Revealing Hidden Drivers: ARMC5 Intronic Variant Coexists with NF2, TRAF7 and AKT1 Mutations in Sporadic Meningiomas

Revealing Hidden Drivers: ARMC5 Intronic Variant Coexists with NF2, TRAF7 and AKT1 Mutations in Sporadic Meningiomas | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Revealing Hidden Drivers: ARMC5 Intronic Variant Coexists with NF2 , TRAF7 and AKT1 Mutations in Sporadic Meningiomas Leonardo J. T. Araújo, Arthur A. M. Salame, Helaine L. Charchar, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7134493/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 8 You are reading this latest preprint version Abstract Background : Sporadic intracranial meningiomas exhibit a diverse molecular landscape. While ARMC5 mutations are recognized in bilateral macronodular adrenal disease (BMAD)-associated meningiomas, their role in sporadic cases is uncertain. Objective : To determine the frequency and implications of ARMC5 variants, particularly intronic alterations, alongside canonical driver mutations in surgically treated sporadic meningiomas. Methods : Forty-one patients undergoing surgical resection for sporadic meningiomas were analyzed. Tumor DNA was screened using targeted next-generation sequencing (NGS) for variants in ARMC5, NF2, TRAF7, AKT1, KLF4, and SMO. Patients were clinically and biochemically evaluated to exclude BMAD. Results : No pathogenic coding variants in ARMC5 were found. However, 58.5% of cases harbored the intronic variant c.1864+250C>T. This variant frequently co-occurred with driver mutations, notably in NF2 (34.1%), TRAF7, AKT1, KLF4, and SMO. Most tumors were WHO grade I and predominantly meningothelial in subtype. Conclusion : Our findings identify a high prevalence of a specific ARMC5 intronic variant in sporadic meningiomas, co-occurring with key oncogenic mutations. These results suggest a potential modifying or synergistic role for this variant, warranting further functional investigation. Meningioma Sporadic ARMC5 Intronic Variant Molecular Genetics Next-generation Sequencing 1. INTRODUCTION Intracranial meningiomas are the most prevalent primary tumors of the central nervous system, characterized by a wide range of histopathological subtypes and clinical outcomes [ 1 , 2 ]. While many cases follow an indolent course, a significant proportion exhibit aggressive behavior, necessitating multidisciplinary management and often leading to substantial morbidity[ 3 , 4 ]. As neurosurgery advances toward a precision medicine framework, understanding the molecular underpinnings of meningiomas is essential for refining diagnosis, risk stratification, and therapeutic decision-making. NF2 inactivation is the most established genetic alteration in meningiomas, found in both sporadic and familial forms, especially among neurofibromatosis type 2 (NF2) patients[ 5 , 6 , 7 ]. More recently, somatic mutations in TRAF7, KLF4, AKT1 , and SMO have been identified, particularly in skull base tumors, forming non-NF2 meningioma subgroups with distinct molecular signatures and clinical profiles[ 8 ]. ARMC5 is implicated in bilateral macronodular adrenal disease (BMAD), where both germline and somatic mutations have been linked to adrenal hyperplasia and, in some cases, meningiomas[ 9 , 10 ]. Notably, intronic variants are emerging as potentially functional genomic elements capable of influencing splicing and gene regulation[ 11 ]. Previous case reports and familial studies have hinted at a role for ARMC5 in meningioma development, yet its significance in sporadic cases remains uncertain[ 12 ]. This study aims to comprehensively evaluate the prevalence and distribution of ARMC5 variants, especially intronic alterations, in a cohort of patients with surgically treated sporadic meningiomas. We also characterize co-occurrence patterns with canonical driver mutations, alongside the established meningioma-associated genes ( NF2, TRAF7, SMO, KLF4 , and AKT1 ), to elucidate potential genetic interactions relevant to tumor biology. 2. MATERIALS AND METHODS 2.1. Cohort and Ethics Statement This study was approved by the local institutional review board (CAAE 25627919.1.0000.0068), and all procedures were conducted in accordance with the principles of the Declaration of Helsinki. All participants were fully informed about the study objectives and procedures, and written informed consent was obtained from each participant and/or their legal guardians. A total of 41 adult patients (mean age: 56.7 years; range: 23–77 years) diagnosed with sporadic intracranial meningioma were enrolled. The cohort was predominantly female (87.8%). All participants underwent brain magnetic resonance imaging (MRI) and had clinical indications for surgical intervention. Patients were followed at the Neurosurgery Outpatient Clinic and had no prior genetic or molecular investigations related to meningioma. None of the participants reported a family history of tumors. Meningioma diagnosis and grading were based on the 2016 World Health Organization (WHO) classification of central nervous system tumors. Histopathological evaluation included assessment of brain invasion, mitotic index, necrosis, prominent nucleoli, and high cellularity as key diagnostic criteria. 