EHLERS-DANLOS SYNDROME, ARTHROCHALASIA (aEDS)

COL1A1, COL1A2

Description

Scientific Background

The very rare arthrochalasia EDS subtype (aEDS) is inherited in an autosomal dominant manner. It is characterized by an extreme, generalized hypermobility of the joints associated with joint subluxations as well as a congenital, bilateral hip dislocation. Additional symptoms may include muscle hypotonia, short stature, osteopenia, kyphoscoliosis, and velvety, hyperextensible skin. Unlike other EDS subtypes, mild dysmorphic signs such as hypertelorism, bilateral epicanthal folds, wide fontanelles, and micrognathia may occur.

aEDS is caused by variants in the collagen genes COL1A1 and COL1A2, which encode the α1- and α2-chains of type I collagen predominant in skin and bone. Almost all of the described variants affect exon 6 of the COL1A1 or COL1A2 genes. These are primarily splice variants, removing the recognition site for cleavage of the N-terminal propeptides in the α-chains of type I procollagen. In addition, a genomic deletion has been described in both the COL1A1 and the COL1A2 gene, which includes exon 6 and also eliminates the recognition site for cleavage of the N-terminal propeptides. To date, outside these defined regions, only a partial duplication of the COL1A2 gene has been described in aEDS; the affected patient exhibited additional symptoms of osteogenesis imperfecta. In total, four different pathogenic variants in the COL1A1 gene and 12 different pathogenic variants in the COL1A2 gene have been described in aEDS. Incompletely processed procollagen chains can also be detected biochemically and a characteristic ultrastructure seen by electron microscopy.

 

References

Malfait et al. 2017, Am J Med Genet C 175:8 / Brady et al. 2017, Am J Med Genet C 175:70 / Klaassens et al. 2012, Clin Genet 82:121 / Giunta et al. 2008, Am Med Genet 146A:1341 / Raff et al. 2000, Hum Genet 106:19 / Nicholls et al. 2000, J Med Genet 37:E33 / Byers et al. 1997, Am J Med Genet 72:94

GENES

COL1A1, COL1A2
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