Identification and Structural Characterization of a Novel COL3A1 Gene Duplication in a Family With Vascular Ehlers-Danlos Syndrome.

BACKGROUND

Vascular Ehlers-Danlos syndrome (vEDS) is caused by alterations in the COL3A1 gene, typically involving missense variants that replace glycine residues. In contrast, short in-frame insertions, deletions, and duplications are rare and pose significant challenges for investigation.

METHODS

The histological examination of vascular tissue from a 26-year-old man, who died from a common iliac artery aneurysm and whose mother died at age 60 from an abdominal aortic dissection, strongly suggested a diagnosis of Ehler-Danlos type IV. Ex vivo collagen phenotype assessment, molecular analysis, and in silico structural studies of type III collagen were subsequently performed.

RESULTS

Ex vivo analysis of the patient's fibroblasts revealed altered collagen synthesis, whereas the molecular testing identified a novel 18-nucleotide in-frame duplication (c.2868_2885dup-GGGTCTTGCAGGACCACC) in the COL3A1 gene, resulting in a six-amino acid insertion, p.(Leu958_Gly963dup). Structural investigation indicated that this duplication led to a local perturbation of the collagen triple helix near a metalloproteinase cleavage site.

CONCLUSION

This study highlights the pathogenic role of a novel in-frame duplication in the COL3A1 gene, demonstrating how this seemingly benign alteration significantly compromises collagen turnover and contributes to the development of vEDS.