Osteogenesis imperfecta, type XVI

Osteogenesis imperfecta (OI), or brittle bone disease, is a heritable disorder of connective tissue characterized by bone fragility and low bone mass. OI is clinically and genetically heterogeneous with severity varying from mild to perinatal lethal. Mutations in the COL1A1 and COL1A2 genes cause approximately 90% of OI cases. COL1A1 and COL1A2 encode the alpha 1 and alpha 2 procollagen chains of type I collagen. Mutations in these genes cause autosomal dominant OI; OI types I (MIM 166200), II (MIM 166210), III (MIM 259420) and IV (MIM 166220). Mutations in the IFITM5 can also cause autosomal dominant OI, OI type V (MIM 610967). IFITM5 encodes interferon-induced transmembrane protein 5, also known as bone restricted ifitm-like protein, a molecule of unknown function. Mutations in twelve genes have been linked to autosomal recessive OI or autosomal recessive OI-like disorders. One of these genes, SERPINF1, encodes pigment epithelium-derived factor (PEDF), a strong inhibitor of angiogenesis. PEDF is thought to function in bone formation and remodelling. Mutations in SERPINF1 cause OI type VI (MIM 613982). Mutations in the CRTAP, LEPRE1 and PPIB genes cause OI types VII (MIM 610682), VIII (MIM 610915) and IX (MIM 259440). These genes encode cartilage-associated protein, prolyl 3-hydroxylase 1 and cyclophilin B, components of a RER protein complex. This complex is involved in prolyl 3-hydroxylation of a single proline, P986, in the alpha 1 chains of type I procollagen. Cyclophilin B is a peptidyl-prolyl cis-trans isomerase that may catalyze the rate limiting step in collagen triple helix formation. Evidence indicates that this complex functions as a molecular chaperone and may also play an important role in the initial association of the C-terminal globular domains of the procollagen alpha chains. SERPINH1 encodes collagen-binding protein 2, also known as heat-shock protein 47 (HSP47). HSP47 is a molecule with known collagen binding properties and is considered to represent another procollagen chaperone. Mutations in SERPINH1 cause OI type X (MIM 613848). Mutations in FKBP10 cause OI type XI (MIM 610968), an OI type with distinctive histological findings. The product of FKBP10, FKBP65, is also localized to RER and has known collagen chaperone functions. Mutations in FKBP10 seem to result in decreased secretion of trimeric procollagen molecules. Interestingly, mutations in FKBP10 have also been reported to cause autosomal recessive Bruck syndrome, an OI-like disorder with associated contractures. PLOD2 autosomal recessive mutations also cause Bruck syndrome (BRKS2; MIM 609220). The zinc finger transcription factor, SP7, is a putative master regulator of bone differentiation. A frameshift mutation in SP7 has been identified in a patient with OI type XII (MIM 613849). OI type XIII (MIM 614856) is caused by mutations in the bone morphogenetic protein 1 gene (BMP1). BMP1 is a metalloproteinase with activity directed against a  number of molecules including type I procollagen C-terminal propeptide cleavage site. OI type XIV (MIM 615066), characterized by a variable degree of severity of multiple fractures and osteopenia, is caused by mutations in TMEM38B. OI type XV (MIM 615220), a moderately severe to progressive form of OI, is caused by mutations in WNT1. OI type XVI, a severe autosomal recessive form of OI, is caused by mutations in the CREB3L1 gene (616229). This gene encodes the endoplasmic reticulum stress transducer, OASIS. Autosomal recessive mutations in SPARC have been reported in individuals with clinical diagnosis of OI type IV (OI type XVII; MIM 616507). SPARC codes for secreted protein, acidic, cysteine-rich, which is also called osteonectin. It binds to collagen I and other matrix proteins. Mutations in PLS3, encoding plastin 3, are a cause of X-linked recessive osteoporosis and osteoporotic fractures, termed bone mineral density quantitative trait locus 18 (BMND18; MIM 300910). Additionally, some females with heterozygous PLS3 mutations may have early onset osteoporosis and vertebral compression fractures.  Plastin 3 is involved in the formation of F-actin.   Cole-Carpenter syndrome is an OI-like disorder. It is characterized by multiple pre- and postnatal bone fractures, craniosynostosis, hydrocephalus, ocular proptosis, and distinctive facial features. Autosomal dominant mutations in P4HB (Cole-Carpenter syndrome 1; MIM 112240) and autosomal recessive mutations in SEC24D (Cole-Carpenter syndrome 2; MIM 616294) can cause this disorder. P4HB and SEC24D code for protein disulfide isomerase (PDI) and protein transport protein Sec24D, respectively.

Panel genes are also offered as individual sequencing and deletion/duplication tests, unless otherwise indicated.


OI Type Genes MIM Mode of Inheritance
I COL1A1 / COL1A2 166200 AD
II COL1A1 / COL1A2 166210 AD
III COL1A1 / COL1A2 259420 AD
IV COL1A1 / COL1A2 166220 AD
V IFITM5 610967 AD
VIII P3H1 (LEPRE1) 610915 AR
IX PPIB 259440 AR
X SERPINH1 613848 AR
XI FKBP10 610968 AR
XII SP7 613849 AR
XIII BMP1 614856 AR
XIV TMEM38B 615066 AR
XV WNT1 615220 AR
XVI CREB3L1 616229 AR
Bruck syndrome 2 PLOD2 609220 AR
BMND18 PLS3 300910 XL
Cole-Carpenter syndrome 1 (CLCRP1) P4HB 112240 AD
Cole-Carpenter syndrome 2 (CLCRP2) SEC24D 616294 AR



Disease Group(s)

Skeletal disorders


81479 x 1


Test Code

Additional Test Codes
1878 —Next Generation Sequencing Only, 1879 — Deletion / Duplication Only

Turnaround Time
Typically 2 to 4 weeks from receipt of a sample in the laboratory. All cases involving ongoing pregnancies will be expedited.

Prenatal Specimens
Cultured cells: 2 confluent T-25 flasks derived from amnio or CVS samples Genomic DNA: minimum of 3 µg (at a concentration of at least 30 ng/µl)

Non-Prenatal Specimens
Whole blood: purple-top (EDTA) tube, minimum of 3 ml Genomic DNA: a minimum of 3 µg (at a concentration of at least 30 ng/µl) Fibroblasts: 2 confluent T-25 flasks Saliva: only samples collected in Oragene DNA Self-Collection Kit or Oragene Saliva Collection Kit for Young Children are accepted

Ship all specimen types at room temperature by overnight courier. Do not freeze. For more details and to download the required forms, please visit our shipping page.

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