Maorong Cai
Yang Liu1,2†- 1The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Nanjing, China
- 2Department of Neurosurgery, The Affiliated Wuxi People’s Hospital of Nanjing Medical University, Wuxi People’s Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China
Objective: To perform genetic testing on a patient with ruptured vertebral artery aneurysm and subarachnoid hemorrhage who was also found to have a thoracic aortic aneurysm/dissection (TAA/D) during preoperative evaluation, along with their family members. The aim was to identify potential pathogenic gene variants, analyze the inheritance pattern, and investigate the association with coexisting intracranial and aortic vascular abnormalities.
Methods: Intracranial vascular lesions (ruptured vertebral artery aneurysm and subarachnoid hemorrhage) were confirmed via computed tomography (CT), computed tomography angiography (CTA), and digital subtraction angiography (DSA). Whole-exome sequencing (WES) via next-generation sequencing (NGS) was conducted on the proband and family members to identify pathogenic gene mutations associated with thoracic aortic aneurysm/dissection (TAA/D) and intracranial vascular abnormalities, thereby elucidating the underlying genetic mechanisms.
Results: This study reports the management of a patient with a ruptured vertebral artery aneurysm, subarachnoid hemorrhage, and concomitant TAA/D incidentally detected during preoperative evaluation. Imaging studies demonstrated occlusion at the vertebral-basilar junction, with the basilar artery being perfused by the anterior circulation. An aneurysm was identified at the vertebral artery confluence, and the right vertebral artery was found to supply the left vertebral artery, left subclavian artery, and descending aorta. The surgical procedure was performed successfully under general anesthesia, and the patient was transferred to the ward in stable condition. NGS revealed two heterozygous mutations in the patient: a maternally inherited MYLK variant (NM_053025.4): c.834_835insGTA (p.Val278dup) and a paternally inherited FBN2 variant (NM_001999.4): c.1478A>G (p.Gln493Arg). Sequence analysis identified novel mutation sites within both genes, which may contribute to the patient’s combined vascular phenotype. Following the procedure, the patient maintained hemodynamic stability and recovered well after discharge without notable cardiopulmonary abnormalities or surgery-related complications.
Conclusion: Our findings expand the mutational spectrum of non-syndromic familial thoracic aortic aneurysm/dissection (TAA/D), highlighting that associated gene mutations may also predispose to intracranial vascular abnormalities. We therefore recommend routine intracranial vascular screening (e.g., CTA/DSA) for patients with familial TAA/D to detect potential intracranial lesions. This case underscores the critical need for comprehensive clinical-genetic evaluation to facilitate early diagnosis and timely intervention, which may improve patient outcomes and reduce morbidity.
1 Introduction
Thoracic Aortic Aneurysm/Dissection (TAAD) is a life-threatening vascular disorders characterized by aortic wall dilatation and potential rupture, with a prevalence of 0.16%–0.34% and an annual incidence of 3.5–10 cases per 100,000 individuals (Berger et al., 2025). Clinically, TAAD manifests as progressive aortic bulging, which may evolve into dissection—a condition marked by insidious onset, acute decompensation, and high mortality, necessitating urgent interventio (Ziganshin and Elefteriades, 2014). Genetically, TAAD is classified into familial (FTAAD, ∼20% of cases) and sporadic forms, with FTAAD typically following an autosomal dominant inheritance pattern. FTAAD patients present at a younger age (58.2 vs. 65.7 years) and exhibit faster aortic expansion (0.21 vs. 0.16 cm/year) than sporadic cases (Ostberg et al., 2020; Hannuksela et al., 2015).
The ClinGen Aortopathy Working Group has identified over 20 TAAD-associated risk genes, with pathogenic mechanisms primarily involving: 1) impaired vascular smooth muscle cell contractility (e.g., ACTA2, MYH11, MYLK, PRKG1 mutations) and 2) dysregulated TGF-β signaling (e.g., FBN1, TGFBR1, TGFBR2 mutations) (Duarte et al., 2023). Notably, ACTA2, MYH11, MYLK, and PRKG1 mutations are particularly relevant, as they can induce dissection at aortic diameters <5.0 cm (Rombouts et al., 2022). Genetic heterogeneity further influences phenotypic severity: the MYLK mutation spectrum, for instance, shows that missense variants confer earlier disease onset and higher risk of aortic symptoms (38% penetrance) compared to null mutations (Wallace et al., 2019).
