Missense Variants in COL4A1/2 Are Associated with Cerebral Aneurysms: A Case Report and Literature Review

Abstract

Background: Although cerebral aneurysm (CA) is a defining complication of COL4A1/2-related vasculopathy, the specific factors influencing its onset remain uncertain. This study aimed to identify and analyze these factors.

Methods: We described a family presenting with a novel variant of the COL4A1 gene complicated with CA. Concurrently, an exhaustive review of previously documented patients with COL4A1/2-related vasculopathy was conducted by sourcing data from PubMed, Web of Science, Google Scholar, and Ichushi databases. We compared the variant types and locations between patients with CA (positive group) and those without CA (negative group).

Results: This study included 53 COL4A1/2 variants from 76 patients. Except for one start codon variant, all the identified variants in CA were missense variants. Otherwise, CA was not associated with other clinical manifestations, such as small-vessel disease or other large-vessel abnormalities. A higher frequency of missense variants (95.5% vs. 58.1%, p = 0.0035) was identified in the CA-positive group.

Conclusions: CA development appears to necessitate qualitative alterations in COL4A1/2, and the underlying mechanism seems independent of small-vessel disease or other large-vessel anomalies. Our findings suggest that a meticulous evaluation of CA is necessary when missense variants in COL4A1/2 are identified.

Keywords: COL4A1; COL4A2; cerebral aneurysm; large vessel abnormality; small vessel disease.

Figure 1

Family tree of the proband. Box and circle symbols represent male and female individuals, respectively. Filled symbols indicate individuals with a history of stroke. Diagonal lines were used to mark deceased family members. Arrows indicate the proband (III-1) and the proband’s mother (II-1).

Figure 2

Brain imaging and the result of sequence analysis. Brain magnetic resonance images (MRIs) of the proband (A–E), including magnetic resonance angiography (MRA) (D) and computed tomography angiography (CTA) (E) as well as MRI and MRA (F,G) of the proband’s mother are presented. (A) Diffusion-weighted image shows acute infarction in the left posterior limb of the internal capsule. (B) Fluid-attenuated inversion recovery image (FLAIR) shows patchy white matter hyperintensities (WMHs) around the lateral ventricles. (C) T2*-weighted image displays multiple microbleeds (arrowheads). (D) Brain magnetic resonance angiography (MRA) shows vertebrobasilar dolichoectasia. (E) Computed tomography angiography (CTA) reveals a large superior cerebellar artery (SCA) aneurysm (marked by an arrowhead) and an aneurysm on the lateral side of the basilar artery (marked by an arrow). (F) T2 weighted image shows diffuse WMHs, and (G) MRA shows an aneurysm of the right ICA just above the ophthalmic artery. (H) Sequence analysis reveals a heterozygous variant, c.3734G>A, in COL4A1 (marked by an arrow).

Figure 3

Color map of an identified missense mutation of COL4A1. Three-dimensional COL4A1 monomer structures generated by PyMol are shown. COL4A1 monomers are shown as green ribbons. The COL4A1 structure reference data were generated using the alphafold2. On the left side are images from the front view, and x, +90° indicate the degree of rotation along the x-axis, respectively. Arrows indicate Gly1245 in COL4A1.

Figure 4

Distribution of variants in COL4A1. In the graph, the exon positions of COL4A1 are presented along the horizontal axis, and the number of mutations is depicted on the vertical axis. Missense mutations in COL4A1 that give rise to charged/branch-chain amino acid substitutions are highlighted in red. These missense mutations are particularly noteworthy as our findings suggest their relevance to cerebral aneurysms (CA). Mutations that resulted in substitutions other than the charged/branch chain amino acids are denoted in blue, while other mutation types are indicated in gray. For splice site mutations, the exons predicted to undergo skipping are shown. The 3′ untranslated region (3′ UTR) is denoted as 3′.