Osteogenesis Imperfecta via the WNT1 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 (van Dijk et al. 2012). 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 CRTAP, FKB10, LEPRE1, PLOD2, PPIB, SERPINF1, SERPINH1, SP7, WNT1, IFITM5, BMP1, TMEM38B and other undefined genes (van Dijk et al. 2012; Valadares et al. 2014).

Pathogenic variants in the WNT1 gene mainly cause autosomal recessive type XV OI, a severe form of OI, which is characterized by early-onset recurrent fractures, bone deformity, significant reduction of bone density, short stature, and, in some patients, blue sclera. However, a heterozygous variant (c.703C>T, p.Arg235Trp) was also found in an autosomal dominant OI family, in addition, at least one heterozygous carrier father (c.859dupC ,p.His287Profs*30) of a recessive OI case showed signs of early-onset osteoporosis at the age of 42 (Keupp et al. 2013). The WNT1 protein belongs to Wnt protein family, which severs as key regulator of osteoblast activity. To date, more than 15 unique causative pathogenic variants have been identified. They are: nonsense (4), missense (6), splicing (1) and small deletions and insertions (5). There are no reported large deletions /duplications (Pyott et al. 2013; Keupp et al. 2013).

WNT1 pathogenic variants were reported in 5 out of 12 OI families in which no pathogenic variants in other OI-related genes were found (Keupp et al. 2013).

This test provides full coverage of all coding exons of the WNT1 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).