A growing body of evidence highlights the multisystem vascular involvement in FTAAD, with patients frequently presenting with concomitant abdominal aortic aneurysms or cerebral aneurysms (Isselbacher et al., 2016; Hamilton, 2011). This observation supports a shared genetic network governing vascular development, though clinical heterogeneity remains a challenge—most FTAAD cases are asymptomatic until acute events (e.g., dissection, rupture) or intracranial hemorrhage, and some are incidentally detected via imaging (Abdelrahman et al., 2023). Such heterogeneity implies that polygenic interactions, beyond established monogenic pathways, may drive disease progression (Liu et al., 2012) This is particularly evident in cases with combined aortic and cerebrovascular malformations (e.g., vertebral artery remodeling), where monogenic models fail to explain the pathology. While dominant mutations in ACTA2 and MYH11 have clarified, the role of biallelic or compound heterozygous mutations remains underexplored—representing a critical gap in understanding TAAD with cerebrovascular comorbidities (Keravnou et al., 2018; Burger et al., 2021).
Here, we report a rare non-syndromic FTAAD case with vertebral artery anatomical malformation. Whole-exome sequencing and familial segregation analysis revealed the patient harbored compound heterozygous mutations: MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup) (maternally inherited), and FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg) (paternally inherited). The co-occurrence of thoracic aortic aneurysm and aberrant vertebral artery perfusion (right vertebral artery supplying the left subclavian artery and descending aorta) suggests a mechanistic model where MYLK-mediated contractility defects and FBN2-dependent elasticity impairment act additively to disrupt vascular mechanohomeostasis (Humphrey and Schwartz, 2021). This discovery not only expands the mutational spectrum of non-syndromic TAAD but also provides a novel molecular framework for combined intracranial-aortic vascular pathologies, underscoring the need for systematic cerebrovascular screening in FTAAD families.
2 Materials and methods
2.1 Ethics Statement
This study was reviewed and approved by the Ethics Committee of Wuxi People’s Hospital of Nanjing Medical University. Written informed consent was obtained from all participants.
2.2 DNA extraction and analysis
Genomic DNA was extracted from peripheral blood samples using the DNeasy Blood Kit (Qiagen) according to the manufacturer’s instructions. For each sample, 1–2 mg genomic DNA was fragmented by M220 Focused-ultrasonicator (Covaris) into ∼250 bp. A whole-genome library was prepared using the TargetCap Core Exome Panel V3.0 (Boke Bioscience, Inc.) according to the manufacturer’s protocol. Captured libraries were amplified in KAPA HiFi HotStart ReadyMix (KAPA Biosystems) and purified using Agencourt AMPure XP beads. Enriched libraries were sequenced in a 150-bp paired-end mode on a DNBSEQ-T7 platform (MGI Tech. Co. Ltd., Shenzhen, China) with an average coverage depth of >100×. Finally, the original image data were converted to raw data in FASTQ format after base calling.
2.3 Variant calling and annotation
Raw sequencing reads were first merged and subjected to quality control using fastp (v0.20.1) to remove low-quality reads and adapter sequences. Clean reads were then aligned to the human reference genome (GRCh37/hg19) using the Sentieon implementation of BWA with default parameters. The resulting BAM files were sorted, deduplicated, realigned around indels, and subjected to base quality score recalibration using Sentieon tools following GATK best practices.