2.2 Clinical and laboratory evaluations All participants underwent clinical and laboratory evaluations to assess the presence of subclinical hypercortisolism and/or metabolic syndrome. Abdominal imaging was performed to exclude the presence of bilateral macronodular adrenal disease (BMAD). Blood pressure, weight, and height were recorded, and body mass index (BMI) was calculated accordingly. To evaluate autonomous cortisol secretion, participants underwent an overnight dexamethasone suppression test (DST), in which 1 mg of oral dexamethasone (or 10 µg/kg for individuals weighing up to 40 kg) was administered at midnight. Serum cortisol was measured the following morning, with post-suppression values < 1.8 µg/dL considered indicative of appropriate suppression. Values above this threshold were interpreted as consistent with autonomous adrenal cortisol secretion. The presence of suppressed ACTH levels in the context of elevated cortisol was considered suggestive of endogenous glucocorticoid production rather than exogenous corticosteroid use. In addition, participants provided 24-hour urine samples for urinary free cortisol measurement and underwent midnight salivary cortisol testing. Saliva samples were collected using Salivette® collection devices (Catalog #51.1534; SARSTEDT AG & Co, Sarstedtstraße, NRW, Germany), stored under refrigeration, and processed according to standardized protocols. 2.3 Targeted panel investigation Paired genomic DNA (gDNA) samples from fresh-frozen tumor tissue and peripheral blood leukocytes were obtained from all 41 participants and submitted for targeted next-generation sequencing (NGS) analysis using a custom gene panel. 2.3.1 DNA extraction from fresh-frozen meningioma tissue Intracranial meningioma specimens were collected intraoperatively during tumor resection and preserved in RNAlater® (Catalog #AM7021; Thermo Scientific, Waltham, MA, USA) at − 80°C until DNA extraction. Genomic DNA was isolated from approximately 30 mg of each frozen tumor sample using the AllPrep DNA/RNA Mini Kit (Catalog #80204; Qiagen, Germantown, MD, USA), in accordance with the manufacturer’s protocol. DNA integrity was evaluated by 0.8% agarose gel electrophoresis, and DNA concentration was quantified using the Qubit™ Broad Range fluorometric assay (Catalog #Q32850; Thermo Scientific, Waltham, MA, USA). 2.3.2 DNA extraction from peripheral blood Peripheral venous blood was collected from each participant in EDTA-containing tubes. Leukocyte gDNA was extracted using the salting-out method, which includes red blood cell lysis, leukocyte lysis, and protein precipitation, followed by ethanol precipitation and washing steps. The DNA pellet was resuspended in buffer, and DNA concentration and purity were assessed using both the Qubit™ Broad Range fluorometric method (Catalog #Q32850; Thermo Scientific, Waltham, MA, USA) and spectrophotometric analysis with the NanoDrop™ One (Thermo Scientific, Waltham, MA, USA). 2.3.3 Custom panel for NGS A custom amplicon panel was designed using the Illumina Design Studio platform to enable targeted mutation profiling of six genes: ARMC5 (Gene ID: 79798; ENST00000268314.9), NF2 (Gene ID: 4771), AKT1 (Gene ID: 207), SMO (Gene ID: 6608), TRAF7 (Gene ID: 84231), and KFL4 (Gene ID: 9314). A total of 199 primers were designed to cover 90.8% of the complete coding region of these six genes. 2.3.4 DNA library preparation and sequencing Library preparation was performed using the AmpliSeq™ for Illumina Custom Panels Kit (Catalog #20020495; Illumina, San Diego, CA, USA) with 50 ng of intact genomic DNA per sample. Fragment size and integrity were assessed using the Agilent TapeStation 2200 system with D1000 ScreenTape and reagents (Catalog #5067–5584 and #5067–5585; Agilent Technologies, Santa Clara, CA, USA). DNA library quantification was conducted using the Qubit™ dsDNA Broad Range Assay Kit (Catalog #Q32853; Thermo Fisher Scientific, Waltham, MA, USA). Sequencing was carried out on the Illumina MiSeq platform using the MiSeq Micro Kit v2 (300 cycles; Catalog #MS-102-2002; Illumina, San Diego, CA, USA). 