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.

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.

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.