Single nucleotide variants (SNVs) and small insertions/deletions (indels) were identified using GATK HaplotypeCaller. Variant calls were further filtered and annotated using an in-house pipeline, which integrates multiple annotation tools and databases, including ANNOVAR (for functional annotation and population frequency, using 1000 Genomes, ExAC, gnomAD, dbSNP, ClinVar, dbscSNV, HGMD, LOVD, OMIM, Orphanet, GSDB, COSMIC, etc.), VEP (Variant Effect Predictor, for transcript and protein effect prediction), and InterVar (for ACMG guideline-based variant classification). Copy number variants (CNVs) were detected using both GATK GermlineCNVCaller (v4.5) and XHMM, and the results were integrated. All identified variants were classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines and the Clinical Genome Resource (ClinGen) recommendations, into five categories: pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, or benign. The final variant interpretation was performed by a multidisciplinary team, integrating genetic, clinical, and family information.
3 Results
3.1 Clinical history
The patient was a 33-year-old woman who presented to the emergency department with a 4-h history of sudden-onset severe headache, nausea, and vomiting.She has no history of smoking and denies any history of hypertension or diabetes. There is no history of dyslipidemia (total cholesterol, LDL-C, HDL-C, and triglycerides are all within normal range), nor is there a family history of premature cardiovascular disease. On admission, vital signs showed left upper arm blood pressure (BP) 93/73 mmHg, right upper arm BP 145/98 mmHg, heart rate 115 bpm, and respiratory rate 37 breaths/min. Laboratory results included hemoglobin 9 g/dL, white blood cell count 16 × 109/L, erythrocyte sedimentation rate 12 mm/h, C-reactive protein 2 mg/dL, D-dimer 942 ng/mL, B-type natriuretic peptide (BNP) 1,000 pg/mL, and troponin T 0.05 ng/mL. Head CT indicated subarachnoid hemorrhage (SAH) with brainstem anterior hematoma (Figure 1A), and subsequent head CTA revealed a columnar protrusion at the vertebral artery confluence, and discontinuity between the vertebral artery and the basilar artery (Figure 1B). The patient had a normal phenotype with no stigmata of connective tissue disorders, no significant medical history, and a prior pregnancy notable for inter-arm BP discrepancy prompting thoracic-abdominal CTA, which incidentally detected a thoracic aortic aneurysm (Figures 1C–F). Family history was negative for aortic disease, and growth and development were unremarkable.
Figure 1. Imaging manifestations of the patient. (A) Head CT demonstrates subarachnoid hemorrhage with an anterior brainstem hematoma (red arrow). (B) Head CTA shows a columnar protrusion at the vertebral artery confluence (red arrow) with discontinuity between the vertebral and basilar arteries. (C–F) Chest CTA reveals a thoracic aortic aneurysm in the patient (red arrow). (G) DSA via a femoral artery approach shows localized saccular dilation of the thoracic aorta (red arrow). (H) DSA image of the right subclavian artery obtained via a right transradial approach. (I) Right vertebral artery DSA shows convergence of the bilateral vertebral arteries intracranially, with no visualization of the basilar artery. (J) Three-dimensional reconstruction and morphometric analysis of the aneurysm. (K) DSA confirms dense packing of the aneurysm, with satisfactory stent position and wall apposition (red arrow). (L) Schematic diagram of the patient’s abnormal blood flow distribution.R-SA:Right Subclavian Artery; L-SA:Left Subclavian Artery; R-CCA:Right Common Carotid Artery; L-CCA:Left Common Carotid Artery; R-VA:Right Vertebral Artery; L-VA:Left Vertebral Artery.
