The type of variants at the COL3A1 gene associates with the phenotype and severity of vascular Ehlers–Danlos syndrome

Abstract

Vascular Ehlers-Danlos syndrome (vEDS) is a rare and severe autosomal dominant disorder caused by variants at the COL3A1 gene. Clinical characteristics and course of disease of 215 molecularly proven patients (146 index cases and 69 relatives) were analysed. We found 126 distincts variants that were divided into five groups: (1) Glycine substitutions (n = 71), (2) splice-site and in-frame insertions-deletions (n = 36), (3) variants leading to haplo-insufficiency (n = 7), (4) non-glycine missense variants within the triple helix (n = 4 variants), and (5) non-glycine missense variants or in-frame insertions-deletions, in the N-or C-terminal part of the protein (n = 8). Overall, our cohort confirmed the severity of the disease with a median age at first complication of 29 years (IQR 22-39), the most frequent being arterial (48%) and digestive (24%) ruptures. Groups 2 and 1 were significantly more severe than groups 3-5, with extreme median ages at first major complication of 23-47 years. Patients of groups 3-5 had a less typical phenotype and remarkably absence of digestive events. The distribution of glycine-replacing amino acids was strongly biased towards more destabilizing residues of the collagen assembly. Thus the natural course of vEDS and the clinical phenotype of patients are influenced by the type of COL3A1 variant. This study also confirms that patients with variants located in the C-and N-termini or leading to haplo-insufficiency have milder course of the disease and less prevalent diagnostic criteria. These findings may help refine diagnostic strategy, genetic counselling and clinical care.

Cervical artery dissections and type A aortic dissection in a family with a novel missense COL3A1 mutation of vascular type Ehlers–Danlos syndrome

“…The presentation of vEDS is extremely variable, and in this case the patient presented only one of the four major diagnostic criteria (Beighton et al, 1998). Although recently some phenotypeegenotype correlations have been suggested (Frank et al, 2015, Fig. 1. a; MRI of the head, axial T2-weighted Turbo Spin Echo sequence shows the presence of the dissection of the left internal carotid artery (arrows), b; MRA of the neck, coronal view, shows the dissection of the vertical part of the left vertebral artery (arrows).…”

Pearls & Oy-sters: Vascular EDS presenting with acute proptosis

“…Reduced synthesis leads to structural defects within procollagen and subsequently type III collagen fibrils. 2 This along with other fibrillary collagens is essential in providing structure and strength to the extracellular matrix of numerous tissues in the body including skin, blood vessel walls, and bowel. 1 Most of the variants are missense substitutions affecting the amino acid glycine, causing incorrect linking of the a 1 chains within the triple helical structure.…”

“…Nonetheless, a formal diagnosis of vEDS requires evidence of a pathogenic mutation within the COL3A1 gene. 2 CCF are abnormal arteriovenous connections between the internal or external carotid arteries and the cavernous sinus. 6 Classification of a CCF is based on the Barrow classification, dividing them into direct or indirect shunts.…”

“…In the vascular subtype, the skin can be thin and transparent with a prominent venous pattern. 1 It has an estimated prevalence of 1 per 150,000 2 and can present with life-threatening features such as arterial dissections, spontaneous arterial ruptures, uterine ruptures, and gastrointestinal perforations, usually from early adulthood. 2,3 In a retrospective study, the median age at diagnosis was 29 years.…”

“…1 Most of the variants are missense substitutions affecting the amino acid glycine, causing incorrect linking of the a 1 chains within the triple helical structure. 2 The classification of EDS (Villefranche classification) comprises 6 subtypes, based on the typical clinical features seen in each, with the vascular subtype being one of them. 4 The potential lack of classic signs and symptoms of hypermobility with vEDS is a principal reason leading to delayed diagnosis and misdiagnosis.…”