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

Abstract

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.

Type V collagen alpha 1 chain promotes the malignancy of glioblastoma through PPRC1-ESM1 axis activation and extracellular matrix remodeling

“…Similar to COL5A1, it has been previously reported that type V collagen can assemble heterotypic fibers with type I collagen members [26]. However, the detailed pathogenesis and mechanism of COL5A1 are still unclear [27,28]. In recent years, various molecular biomarkers and genetic events have been used for classification and prognosis, which has continuously improved the accuracy of brain cancer treatment [29].…”

Clinical and molecular characteristics of 168 probands and 65 relatives with a clinical presentation of classical Ehlers–Danlos syndrome

“…Two individuals with pathogenic COL5A1 variants and one with a COL5A1 VUS had vascular complications. Severe vascular complications have been reported in another 16 and two probands with (likely) pathogenic variants in COL5A1 and COL5A2 , respectively (Angwin et al, 2020; Borck et al, 2010; Karaa & Stoler, 2013; Mehta et al, 2012; Monroe et al, 2015; Richer et al, 2020; Weerakkody et al, 2018; Yasuda et al, 2013; Ziganshin et al, 2015) (Table ). Remarkably, 10 COL5A1 variants and both COL5A2 variants concerned a glycine substitution.…”

“…Remarkably, 10 COL5A1 variants and both COL5A2 variants concerned a glycine substitution. Recently, four probands with multifocal fibromuscular dysplasia and varying, but generally mild manifestations of cEDS were described who harbored the same COL5A1 c.1540G>A, p.(Gly514Ser) variant (Richer et al, 2020). Notably, our patient harboring the COL5A1 VUS c.1477G>A, p.(Gly493Arg), located in the same region, had a hepatic and external iliac artery dissection and several pseudoaneurysms.…”

Single-Cell RNA Sequencing and Quantitative Proteomics Analysis Elucidate Marker Genes and Molecular Mechanisms in Hypoplastic Left Heart Patients With Heart Failure

“…Moreover, both the MMP2 expression level in myocardial tissue and blood circulation was most frequently reported to represent myocardial remodeling accompanied by myofibrosis, inflammation, and consequent development of heart failure (George et al, 2005;Andreasová et al, 2020). It has been reported that COL5A1 mutations are closely related to the abnormal heart or arterial development (Weerakkody et al, 2016;Richer et al, 2020). Ramirez et al (2012) identified that the expression level of COL5A1, reflecting the status of inflammatory and extracellular adhesion, was increased in left ventricle tissues in relation to the hypoxia response.…”