Given the diagnosis, the patient underwent emergency cerebral angiography. This confirmed the presence of a saccular aneurysm at the vertebral artery confluence. Subsequently, a single-stage stent-assisted coiling procedure was performed. During the procedure, an interventional access was established via the right femoral artery. Attempts to advance the angiographic catheter to the aortic arch encountered resistance. Contrast injection revealed a localized spherical dilatation of the thoracic aorta, with blood supply originating from the left subclavian artery; no patent channel toward the ascending aorta was identified, suggesting a thoracic aortic aneurysm (Figure 1G). DSA was performed via a right transradial approach. Angiography of the right subclavian artery revealed multiple local vascular variations (Figure 1H). The catheter was selectively advanced into the right vertebral artery. Subsequent angiography showed that the intracranial segments of the bilateral vertebral arteries converged; however, continuity with the basilar artery was lost, and the right vertebral artery supplied blood flow to the left vertebral artery (Figure 1I). Three-dimensional rotational angiography confirmed an aneurysm at the terminal point of the right vertebral artery. The aneurysm was irregular in shape, with a neck measuring 2.16 mm and a dome height of 4.08 mm (Figure 1J). These findings were consistent with the preoperative CTA results. The angiographic findings were discussed with the patient’s family. Subsequently, the preoperatively planned aneurysm embolization procedure was performed. This aneurysm was successfully treated with stent-assisted coiling. Post-procedural angiography confirmed dense packing of the aneurysm and satisfactory positioning and wall apposition of the stent (Figure 1K). The procedure was uneventful, general anesthesia was effective, and the patient recovered well postoperatively. Integrating the findings from the previous thoracic CTA and the significant inter-arm blood pressure difference, the diagnosis was a thoracic aortic aneurysm involving the proximal segment. This was associated with aberrant blood flow distribution: the ascending aorta had only a small channel connecting to the thoracic aorta, and blood flow from the right vertebral artery passed retrograde via the left vertebral artery to supply the left subclavian artery and the descending aorta (Figure 1L).
3.2 Targeted sequencing and genetic analysis
Considering the patient’s young age and idiopathic presentation, we suspected the presence of pathogenic genetic variants underlying her condition. Therefore, we collected blood samples from the patient and their parents and conducted whole-exome sequencing (NGS). The sequencing results identified germline mutations in 504 (patient), 514 (father), and 513 (mother) genes. Comparative analysis showed 252 shared genes between patient and father, 276 between patient and mother, and 25 common to all three, indicating parental inheritance. Screening of genes known to be potentially associated with vascular diseases revealed that the patient carried heterozygous mutations in FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg) (paternally inherited) and MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup) (maternally inherited) (Figure 2A). However, imaging screening confirmed that both parents were unaffected and without a clinical history of TAAD (Figure 2B).
Figure 2. NGS testing of the case family. (A) A Venn diagram of mutated genes in the proband and her parents, with genes potentially associated with vascular diseases annotated. (B) Family pedigree. White circles/squares indicate unaffected family members, and the black arrow indicates the proband.
A novel heterozygous germline missense variant in FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg) was detected in the proband’s sample (Figures 3A,B).
Figure 3. Visualization of FBN2 Gene Mutation. Figure 3 includes two parts for the variant of FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg): (A) A screenshot from Integrative Genomics Viewer (IGV) showing next-generation sequencing (NGS) reads, confirming the heterozygous germline missense variant in the FBN2 gene; (B) A schematic diagram illustrating how the DNA-level variation (c.1478A>G) results in the corresponding amino acid change (p.Gln493Arg) in the FBN2 protein, as well as the location of this protein-level variant relative to different functional domains of the full-length FBN2 protein.
This mutation is absent in population databases (1000G, ExAC, gnomAD), satisfying the PM2_Supporting criterion of ACMG guidelines. Functional prediction tools (LRT, MutationTaster, Gerp+, CADD) all consistently support its potential pathogenicity. Additionally, a novel heterozygous germline non-frameshift duplication variant in MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup) was identified; this variant is located in a non-repetitive genomic region, causes protein length alteration (satisfying the PM4 criterion of ACMG guidelines), and is also absent from the above-mentioned databases (meeting the PM2_Supporting criterion)(Figures 4A,B). Taken together, these findings suggest that FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg) and MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup) may serve as key genetic determinants contributing to the patient’s early-onset vertebral artery aneurysm and heightened risk of TAA/D (Table 1).
Figure 4. Visualization of MYLK Gene Mutation. Figure 4 includes two parts for the variant of MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup): (A) A screenshot from Integrative Genomics Viewer (IGV) showing next-generation sequencing (NGS) reads, confirming the heterozygous germline non-frameshift duplication variant in the MYLK gene; (B) A schematic diagram illustrating how the DNA-level variation (c.834_835insGTA) results in the corresponding amino acid change (p.Val278dup) in the MYLK protein, as well as the location of this protein-level variant relative to different functional domains of the full-length MYLK protein.
