Vascular Ehlers-Danlos Syndrome in siblings with biallelic COL3A1 sequence variants and marked clinical variability in the extended family

Abstract

Vascular Ehlers-Danlos Syndrome (vEDS), also known as EDS type IV, is considered to be an autosomal dominant disorder caused by sequence variants in COL3A1, which encodes the chains of type III procollagen. We identified a family in which there was marked clinical variation with the earliest death due to extensive aortic dissection at age 15 years and other family members in their eighties with no complications. The proband was born with right-sided clubfoot but was otherwise healthy until he died unexpectedly at 15 years. His sister, in addition to signs consistent with vascular EDS, had bilateral frontal and parietal polymicrogyria. The proband and his sister each had two COL3A1 sequence variants, c.1786C>T, p.(Arg596*) in exon 26 and c.3851G>A, p.(Gly1284Glu) in exon 50 on different alleles. Cells from the compound heterozygote produced a reduced amount of type III procollagen, all the chains of which had abnormal electrophoretic mobility. Biallelic sequence variants have a significantly worse outcome than heterozygous variants for either null mutations or missense mutations, and frontoparietal polymicrogyria may be an added phenotype feature. This genetic constellation provides a very rare explanation for marked intrafamilial clinical variation due to sequence variants in COL3A1.

Figure 1

(a) MR angiography (MRA) of patient III-3, coronal view; Cr: cranial, Ca: caudal, R: right, L: left, thick arrows: internal carotid arteries; thin arrows: vertebral arteries; arrowhead: basilar artery. There is occlusion/subocclusion along the dissected right ICA. The left ICA is ectatic with irregular caliber in the precranial segment. (b) 3T MRA 10 months later reveals an established collateral network along the dissected segment of the right ICA indicating recanalized arterial segment, and also verifies a dissection flap along the ectatic left ICA. The caliber of the right ICA is still smaller than that of the left. (c) MRI of the head, T2-weighted axial view; A: anterior, P: posterior, R: right, L: left, and (d) T1-weighted saggital view from left side. Both views showing thickened cortices bilaterally, predominantly frontal but extending over parietal lobes limited by the central sulci, small gyri and findings consistent with pachy micropolygyria.

Figure 2

Analysis of COL3A1 genomic sequence and of collagenous proteins synthesized in dermal fibroblasts. (a) Single amino acid codons of gDNA sequencing results for family members as indicated. (b) Protein electrophoresis studies of cultured dermal fibroblasts: Procollagens were separated under reducing conditions on SDS-PAGE. In proteins secreted into the medium from the individual with two mutant alleles (III-3), the amount of type III procollagen and collagen, α1(III)₃, are reduced and the electrophoretic mobility of the proα1(III) chains (b) and of the trimer of type III collagen (c) are slowed. The amount of type III procollagen secreted by the cells from II-5 was reduced. There was subtle shift in electrophoretic mobility of some proα1(III) chains made by the cells from II-6.

Figure 3

Sequence of the C-terminal propeptide of the proα1(III) chain. The sequence begins with 1 (residue 1222 of the chain) that is the site of the enzymatic cleavage from the remainder of the chain. The last residue, 245 in this figure, is position 1466 of the proα1(III) chain, the last encoded residue of the chain. There are eight cysteine residues in the chain (numbered 1–8). There are three sets of intrachain disulfide bonds (1–4, 5–8 and 6–7). Cysteine residues 2 and 3 are involved in interchain disulfide bonds that stabilize the trimer. The glycine (G) that precedes cysteine 3 is substituted by glutamic acid (E) in the products of one of the mutant alleles. ▴, regions of α-helix; ▪, regions of β-sheet; •, residues involved in coordinating a Ca⁺⁺ ion. The standard single letter code is used to designate amino acids. The chain-association region is underlined and the regions of the structure as determined by Bourhis et al are described (stalk, base, and petal). This figure is adapted from Figure 1 along with information from publication by Bourhis et al, and the spacing of residues is retained to account for regions that are missing in the C-propeptides of other fibrillar collagen genes.