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. 2025 Jun 12;13(6):1451.
doi: 10.3390/biomedicines13061451.

Functional Enrichment Analysis of Rare Mutations in Patients with Brain Arteriovenous Malformations

Elena Zholdybayeva  1 , Ayazhan Bekbayeva  1 , Karashash Menlibayeva  2   3 , Alua Gusmaulemova  1 , Botakoz Kurentay  1 , Bekbolat Tynysbekov  1 , Almas Auganov  1 , Ilyas Akhmetollayev  1 , Chingiz Nurimanov  2
Affiliations

Functional Enrichment Analysis of Rare Mutations in Patients with Brain Arteriovenous Malformations

Elena Zholdybayeva et al. Biomedicines. .

Abstract

Background/Objectives: Brain arteriovenous malformations (bAVMs) are rare vascular anomalies characterized by direct connections between arteries and veins, bypassing the capillary network. This study aimed to identify potential genetic factors contributing to the development of sporadic bAVMs. Methods: Three patients (AVM1-3) from Kazakhstan who underwent microsurgical resection at the National Centre for Neurosurgery (NCN) in Astana, Kazakhstan, were analyzed. Brain AVMs were diagnosed using magnetic resonance imaging (MRI). Genomic DNA was isolated from whole venous blood samples, and whole-exome sequencing was performed on the NovaSeq 6000 platform (Illumina). Variants were filtered according to standard bioinformatics protocols, and candidate gene prioritization was conducted using the ToppGene tool. Results: In silico analysis further revealed candidate genes likely associated with lesion development, including COL3A1, CTNNB1, LAMA1, NPHP3, SLIT2, SLIT3, SMO, MAPK3, LRRK2, TTN, ERBB2, PARD3, and OBSL1. It is essential to focus on the genetic variants affecting the following prioritized genes: ERBB2, SLIT3, SMO, MAPK3, and TTN. Mutations in these genes were predicted to be "damaging". Most of these genes are involved in signaling pathways that control vasculogenesis and angiogenesis. Conclusions: Defects in genes associated with ciliary structure and function may be critical to the pathogenesis of brain AVMs. These findings provide valuable insights into the molecular underpinnings of bAVM development, emphasizing key biological pathways and potential candidate genes. Further research is needed to establish robust correlations between specific genetic mutations and clinical phenotypes, which could ultimately inform the development of improved diagnostic, therapeutic, and prognostic approaches.

Keywords: brain arteriovenous malformation; candidate genes; enrichment analysis; exome sequencing; mutation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure A1
Figure A1
Validation analysis of the candidate variants (p.Gly2385Arg, rs34778348) in the genes LRRK2.
Figure A2
Figure A2
Validation analysis of the candidate variants (p.Arg1454Gln, rs183329050) in the genes OBSL1.
Figure A3
Figure A3
Validation analysis of the candidate variants (p.Ala1418Val, rs143417693) in the genes SLIT2.
Figure A4
Figure A4
Validation analysis of the candidate variants (p.Pro489Leu, rs142456637) in the genes ERBB2.
Figure A5
Figure A5
Validation analysis of the candidate variants (p.Arg710His, rs200308943) in the genes CTNNB1.
Figure A6
Figure A6
Validation analysis of the candidate variants (p.Ala1045Thr, rs149722210) in the genes COL3A1.
Figure A7
Figure A7
Validation analysis of the candidate variants (p.Val61Ile, rs147676957) in the genes LAMA1.
Figure A8
Figure A8
Validation analysis of the candidate variants (p.Arg395Gln, rs2288792) in the genes SLIT3.
Figure A9
Figure A9
Validation analysis of the candidate variants (p.Asn321Ile, rs151124318) in the genes NRP2.
Figure A10
Figure A10
Validation analysis of the candidate variants p.Thr179Met, rs115491500) in the genes SMO.
Figure A11
Figure A11
Validation analysis of the candidate variants p.Arg98Trp, rs143386487) in the genes. LAMA5 (control (conditionally healthy).
Figure 1
Figure 1
Neuroradiological imaging findings of bAVM lesions, including cerebral angiograms in both anterior and lateral projections and MRI scans (T2-weighted sequences) in the axial and coronal planes. The images correspond to the three patients described in the study: (1) AVM1—located in the left frontal lobe, (2) AVM2—located in the right parietal lobe, and (3) AVM3—located in the right temporal lobe.
Figure 2
Figure 2
Validation analysis of the candidate variant in the gene SMO (c.536C>T; rs115491500).
Figure 3
Figure 3
Functional network of prioritized genes. The image describes observed and inferred functional interactions linking prioritized genes. Nodes represent input proteins, while edges represent protein–protein associations. Note: known interaction (from curated databases)—light blue; gene co-occurrence—blue; experimentally determined—violet; textmining—light green; co-expression—black. The interaction network was constructed using the STRING tool, Version 12.0 (https://string-db.org/, accessed on 5 February 2025).
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