COL2A1

The COL2A1 gene encodes type II collagen, a structural protein essential for the development and maintenance of cartilage, the vitreous humor of the eye, and intervertebral discs. 

Mutations in COL2A1 cause a spectrum of connective tissue disorders, known as type II collagenopathies. These disorders range from severe skeletal dysplasias to milder conditions such as Stickler syndrome and early-onset osteoarthritis.

What is COL2A1?

The COL2A1 gene encodes the alpha-1 chain of type II collagen, a critical structural protein in cartilage, the vitreous humor of the eye, the inner ear, and intervertebral discs. 

Located on chromosome 12q13.1–q13.2, COL2A1 produces a triple-helix protein, type II collagen, made of three identical chains. After it is produced, it goes through chemical changes and assembles into strong fibers. These fibers give connective tissues strength, flexibility, and support, helping them maintain their structure and function.

Role in Connective Tissue Health

Type II collagen is synthesized by chondrocytes and forms a dense extracellular matrix, supporting skeletal development, joint function, and ocular stability. Its triple-helical structure, composed of Gly-X-Y repeats, is essential for proper fibril formation and mechanical resilience.

COL2A1 Mutations and Type II Collagenopathies

More than 600 pathogenic COL2A1 variants have been identified, leading to type II collagenopathies, a group of autosomal dominant disorders affecting the skeleton, eyes, and auditory system. The severity of these conditions correlates with mutation type and location, with glycine substitutions in the triple-helical domain often causing severe phenotypes.

Key COL2A1-related disorders include:

Severe Lethal Dysplasias

Achondrogenesis Type II and Hypochondrogenesis are among the most severe, lethal skeletal dysplasias caused by COL2A1 mutations. 

These conditions are characterized by extreme short stature, poor bone development, and respiratory failure due to underdeveloped ribs and lungs, leading to neonatal fatality.

Non-Lethal Skeletal Dysplasias

Non-lethal skeletal dysplasias include Spondyloepiphyseal Dysplasia Congenita (SEDC) and Kniest Dysplasia, both of which significantly impact bone growth and joint function. 

SEDC presents with short stature, spinal abnormalities, clubfoot, cleft palate, vision issues such as myopia and retinal detachment, and hearing loss. 

Kniest Dysplasia is characterized by short stature, enlarged joints, scoliosis, and distinct facial features. It often leads to progressive vision and hearing impairment.

Mild Phenotypes

Milder phenotypes associated with COL2A1 mutations include Stickler Syndrome Type 1, Avascular Necrosis of the Femoral Head (ANFH), and Early-Onset Osteoarthritis. 

Stickler Syndrome primarily affects the eyes, ears, joints, and bones, causing severe nearsightedness, retinal detachment, hearing loss, joint hypermobility, and in some cases, cleft palate. 

ANFH occurs when the femoral head loses its blood supply, leading to joint pain, bone collapse, and early arthritis. 

Early-onset osteoarthritis is a progressive disorder that leads to premature joint degeneration, stiffness, and mobility issues. It appears earlier in life than typical osteoarthritis.

Who Should Consider COL2A1 Testing?

The following groups of people may consider COL2A1 genetic testing:

Individuals with Skeletal Dysplasia or Chondrodysplasia

Skeletal dysplasia and/or chondroplasia can manifest with: 

• Short stature, scoliosis, joint hypermobility, or early-onset osteoarthritis
• Clinical or radiographic features suggestive of spondyloepiphyseal dysplasia congenita (SEDC), Kniest dysplasia, or other skeletal dysplasias

Individuals with Features of Stickler Syndrome or Related Connective Tissue Disorders

Symptoms of Stickler Syndrome of related connective tissue disorders may include: 

• Ocular abnormalities (high myopia, vitreous anomalies, retinal detachment)
• Hearing impairments (sensorineural hearing loss)
• Craniofacial anomalies (Pierre Robin sequence, cleft palate)

Patients with Unexplained Joint Pain or Early-Onset Osteoarthritis

• Persistent joint pain, cartilage degeneration, or osteochondritis at a young age
• History of avascular necrosis of the femoral head (ANFH)

Individuals with a MASS-Like Phenotype (Marfan-Like Features)

• Presentations including tall stature, arachnodactyly, scoliosis, and skeletal deformities
• Patients negative for FBN1 mutations (ruling out Marfan syndrome)

Family Members of Individuals with Known COL2A1 Mutations

• First-degree relatives of patients diagnosed with type II collagenopathies
• Asymptomatic carriers who may be at risk for mild or late-onset symptoms

Prenatal and Carrier Screening for High-Risk Families

• Couples with a family history of COL2A1-related disorders planning a pregnancy
• Prenatal testing when a COL2A1 mutation has been identified in one or both parents

Unexplained Vision, Hearing, and Skeletal Issues Across Multiple Systems

• Individuals with a combination of joint issues, early-onset arthritis, vision loss, and hearing loss
• Cases where other genetic disorders (e.g., FBN1 mutations) have been ruled out

Individuals with Severe Prenatal Skeletal Abnormalities

• Ultrasound findings suggestive of skeletal dysplasia (e.g., short femurs, abnormal spine curvature, underdeveloped cartilage structures)
• Families with a history of lethal or severe skeletal disorders

Test Procedure and Interpretation

The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for COL2A1 genetic testing are considered to be without mutations that can alter the activity of the COL2A1 proteins.

Clinical Implications of Positive COL2A1 Mutations

The clinical implications of a positive COL2A1 mutation test result will vary by individual, although COL2A1 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of skin, soft tissue or musculoskeletal symptoms. 

Patients or practitioners with questions about the clinical implications of COL2A1 mutations should seek further assessment with a genetic counselor or expert. 

Order Genetic Testing

Click here to compare genetic test panels and order genetic testing for health-related SNPs.