A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia

Arterioscler Thromb Vasc Biol. 2020 Nov;40(11):2686-2699. doi: 10.1161/ATVBAHA.119.313885. Epub 2020 Sep 17.


Objective: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005).

Conclusions: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.

Keywords: Ehlers-Danlos syndrome; arterial disease; collagen; fibromuscular dysplasia; genetics; phenotype.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aortic Dissection / diagnostic imaging
  • Aortic Dissection / genetics*
  • Aortic Dissection / pathology
  • Arteries / diagnostic imaging
  • Arteries / pathology*
  • Collagen Type V / genetics*
  • Ehlers-Danlos Syndrome / diagnostic imaging
  • Ehlers-Danlos Syndrome / genetics*
  • Ehlers-Danlos Syndrome / pathology
  • Female
  • Fibromuscular Dysplasia / diagnostic imaging
  • Fibromuscular Dysplasia / genetics*
  • Fibromuscular Dysplasia / pathology
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Male
  • Middle Aged
  • Phenotype
  • Polymorphism, Single Nucleotide*
  • Young Adult


  • COL5A1 protein, human
  • Collagen Type V