Table 1. NGS and family validation confirmed that the proband had mutations in the MYLK and FBN2 genes, inherited from the father and mother, respectively.
4 Discussion
In this report, we presented the endovascular management of a patient with a ruptured vertebral artery aneurysm accompanied by subarachnoid hemorrhage (SAH) and concurrent thoracic aortic aneurysm/dissection (TAAD). Whole-exome sequencing identified a novel heterozygous germline missense variant in FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg) and a novel heterozygous germline non-frameshift duplication in MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup). Although neither variant has been previously reported in the literature, functional predictions suggest they may act synergistically to disrupt vascular wall integrity, ultimately leading to aneurysm formation at multiple sites. This finding underscores the critical importance of systematic genetic testing: clinically significant hereditary variants may be identified even in patients lacking a typical family history (Yamaguchi et al., 2025).
The MYLK gene is the causative gene for Familial Thoracic Aortic Aneurysm and Dissection Type 7 (FTAAD7, OMIM:613780), following an autosomal dominant inheritance pattern with incomplete penetrance (Shalata et al., 2018). MYLK encodes smooth muscle myosin light chain kinase (MLCK), a key regulatory protein for smooth muscle cell contraction. MLCK binds to the calmodulin complex to phosphorylate the 20 kDa regulatory light chain of myosin, thereby increasing myosin II ATPase activity. This releases energy to drive the cross-bridge cycling of β-myosin heavy chain with α-actin, resulting in smooth muscle contraction (Khapchaev and Shirinsky, 2016). MYLK mutations can lead to dysfunction of smooth muscle contraction through a loss-of-function mechanism. For instance, MYLK nonsense mutations have been reported to disrupt the kinase domain of MLCK via premature termination of translation, resulting in insufficient phosphorylation of myosin light chains and failure of smooth muscle cell contraction, thereby predisposing to thoracic aortic aneurysms and dissections (Luyckx et al., 2017). Consistent with this, MYLK knock-in mice carrying kinase-inactivating mutations develop ascending aortic aneurysms before 6 months of age, further confirming that defective smooth muscle cell contraction is sufficient to trigger aneurysmal dilation (Wang et al., 2010). This functional impairment is particularly critical in the aorta, where rhythmic smooth muscle contraction works in concert with elastic fibers to maintain vascular wall tension and elasticity; when this regulation is disrupted, the vessel wall becomes unable to withstand hemodynamic stress, ultimately leading to aneurysmal dilation or dissection (Milewicz et al., 2017). Notably, the impact of MYLK mutations is not limited to large vessels, as loss of function can also impair intestinal smooth muscle contraction, causing megacystis microcolon intestinal hypoperistalsis syndrome, which further underscores the pivotal role of this gene in smooth muscle function (Halim et al., 2017).
The FBN2 gene is the causative gene for Congenital Contractural Arachnodactyly (CCA, OMIM:121050), inherited in an autosomal dominant manner with near-complete penetrance (Xu et al., 2020). FBN2 encodes Fibrillin-2, a major component of connective tissue microfibrils. It plays a crucial role in the early stages of elastic fiber assembly, providing structural support, strength, and flexibility to connective tissues (Mahdizadehi et al., 2023). When an FBN2 mutation occurs, the resulting abnormal fibrillin-2 protein incorporates into microfibrils through a dominant-negative effect, leading to structural defects and reduced stability in the microfibrils (Deng et al., 2025). These compromised microfibrils are unable to effectively guide and facilitate the orderly aggregation and covalent cross-linking of tropoelastin, ultimately resulting in the formation of elastic fibers that are morphologically abnormal, structurally disorganized, and mechanically compromised, manifesting as diminished tissue elasticity and tensile strength (Mead et al., 2024). The prognosis for most CCA patients is generally favorable. Unlike Marfan syndrome (MFS), cardiovascular involvement is rare in CCA (Singh and Wanjari, 2022). Notably, although cardiovascular involvement is uncommon in CCA, recent case reports suggest an association between FBN2 mutations and intracranial aneurysms, highlighting the gene’s potential role in cerebrovascular disease (Ridha et al., 2019).
