Collagen XII Related Disorders

Collagen XII related disorders (COL12-RD) are characterized by genetic mutations in the COL12a1 gene. This gene encodes the alpha chain type XII collagen family (COL12), and is a member of the FACIT (fibrilassociated collagens with interrupted triple helices collagen family) that interacts with other extracellular matrix proteins.

Clinical Features of COL12-RD

  • Hypermobile distal joints

  • Proximal joint contractures

  • Scoliosis and/or Kyphosis

  • Facial Weakness

  • High arched palate

  • Motor milestones delayed or never acheived

  • Respiratory insufficiency

Many COL12-RD affected individuals do not manifest all of these symptoms, making diagnostics confirmation complex.

Collagen 12 gene
(COL12a1 gene)

Outside of the presentation of the above listed clinical features, genetic testing may identify mutations in this gene. However, given the rarity of this condition, and that mutations leading to Collagen 12 gene (COL12a1 gene) were only recently discovered, genetic testing may often be inconclusive, returning variants of unknown significance (VOUS/VUS). Inconclusive testing results will require further testing and examination by highly qualified neuromuscular specialists to confirm a diagnosis of Collagen 12 gene (COL12a1 gene) . Additional testing may include muscle imaging and a skin biopsy to stain for Collagen 12 gene (COL12a1 gene)  antibodies.

Physiology of COL12a1

The COL12a1 gene interacts with other extracellular matrix proteins to form the environment that surrounds muscle cells. It performs critical functions by supporting muscle cell stability and regeneration while allowing the muscle cell to adhere to the matrix.  Genetic mutations in COL12a1 may lead to COL12-RD, but not all genetic mutations cause disease.  Inheritance of mutations may be either autosomal dominant, autosomal recessive or de novo (spontaneous). COL12-RD is a spectrum disorder that may manifest with mild or severe symptoms. The ability to walk will vary, ranging from gaining and retaining ambulation, to delayed ambulation to achieving or losing ambulation later in life, requiring mobility assistance such as a wheelchair or scooter.  Creatine kinase levels in the blood may be normal to slightly elevated.

COL12a1 is a large gene with few confirmed disease causing mutations making diagnosis of COL12-RD very complex.  There is also symptom overlap with Myopathic Ehlers-Danlos Syndrome (mEDS), further complicating accurate diagnosis. Research is ongoing to identify more variants causing these disorders.


If you have received genetic testing results that indicate a possible diagnosis of Collagen 12 gene (COL12a1 gene) or mEDS, please get in touch with the Cure CMD staff so that we can connect you with neuromuscular experts leading the effort to confirm or eliminate Collagen 12 gene as a diagnosis for you or your child.

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