a key role in bone homeostasis and immune response (Lo Iacono N. et al. 2013). To date, only a few unique TNFSF11 pathogenic variants have been reported. They are: missense, nonsense, and small deletion. No large TNFSF11 deletions/duplications have been reported in patients with osteopetrosis (Sobacchi C. et al. 2007; Lo Iacono N. et al. 2013; Human Gene Mutation Database).

TNFSF11 pathogenic variants were identified in 4 out of 40 patients affected with osteopetrosis. The four patients showed absence of osteoclasts in bone biopsy (Sobacchi C. et al. 2007). No large deletions/duplications have been reported in patients with osteopetrosis (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the TNFSF11 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).