The proband carries heterozygous mutations in both MYLK and FBN2. These mutations may synergistically disrupt vascular homeostasis through distinct pathways: the MYLK mutation impairs smooth muscle contractile function, reducing the vessel wall’s ability to withstand hemodynamic shear stress, while the FBN2 mutation compromises elastic fiber integrity, exacerbating structural weakness (Wang et al., 2010; Zodanu et al., 2024). This “dual-pathway synergistic disruption” model may explain the patient’s severe phenotype of early-onset, multi-site aneurysms (Dreher et al., 2025). In contrast, her parents carry only a single mutation each (father: FBN2; mother: MYLK) and exhibit no phenotype, likely due to incomplete penetrance.
Intracranial aneurysms (IA) and thoracic aortic aneurysms/dissections (TAA/D) are life-threatening conditions. Despite occurring in different locations, they share similarities and correlations in pathogenesis, epidemiology, and genomics (Changez et al., 2025). Regarding age of onset, the incidence of both increases with age, predominantly affecting individuals over 40 years old, likely due to vascular aging, reduced elasticity, and cumulative damage (Berger et al., 2025; Caffes et al., 2021). In terms of sex distribution, IA incidence is higher in women within specific age groups, while TAA/D overall shows a higher incidence in men, although certain types are also significant in women (Cai et al., 2022; Cote et al., 2022). This suggests sex factors may play a role in both diseases, implying common underlying risk factors. Furthermore, some genetic syndromes (e.g., Marfan syndrome) increase the risk for both TAA/D and potentially IA, indicating that patients with specific genetic backgrounds may face a dual risk (Vornetti et al., 2023).
Both diseases involve structural abnormalities of the vessel wall. IA formation is associated with localized weakness of the intracranial arterial wall, often due to deficiency or disruption of the medial muscle layer and elastic fibers. TAA/D primarily results from degenerative changes in the aortic media, including elastic fiber fragmentation and collagen reduction (Xu et al., 2019; Annambhotla et al., 2008). These similar structural alterations may stem from common pathophysiological mechanisms such as genetic predisposition, hemodynamic stress, and inflammation. Mutations in certain genes affecting vascular wall structure and function (e.g., elastin and collagen genes) may increase the risk for both conditions (Cocciolone et al., 2018; Arteaga-Solis et al., 2000).
Regarding genomic research, the pathogenesis of IA is not fully understood but is recognized as a complex disease involving genetic and environmental risk factors (Xu et al., 2019). Studies have implicated numerous genes in IA susceptibility and development, including ACE, elastin (ELN), endoglin (ENG), COL3A1, matrix metalloproteinase genes (MMPs), endothelial nitric oxide synthase (eNOS/NOS3), interleukin genes (ILs), tumor necrosis factor-alpha (TNF-α), apolipoprotein genes (APOEs), PRDM, ANRIL, and methylenetetrahydrofolate reductase (MTHFR) (Toader et al., 2023; Tromp et al., 2014). Significant progress has also been made in identifying genetic factors for TAA/D, with at least 31 candidate genes established for hereditary forms (e.g., ACTA2, COL3A1). The development of next-generation sequencing (NGS) continues to expand the genetic spectrum of affected patients (MILEWICZ et al., 2021).
