Osteogenesis Imperfecta via the FKBP10 Gene

Osteogenesis imperfecta (OI) is a clinically and genetically heterogeneous skeletal disorder characterized by frequent bone fractures with or without minimal trauma. Clinical signs of OI can range from mild to severe. In addition to bone fractures, patients may have scoliosis, bowing of long bones, short stature, blue sclera, hearing loss, dentin defects, muscle weakness or joint laxity. The incidence is approximately 6-7/100,000 (Dijk et al. 2012). ~90% of clinically diagnosed OI is caused by mutations in the COL1A1 and COL1A2 genes, while ~10% is caused by mutations in the CRTAP, FKB10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, IFITM5, BMP1, TMEM38B and other undefined genes (Dijk et al. 2012; Valadares et al. 2014).

Mutations in the FKBP10 gene cause a rare severe form of autosomal recessive type XI OI, Bruck syndrome and Kuskokwim syndrome. Bruck syndrome, an osteogenesis imperfecta phenotypic spectrum disorder, is characterized by congenital contractures with pterygia, bone fractures in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis. Kuskokwim syndrome is defined by congenital joint contracture with minor bone fractures and occurs solely among populations in Central Alaskan Yupik. The FKBP65 protein coded by the FKBP10 gene belongs to a family of immunophilins and may serve as a peptidylprolyl isomerase required for lysyl hydroxylase activity in forming mature cross-links in bone collagen. To date, ~ 20 unique causative mutations have been identified. They are missense, nonsense, splicing site and small deletions/insertions. No large deletions or duplications have been reported (Shaheen et al. 2010; Barnes et al. 2013; Human Gene Mutation Database). A founder mutation c.948dup (p.Ile317Tyrfs*56) was found in patients from Samoa and nearby islands in the South Pacific (Schwarze (2013). Another founder mutation c.877_879delTAC (p.Tyr293del) was seen in Kuskokwim syndrome. ~ 3% of the population in Central Alaskan Yupik are carriers for this mutation (Barnes et al. 2013).

Due to limited publications, clinical sensitivity is currently unknown. In one publication, FKBP10 mutations were identified in 21 families affected with either autosomal recessive OI or Bruck syndrome (Schwarze et al. 2013). The mutation detection rate should be high, because all reported FKBP10 mutations are point mutations or small deletions and insertions, which can be detected by sequencing.

This test provides full coverage of all coding exons of the FKBP10 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).