SCIENTIFIC BACKGROUND

COL3A1

Scientific Background

Vascular EDS (vEDS) has a high risk of rupture of arteries, uterus and internal organs with fatal bleeding. Type III collagen represents an important component of the walls of arteries and internal organs (up to 45%), so that these tissues are particularly affected in vEDS. The main clinical criteria according to the 2017 classification are arterial rupture at a young age, spontaneous perforation of the sigmoid colon, uterine rupture during the third trimester, AV fistulas between the carotid artery and cavernous sinus, and a positive family history with a confirmed pathogenic COL3A1 variant. The mode of inheritance is autosomal dominant, and the prevalence is estimated at 1:50,000.

To date, only pathogenic variants in the COL3A1 gene have been published as found in patients with vEDS; biochemically this results in altered synthesis, structure, or secretion of type III procollagen. The composition of the identified types of nucleotide alterations in the COL3A1 gene includes glycine substitutions within the triple helix domain of the pro-α1 (III) chain (approximately 65%), variants leading to premature translational arrest and resulting in structurally altered or unstable polypeptides (30%), and genomic deletions and complex rearrangements affecting whole or multiple exons (less than 5%). The type of variant has an impact on the clinical course: patients with null alleles have a later onset of vascular complications and increased life expectancy compared with patients carrying other variants, whereas patients with glycine substitutions and exon skipping variants have the least favorable prognosis. The localization of the variant within the gene has no influence.

Clinical indicators for the genetic diagnosis of suspected vEDS are a positive family history and the presence of arterial rupture or dissection before the age of 40 years, spontaneous sigmoid perforation, or spontaneous pneumothorax. The clinical diagnosis of vEDS can be confirmed by detection of a pathogenic variant in the COL3A1 gene or by the altered synthesis, structure or secretion of type III procollagen in cultured skin fibroblasts. Although COL3A1 is the only altered gene in vEDS, the genetic detection rate often remains low because the clinical phenotype in patients is frequently incomplete. In the literature, the detection rate of the COL3A1 gene is 95-100% for biochemically detected, structurally altered type III collagen. In patients with a clinical diagnosis of vEDS without evidence of a pathogenic COL3A1 variant, analysis of other genes in the TGFß signal transduction pathway may be considered.

 

References

Byers et al. in: Pagon RA, Adam MP, Ardinger HH, et al, editors. GeneReviews® (updated 2019 Feb 21) / Kuivaniemi and Tromp 2019, Gene 707:151 / Malfait et al. 2017, Am J Med Genet C 175:8 / Byers et al. 2017, Am J Med Genet C 175:40 / Frank et al. 2015, Eur J Hum Genet 23:1657 / Pepin et al. 2014, Genet Med 16:881 / Mayer et al. 2013, Eur J Hum Genet 21, update 2012 / Ong et al. 2012, Virchows Arch 460:637 / Germain 2007, Orphanet J Rare Dis 2:32 / Pepin et al. 2000, N Engl J Med 342:673

GENES

COL3A1
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