This study has several limitations that should be acknowledged. First, the assessment of pathogenicity for the novel FBN2 (NM_001999.4): c.1478A>G (p.Gln493Arg) and MYLK (NM_053025.4): c.834_835insGTA (p.Val278dup) variants relies primarily on in silico prediction tools (e.g., LRT, MutationTaster), which have inherent limitations in accurately predicting functional consequences in vivo; thus, our pathogenicity claims remain preliminary without further functional validation. Although literature suggests FBN2 mutations may disrupt elastic fiber assembly and MYLK mutations could impair smooth muscle contraction, biochemical evidence is still needed for these specific variants (Mahdizadehi et al., 2023; Khapchaev and Shirinsky, 2016; Hannuksela et al., 2016). Second, the genetic analysis is constrained by the small family cohort (only the proband and parents); although we attempted to recruit additional relatives (grandparents and siblings) for segregation analysis, they were unavailable due to geographical and personal constraints. Third, while whole-exome sequencing (WES) was selected for its cost-effectiveness and efficiency in detecting coding variants in known vascular genes, it has limited sensitivity for non-coding variants (e.g., promoter/enhancer mutations) and structural variants compared to whole-genome sequencing (WGS). To partially mitigate this, copy number variants (CNVs) analysis was performed and ruled out large deletions/duplications in other vascular-related genes. Despite these limitations, our findings contribute to the growing evidence of shared mechanisms between intracranial and aortic vascular diseases and highlight the importance of comprehensive genetic evaluation in such cases.
In conclusion, intracranial aneurysms and thoracic aortic aneurysms/dissections exhibit correlations in epidemiology, pathophysiology, diagnosis, and management. Deeper investigation into these relationships will enhance our understanding of the pathogenic mechanisms underlying both diseases, improve diagnostic accuracy and therapeutic outcomes, and ultimately facilitate the delivery of more personalized medical care for patients.
5 Conclusion
This case highlights the interrelationship between intracranial aneurysms and thoracic aortic aneurysms across pathological mechanisms, clinical phenotypes, epidemiological patterns, and genomic landscapes. Genetic testing identified compound heterozygous mutations in MYLK and FBN2, shedding light on a novel genetic basis for complex vascular phenotypes. These findings expand the known mutational spectrum of thoracic aortic aneurysm/dissection (TAAD) and intracranial aneurysms, underscoring the value of integrative genetic analysis in unexplained cases. Further exploration of these shared pathways will deepen our understanding of disease pathogenesis, providing critical insights for early diagnosis, risk stratification, and targeted therapy. With ongoing research and technological advancements, it is anticipated that more precise preventive and therapeutic strategies for these life-threatening vascular disorders will emerge.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving humans were approved by the Ethics Committee of Wuxi People’s Hospital of Nanjing Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.
Author contributions
MC: Data curation, Writing – original draft. YL: Data curation, Writing – original draft. ZL: Writing – review and editing. YW: Writing – review and editing. JJ: Writing – review and editing.
Funding
The author(s) declare that financial support was received for the research and/or publication of this article. This research was funded by the Wuxi Double Hundred Talents Project (BJ2023013) and Jiangsu Provincial Health Commission General Project (M2021075).
Acknowledgments
We would like to thank the patients and their families for their participation in the study. We thank Aiqiang Xia for his assistance with the bioinformatic of the NGS data.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declare that no Generative AI was used in the creation of this manuscript.
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Keywords: thoracic aortic aneurysm/dissection (TAA/D), intracranial vascular abnormalities, whole-exome sequencing (WES), MYLK mutation, FBN2 mutation, dual gene mutations, intracranial vascular screening
Citation: Cai M, Liu Y, Liao Z, Wu Y and Jiao J (2025) Thoracic aortic aneurysm combined with intracranial vascular abnormalities caused by dual mutations in MYLK and FBN2: a case report. Front. Genet. 16:1672342. doi: 10.3389/fgene.2025.1672342
Received: 24 July 2025; Accepted: 06 October 2025;
Published: 13 October 2025.
Edited by:
Yanghui Chen, Huazhong University of Science and Technology, ChinaReviewed by:
Qianqian Li, Institute of Basic Medical Sciences, ChinaElena Tarca, Grigore T. Popa University of Medicine and Pharmacy, Romania
Copyright © 2025 Cai, Liu, Liao, Wu and Jiao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Zhaodi Liao, bGlhb3poYW9kaTA0MjhAMTYzLmNvbQ==; Yiping Wu, amVzc2U1MjJAMTYzLmNvbQ==; Jiantong Jiao, dG9uZ2ppYW5qaWFvQDEyNi5jb20=
†These authors have contributed equally to this work and share first authorship