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Missense Variants in COL4A1/2 Are Associated with Cerebral Aneurysms: A Case Report and Literature Review
Masahiro Uemura1, Natsuki Tanaka2, Shoichiro Ando1
1Department of Neurology, Brain Research Institute, Niigata University, Niigata 951-8585, Japan.
Insights
Cerebral aneurysms in COL4A1/2-related vasculopathy are strongly linked to missense variants, not small-vessel disease. This highlights the need for careful cerebral aneurysm evaluation in patients with these specific COL4A1/2 gene variants.
Area of Science:
- Genetics
- Vascular Biology
- Neurology
Background:
- Cerebral aneurysms (CA) are a known complication of COL4A1/2-related vasculopathy, but the precise factors driving their development are unclear.
- This study investigates the genetic and clinical factors associated with CA in individuals with COL4A1/2 variants.
Observation:
- A family with a novel COL4A1 variant and CA was studied alongside a comprehensive review of existing literature on COL4A1/2-related vasculopathy.
- Analysis compared variant types and locations between patients with and without CA.
Findings:
- Out of 76 patients and 53 COL4A1/2 variants, missense variants were significantly more frequent in patients with CA (95.5%) compared to those without (58.1%).
- Cerebral aneurysms were not associated with small-vessel disease or other large-vessel abnormalities in this cohort.
- The majority of variants linked to CA were missense, with only one start codon variant observed.
Implications:
- The development of CA in COL4A1/2-related vasculopathy appears to be driven by qualitative changes in the COL4A1/2 genes, independent of other vascular anomalies.
- Identifying missense variants in COL4A1/2 warrants a thorough assessment for cerebral aneurysms.
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.
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