Osteogenesis Imperfecta via the TMEM38B 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 (Steiner et al. 2013). Approximately 90% of clinically diagnosed OI is caused by pathogenic variants in the COL1A1 and COL1A2 genes, while ~10% is caused by pathogenic variants in the BMP1, CREB3L1, CRTAP, FKBP10, IFITM5, P3H1(also called LEPRE1), PLOD2, PPIB, SEC24D, SERPINF1, SERPINH1, SP7, WNT1, TMEM38B and other undefined genes (van Dijk and Sillence 2014; Valadares et al. 2014).

Pathogenic variants in the TMEM38B gene cause autosomal recessive OI (type XIV OI). The TMEMB38 protein may serve as a modulator of intracellular calcium. So far, only a few TMEM38B pathogenic variants were reported: nonsense (1), splicing (1), frameshift (1) and gross deletion (3) (Shaheen et al. 2012; Volodarsky et al. 2013; Cabral et al. 2016; Human Gene Mutation Database).

Pathogenic variants in TMEM38B appear to account for a small portion of autosomal recessive Osteogenesis Imperfecta (OI). Pathogenic variants in the TMEM38B gene were found in 3 of 11 studied AR OI families (Shaheen et al. 2012).

This test provides full coverage of all coding exons of the TMEM38B 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).