Dataset Information

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.

SUBMITTER: Richer J

PROVIDER: S-EPMC7953329 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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A Novel Recurrent <i>COL5A1</i> Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia.

Richer Julie J Hill Hannah L HL Wang Yu Y Yang Min-Lee ML Hunker Kristina L KL Lane Jamie J Blackburn Susan S Coleman Dawn M DM Eliason Jonathan J Sillon Guillaume G D'Agostino Maria-Daniela MD Jetty Prasad P Mongeon François-Pierre FP Laberge Anne-Marie AM Ryan Stephen E SE Fendrikova-Mahlay Natalia N Coutinho Thais T Mathis Michael R MR Zawistowski Matthew M Hazen Stanley L SL Katz Alexander E AE Gornik Heather L HL Brummett Chad M CM Abecasis Goncalo G Bergin Ingrid L IL Stanley James C JC Li Jun Z JZ Ganesh Santhi K SK

Arteriosclerosis, thrombosis, and vascular biology 20200917 11

<h4>Objective</h4>While rare variants in the <i>COL5A1</i> gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in <i>COL5A1</i> 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 <i>COL5A1</i> pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arteri ...[more]

PMID: 32938213

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