Survival is affected by mutation type and molecular mechanism in vascular Ehlers–Danlos syndrome (EDS type IV)

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

“…We could not confirm this tendency in this larger cohort of affected individuals (data not shown), consistently with the findings observed in the even greater US cohort. 2,13 We also found a strong distribution bias of the glycine replacements, consistently with previous reports suggesting that for the COL3A1 gene the most destabilizing variants are overrepresented in comparison to less destabilizing residues. 12 Indeed, in our series 73% (58/79) of the mutated residues in index cases were either Val, Glu or Asp, much more frequent than Ala and Ser (18/79, 23%), proportions that diverge significantly from that expected of the possible outcomes of a single base pair substitution in a glycine codon (Po0.001 for the two subgroups).…”

“…12 Indeed, in our series 73% (58/79) of the mutated residues in index cases were either Val, Glu or Asp, much more frequent than Ala and Ser (18/79, 23%), proportions that diverge significantly from that expected of the possible outcomes of a single base pair substitution in a glycine codon (Po0.001 for the two subgroups). This selection bias that was also recently observed by Pepin et al 13 cannot be explained by the transition/transversion rate bias in the human coding sequences and is positively correlated to the triple helix destabilizing effect of the corresponding variants. 14 The collagen triple helical structure is indeed disrupted more profoundly when Gly is replaced by a large charged amino acid such as Asp, than by a smaller residue such as Ala. A recent in vitro study tested the effect of two types of missense variants (Gly-to-Val and Gly-to-Ala) on the type III collagen folding using a bacterial system for production of homotrimeric model polypeptides.…”

“…We did not observe a significant gender effect, contrary to the recent survival analysis made by Byers's group. 13 However, our cohort differs from the US cohort 2,13 in several aspects because of different recruitment and clinical monitoring modalities: index patients and their relatives described here were approximately 5 years older at the time of diagnosis, and number of symptom-free index cases at referral was only 11% in this cohort versus 39% in the US cohort. This important difference has multiple explanations: patients older in our cohort, possible referral bias for more severe subjects, increasing awareness of the disease, and improved imaging modalities and accessibility of genetic testing.…”

“…13,16 Eighteen out of the 36 distinct variants were already shown to lead to exon skipping or to cryptic splice-site activation and to decreased secretion of procollagen trimers. 16,17 Even though there was no variant hotspot in our cohort, a few recurrent substitutions were present, especially the Distribution of observed and expected AA residues substituting a Glycine residue.…”

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

“…Of note, CeAD has been odserved in 2% of patients with genetically described vEDS (North et al, 1995, Pepin et al, 2000, and vEDS was found in less than 2% among large CeAD series (Debette and Markus, 2009). Although vEDS appears to be genetically homogeneous, there is remarkable allelic heterogeneity, which results in varied natural history with gender and type of mutation of a COL3A1 (Pepin et al, 2014). Here we describe a case of a young woman with CeAd as the single manifestation of genetically verified vEDS.…”