Osteogenesis Imperfecta via the COL1A1 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). ~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 (van Dijk et al. 2012; Valadares et al. 2014).

Mutations in the COL1A1 gene cause autosomal dominant OI types I, II, III and IV, as well as Ehlers-Danlos syndrome and Caffey disease (Steiner et al. 2013). Type I OI is characterized by fractures, blue sclerae and hearing loss, but with minimal bone deformity and dentin defects. Type II OI is perinatal lethal with bowed long bones, severe bone fractures and early death due to respiratory failure caused by small thorax and rib fractures. Type III OI is the severe non-lethal form, patients may show dysmorphic facial features, blue sclerae, dentin defects, scoliosis and extremely short status. Type IV OI has mild to moderate bone deformity, and normal to grey sclerae. Type I collagen, containing two proα1 (I) and one proα2 (II) chains coded by COL1A1 and COL1A2 genes, respectively, is the major structural protein in bone, tendon and ligament. To date, more than 600 COL1A1 pathogenic variants have been documented (Human Gene Mutation Database). No clear genotype-phenotype correlation have been established, but some studies suggested that frameshift, nonsense and splice site mutations in COL1A1 and COL1A2 are seen more in patients affected with mild OI type I that lead to haploinsufficiency, while glycine substitutions in the conserved triple helix domain of the Type I collagen protein are common pathogenic variants in patients affected with OI types II and III (Ben Amor et al. 2011; van Dijk et al. 2013). Almost all cases of type II and type III OI are caused by de novo mutations in COL1A1 or COL1A2. Gonadal mosaicism may explain 3%-5% of cases. The penetrance for an individual who carries a heterozygous COL1A1 and COL1A2 mutation is complete.

Mutations in COL1A1 and COL1A2 were found in 90% of individuals with OI types I, II, III, or IV (Steiner et al. 2013). A recent study reported that COL1A1 and COL1A2 mutations were identified in 56% (14/35) and 44% (11/35) of the OI cases, respectively (Stephen et al. 2014). Sequencing analysis can detect more than 95% of mutations in the COL1A1 and COL1A2 genes, while deletion and duplication studies can detect 1% -2% of COL1A1 and COL1A2 mutations (van Dijk et al. 2012, Steiner et al. 2013).

This test provides full coverage of all coding exons of the COL1A1 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.