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.

Figure 1

Age of onset of the first major complication in 215 vEDS patients.

Figure 2

COL3A1 gene variants detected in 146 unrelated index cases with vEDS. Boxes represent exons of the COL3A1 gene (NG_007404.1) with colour code representing protein domains (yellow: N- and C-terminal domains, green: transition domains, blue: collagen helical domain). Glycine substitutions are presented on the left in a shortened, nonofficial nomenclature. The complete nomenclature of each variant can be found in the Supplementary Table S4, in which variants detected on the genomic but not on the cDNA sequence are indicated with parentheses, for example, p.(Gly324Ser). All of them have been reported in the Ehlers–Danlos Syndrome Variant Database (see Methods, Genetic analysis). Substitutions for other amino acids, splice-site variants and insertions/deletions are shown on the right. indicates the variants found more than once in the index cases cohort; †indicates previously undescribed variants.

Figure 3

Age of onset of the first major complication as a function of type of COL3A1 variant in 215 patients with vEDS. Abbreviations: Splice/del/ins/dup, insertion, deletion, duplication or splice-site variant in the triple helix; Gly, Glycine; C/N domain, C-terminal or N-terminal domain of the protein; TH, triple helix.

Figure 4

Distribution of observed and expected AA residues substituting a Glycine residue. Expected substitutions are calculated from the corrected expected numbers as previously reported. Yates' chi-squared, P<0.001.