Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers–Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility

Abstract

The Ehlers-Danlos syndromes (EDS) are a group of rare inherited connective tissue disorders. Vascular EDS (vEDS) is caused by pathogenic variants in COL3A1, most frequently glycine substitutions. We describe the phenotype of the largest series of vEDS patients with glutamic acid to lysine substitutions (Glu>Lys) in COL3A1, which were all previously considered to be variants of unknown significance. Methods: Clinical and molecular data for seven families with three different Glu>Lys substitutions in COL3A1 were analyzed. Results: These Glu>Lys variants were reclassified from variants of unknown significance to either pathogenic or likely pathogenic in accordance with American College of Medical Genetics and Genomics guidelines. All individuals with these atypical variants exhibited skin hyperextensibility as seen in individuals with classical EDS and classical-like EDS and evidence of tissue fragility as seen in individuals with vEDS. Conclusion: The clinical data demonstrate the overlap between the different EDS subtypes and underline the importance of nextgeneration sequencing gene panel analysis. The three different Glu>Lys variants point toward a new variant type in COL3A1 causative of vEDS, which has consistent clinical features. This is important knowledge for COL3A1 variant interpretation. Further follow-up data are required to establish the severity of tissue fragility complications compared with patients with other recognized molecular causes of vEDS.

A novel mutation in COL3A1 associates to vascular Ehlers–Danlos syndrome with predominant musculoskeletal involvement

“…In literature, most mutations described involve glycine residues which are essential for triple helix of type III collagen structure. In the last few years mutations in codons different from glycine have been described associated with various EDS phenotypes (Ghali et al, 2019 ). Several mutations in different domains of the protein have been described mostly associated with vascular and classical EDS subtypes.…”

Acute Type A Aortic Dissection Confounded by Aberrant Symptoms

“…However, this particular variant has not been reported in the literature in individuals with COL5A1 related conditions but is highly conserved and predicted to disrupt protein function. Interestingly aortic dissections and aneurysms are usually associated with the vascular subtype (type IV) of EDS, which usually results from pathogenic variants in COL3A1 often with glutamic acid to lysine substitutions (Glu>Lys) [ 27 ]. Consequently, it is currently unclear if the mutation contributed to his vascular disorders or not, and further research like cohort and case-control studies are required to clarify this.…”

Four decades in the making: Collagen III and mechanisms of vascular Ehlers Danlos Syndrome

“…Missense variants in the C-propeptide of the proα1(III) chain, and substitutions in the Xaa and Yaa-positions in the triple helical domain can be associated with mild signs of vEDS and arterial fragility [37] . Among the latter group, substitutions of glutamic acid by lysine were recently shown to be associated with a skin phenotype that is more similar to that seen in classical EDS (skin hyperextensibility, delayed wound healing, joint hypermobility), combined with gastro-intestinal and vascular fragility [38] . The crystal structure of the C-propeptide also provided insight that most severe mutations in this domain are located at the petal-base region interface, the petal tips and the base region, and affect intrachain disulfide bonds, interchain interactions or stability of the hydrophobic core [21] .…”