• Turnaround time:
    10–21 calendar days (14 days on average)
  • Preferred specimen:
    3mL whole blood in a purple-top tube
  • Alternate specimens:
    DNA or saliva/assisted saliva
  • Sample requirements
  • Request a sample kit



EDSC; OI1; OI2; OI3; OI4

Associated disorders

The COL1A1 gene is associated with autosomal dominant osteogenesis imperfecta (MedGen UID: 45246), Ehlers-Danlos syndrome, arthrochalasia type (MedGen UID: 78662), and Caffey disease (PMID: 24389367).

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Pathogenic variants in COL1A1 are the only known cause of Caffey disease and a rare cause of classic Ehlers-Danlos syndrome. Together, pathogenic variants in COL1A1 and COL1A2 cause >90% of clinical cases of Osteogenesis Imperfecta types I, II, III, and IV and are the only known cause of Ehlers-Danlos, arthrochalasia type.

The COL1A1 gene encodes pro-alpha1(I) that, along with pro-alpha 2(I), forms type I collagen (PMID: 23692737). Type I collagen is the most abundant form of collagen, which strengthens and supports bones, cartilige, tendons, teeth, skin and the sclera of the eye (PMID: 23692737).

Osteogenesis imperfecta
MedGen UID: 45246

Clinical condition
COL1A1 (OMIM 129150) and COL1A2 (OMIM 120160) are associated with osteogenesis imperfecta (OI), a disorder characterized by bone fragility. Pathogenic variants in COL1A1 and COL1A2 are identified in over 90% of individuals with OI, and testing for these variants is recommended in individuals with a personal or family history of fractures not caused by trauma. Some affected individuals exhibit joint laxity and easy bruisability. Identifying radiologic findings include wormian bones, codfish vertebrae, evidence of old, healed fractures, and osteopenia (PMID: 20301472).

Testing for COL1A1 and COL1A2 is often recommended in infants and children with unexplained fractures. Diagnostic clinical and radiologic findings may not be relevant in these situations (PMID: 26566591).

Most cases of OI type I (OMIM 166200) are caused by pathogenic variants in COL1A1. Pathogenic variants in either COL1A1 or COL1A2 are associated with OI types II (OMIM 166210), III (OMIM 259420), and IV (OMIM 166220). OI type I is the mildest form, with affected individuals typically exhibiting blue/gray sclerae and hearing loss in adulthood. OI type II is the most severe and can be life threatening in infancy. Other types of OI have signs and symptoms that vary in severity. (PMID: 20301472, National Library of Medicine. Genetics Home Reference. Osteogenesis Imperfecta. https://ghr.nlm.nih.gov/condition/osteogenesis-imperfecta. Accessed May 2017).

Differential diagnosis
Ehler-Danlos Syndrome (EDS; OMIM 13000) is a heterogenous group of connective tissue disorders, which have some overlap with OI. Typically, affected individuals with EDS have pathogenic variants in COL5A1 and COL5A2, although COL1A1 and COL1A2 pathogenic variants have also been identified in this patient population (PMID: 15580559).

When a short stature syndrome is identified in utero, hypophosphatasia, thanatophoric dysplasia, campomelic dysplasia, and achondroplasia may be considered in addition to a perinatal form of OI (PMID: 19265753).

Additionally, a form of autosomal dominant dentinogenesis imperfecta exists that is distinct from OI (National Library of Medicine. Genetics Home Reference. Dentinogenesis Imperfecta. https://ghr.nlm.nih.gov/condition/dentinogenesis-imperfecta. Accessed May 2017).

Pathogenic variants in CRTAP and P3H1 are associated with rare, often severe, autosomal recessive forms of OI type VII (OMIM 610682) and VIII (OMIM 610915) (PMID: 19550437, National Library of Medicine. Genetics Home Reference. CRTAP gene. https://ghr.nlm.nih.gov/gene/CRTAP. P3H1 gene. https://ghr.nlm.nih.gov/gene/P3H1. Accessed May 2017).

Gene information
The COL1A1 gene codes for pro-alpha1 chains of type I collagen, which belongs to a family of proteins that provide support to many skeletal tissues (National Library of Medicine. Genetics Home Reference. COL1A1 gene. https://ghr.nlm.nih.gov/gene/COL1A1. Accessed May 2017; NCBI. Gene. Gene ID: 1277. https://www.ncbi.nlm.nih.gov/gene/1277. Accessed May 2017). Type I collagen is composed of three chains of pro-collagen molecules: two pro-alpha1 chains and one pro-alpha2 chain, which is produced by the COL1A2 gene (National Library of Medicine. Genetics Home Reference. COL1A2 gene. https://ghr.nlm.nih.gov/gene/COL1A2. Accessed May 2017; NCBI. Gene. Gene ID: 1278. https://www.ncbi.nlm.nih.gov/gene/1278. Accessed May 2017). Pathogenic variants in COL1A1 reduce the amount of type I collagen, leading to the bone fragility.

A mutation in COL1A1 is thought to be the cause of Caffey disease, which presents in infancy with hyperostosis or excessive bone formation, joint swelling, and pain. The symptoms usually improve with age, but joint laxity may persist (National Library of Medicine. Genetics Home Reference. Caffey disease. https://ghr.nlm.nih.gov/condition/caffey-disease. Accessed May 2017).

COL1A1 and COL1A2 show autosomal dominant inheritance. This means that an individual with a pathogenic variant in COL1A1 or COL1A2 has a 50% chance of passing the condition on to their offspring. With this result, it is possible to identify at-risk relatives who can pursue testing for this specific familial variant. OI may be inherited from a parent, but many cases occur spontaneously (in 60% to 100% of affected individuals depending on the OI subtype; PMID: 20301472). OI may be inherited in an autosomal recessive fashion but it is less common.

Treatment by a multidisciplinary team is highly recommended. For a list of OI treatment centers, please see the OI Clinic Directory.

Affected individuals are seen by orthopedists, orthopedic surgeons, pediatric dentists, and rehabilitation specialists. Evaluations for hearing, bone density, scoliosis, vertebral compression fractures, and assessment for craniocervical junction abnormalities are necessary (PMID: 28009709). Surgery presents a particular set of potential problems for affected individuals necessitating appropriate evaluations. Evidence also suggests that there may be some cardiovascular implications for OI patients (PMID: 2764717).

It is common for individuals with OI to receive either IV or oral bisphosphonate therapy. Bisphosphonates increase bone density and decrease fracture rates in affected children and adults, although the extent to which they improve clinical well-being is still debated (PMID: 27760454). New therapies are currently under development (PMID: 27813341).

Review date: May 2017

Assay and technical information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below. In addition, the analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
COL1A1 NM_000088.3