Ehlers Danlos syndrome with a likely monogenic cause

Gene: COL12A1

Green List (high evidence)

Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least five COL12A1 variants have been reported in at least five unrelated cases. Supportive functional studies using patient's fibroblasts were presented for each of the five variants (PMID: 24334604, 24334769, 27348394, 35019233).

Created: 15 Jun 2023, 4:40 p.m. | Last Modified: 15 Jun 2023, 4:40 p.m.

Panel Version: 3.2

Publications

• 35019233

Comment on phenotypes: Previous phenotypes:
Myopathic EDS;mEDS;EDS/Myopathy overlap syndrome;Ehlers-Danlos syndrome, Myopathic type

Created: 18 Mar 2021, 1:38 p.m. | Last Modified: 18 Mar 2021, 1:38 p.m.

Panel Version: 2.18

Green List (high evidence)

I don't know

This gene was part of an initial gene list collated by Duncan Baker, Sheffield Diagnostic Genetics Service, January 2019 on behalf of the GMS Musculoskeletal Specialist Group; Gene symbol submitted: COL12A1; Suggested initial gene rating: green

Created: 3 Apr 2019, 3:41 p.m.

Green List (high evidence)

Green List (high evidence)

Comment on list classification: changed status from amber to green, there is enough evidence in the literature. To date, nine patients from five families with myopathic EDS have been reported: Hicks et al., 2014 (PMID:24334769), Zou et al., 2014 (PMID:24334604) and Punetha et al., 2017 (PMID:273483940).

Created: 26 Apr 2017, 9:29 a.m.

This is a rare form of EDS. The spectrum of diseases characterized by muscle weakness, hypotonia, myopathy, and connective tissue symptoms and was first associated with mutations in the genes that code for collagen type VI. However, these conditions have a wide spectrum of severity that ranges from the most severe Ullrich congenital muscular dystrophy to the milder Bethlem myopathy. Hicks et al., 2014 (PMID:24334769), Zou et al., 2014 (PMID:24334604) investigated groups of patients that had some symptoms of myopathies but presented with a distinctive phenotype and did not have mutations affecting type VI collagen and with these studies they identified patients with autosomal recessive and dominant forms of EDS/myopathy PMID:28306225.

Created: 26 Apr 2017, 9:23 a.m.

Comment on phenotypes: removed Bethlem myopathy 2, 616471; ?Ullrich congenital muscular dystrophy 2616470 these are not confirmed gene- phenotype relationships but there is with Myopathic EDS

Created: 26 Apr 2017, 9:12 a.m.

Review from Dr Anthony Vandersteen, IWK Health centre in Halifax, Nova Scotia, Canada : 'Collagen (XII) was categorised as myopathic EDS In latest classification, only a small number of families, if one was to include this, then COL6A1, COL6A2 and COL6A3 should also be included.'

Created: 26 Apr 2017, 9 a.m.

Myopathic EDS which is caused by heterozygous or biallelic mutations in COL12A1 (mEDS) and which clinically overlaps with Bethlem Myopathy and Ullrich congenital muscular dystrophy (PMID:28306229)- which are other heritable connective tissue disorders (HCTDs) as a result of other mutations, for example in COL12A1, COL6A1, COL6A2, COL6A3

Created: 26 Apr 2017, 8:09 a.m.

Comment on phenotypes: The clinical phenotype highly overlaps with collagen type VI-related myopathies, that is, Bethlem Myopathy, and Ullrich Congenital Muscular Dystrophy (PMID:28306229)

Created: 25 Apr 2017, 1:55 p.m.

Comment on list classification: Awaiting expert review on whether this can be made Green

Created: 6 Apr 2017, 3:57 p.m.

In relation to the EDS pathogenetic scheme, COL12A1 belongs to 'Disorders of structure and function of myomatrix, the interface between muscle and ECM'. The scheme regroups EDS subtypes for which the proteins, coded by the causative genes, function within the same pathway, and which are likely to have shared pathogenic mechanisms, based on current knowledge.

Created: 4 Apr 2017, 12:56 p.m.

To date, nine patients from five families with myopathic EDS have been reported: Hicks et al., 2014 (PMID:24334769), Zou et al., 2014 (PMID:24334604) and Punetha et al., 2017 (PMID:273483940). The mutations include four heterozygous missense mutations that have an autosomal dominant mode of inheritance: c.7167 T>C, p. (Ile2334Thr), c.C5893T, p.(Arg1965Cys), 8329G>C, p.(Gly2777Arg), and c. G8357A, p.(Gly2786Asp), and one homozygous frameshift mutation, introducing a PTC, associated with autosomal recessive inheritance (c.8006 þ1 G>A, p. (2567Asp>Phefs0 2). However it has been noted that the severity ranges from a severe autosomal recessive neonatal form that was described in two boys born to a consanguineous couple, to a milder autosomal dominant form that presents in childhood with muscle weakness, large joint contractures, and variable degrees of joint hypermobility and hypertrophic scarring. The phenotype may not be fully understood as there are so few reported cases PMID:28306225.

Created: 4 Apr 2017, 12:50 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Myopathic EDS; mEDS; EDS/Myopathy overlap syndrome

Publications

• 28306229
• 28306225
• 24334769
• 24334604
• 27348394