2.3.5 Variant calling and classification workflow The bioinformatic workflow for variant analysis consisted of multiple stages, each incorporating specialized analytical tools, including: Quality Control : Evaluation of raw sequencing data for base quality, read length, and coverage using FastQC and the Illumina platform's native metrics. Alignment and Variant Calling : High-quality reads were aligned to the human reference genome (hg19 UCSC | b37 GRC/NCBI) using the Burrows-Wheeler Aligner (BWA), and variant calling was performed using GATK or a platform-optimized variant caller. Annotation and Filtering : Identified variants were annotated using ANNOVAR and filtered based on allele frequency, predicted pathogenicity, and coverage thresholds. Classification : Variants were interpreted and classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines, integrating information from databases such as ClinVar[ 13 ], dbSNP, gnomAD, and COSMIC[ 14 ]. This multi-step analytical framework enabled the identification and prioritization of potentially pathogenic variants in both tumor and matched germline samples. Samples harboring at least one candidate variant associated with meningioma development were considered positive. Variants that failed to meet standard sequencing quality control thresholds were excluded from further analysis. Candidate variants were selected based on a comprehensive set of criteria, including: absence from population frequency databases (e.g., gnomAD), location within coding regions or canonical splice sites, predicted nonsynonymous effects or splicing alterations (as determined by SpliceAI), presence in the Catalogue of Somatic Mutations in Cancer (COSMIC) 14 , variant allele frequency (VAF) > 10%, and lack of strand bias. Somatic variants were subsequently classified according to their potential clinical relevance using two categories of reference databases: (1) variant catalogs, such as COSMIC, which catalog somatic mutations observed in cancer; and (2) interpretive databases, including ClinVar[ 13 ], Franklin by Genoox[ 15 ], and My Cancer Genome[ 16 ]. These databases integrate expert-curated information regarding the functional and therapeutic implications of tumor-specific variants, particularly their potential to guide targeted treatment strategies. 3. RESULTS Clinical and laboratory evaluations did not identify evidence of autonomous cortisol secretion. All participants demonstrated adequate suppression following the dexamethasone suppression test (DST), and no abnormalities were observed in midnight salivary cortisol or 24-hour urinary free cortisol levels (Table 1 ). Table 1 Clinical data of meningioma patients Participants N (%) Female N (%) Male N (%) Mean age (yrs) 57 54 60 Obesity 11 (26.8) 10 (90.9) 1 (9.1) Blood hypertention 10 (24.4) 9 (90.0) 1 (10.0) Diabetes 4 (9.8) 3 (75.0) 1 (25.0) Dyslipidemia 19 (43.3) 15 (78.9) 4 (21.1) Total 41 (100) 36 (87.8) 5 (12.2) Obesity classification: BMI ≥ 30 cm/kg 2 . All participants received medical care, and their other medical conditions/comorbidities were well-managed. Regarding metabolic comorbidities, 11 participants (26.8%) met the criteria for obesity (BMI > 30 kg/m²), 10 (24.4%) had systemic arterial hypertension, four (9.8%) had diabetes mellitus, and 19 (46.3%) had dyslipidemia. The prevalence and sex-based distribution of these comorbid conditions are summarized in Table 1 . The most frequent anatomical locations of the surgically resected meningiomas were the sphenoid wing (n = 13), clinoid region (n = 7), and olfactory groove (n = 4), as detailed in Table 2 . Table 2 Somatic variants from each meningioma sample, according to their topography. Sample Grade Histology Topography Gene Variant(s) Oncogenicity Consequence ARMC5* 1A 1 Transitional Petroclival AKT1 c.49G > A p.(Glu17Lys) Oncogenic Missense C/T 1B 1 Meningothelial Foramen Magnum no variant observed 1C 1 Transitional Petroclival NF2 c.1499T > C p.(Leu500Pro) VUS Missense T/T 1D 1 Transitional Sphenoid Wing TRAF7 c.1935T > G p.(Ser645Arg) VUS Missense WT 1E 1 Meningothelial Clinoid NF2 c.889C > T p.(Leu297Phe) VUS Missense C/T 1F 1 Meningothelial Clinoid NF2 c.1633G > A p.(Glu545Lys) VUS Missense T/T NF2 c.1639G > A p.(Glu547Lys) VUS Missense TRAF7 c.1559A > G p.(Asn520Ser) Likely Oncogenic Missense 1G 1 Transitional Olfactory Groove no variant observed CT 1H 1 Transitional Sphenoid Wing NF2 c.227A > G p.(Lys76Arg) VUS Missense WT 1I 1 Meningothelial Anterior Petrous Crest no variant observed 3A 1 Transitional Clinoid NF2 c.784C > T p.(Arg262) Oncogenic Stop-gain C/T 3B 1 Meningothelial Petroclival KLF4 c.1225A > C p.(Lys409Gln) Oncogenic Missense WT 3C 1 Psammomatous Optic Nerve Sheath no variant observed C/T 3D 1 Meningothelial Sellar Tubercle TRAF7 c.475 + 2T > A p.? Likely Oncogenic Splice Donor C/T 3E 1 Angiomatous Sphenoid Wing KLF4 c.1225A > C p.(Lys409Gln) Oncogenic Missense C/T 3F 1 Meningothelial Sphenoid Wing KLF4 c.1225A > C p.(Lys409Gln) Oncogenic Missense C/T TRAF7 c.1559A > G p.(Asn520Ser) Likely Oncogenic Missense 3G 1 Meningothelial Sphenoid Wing TRAF7 c.1559A > G p.(Asn520Ser) Likely Oncogenic Missense WT 3H 1 Meningothelial Sphenoid Wing TRAF7 c.1958G > C p.(Arg653Pro) VUS Missense WT 3l 1 Transitional Tentorial NF2 c.889C > T p.(Leu297Phe) VUS Missense C/T 5A 1 Transitional Clinoid KLF4 c.1225A > C p.(Lys409Gln) Oncogenic Missense WT 5B 1 Meningothelial Olfactory Groove TRAF7 c.1958G > A p.(Arg653Gln) VUS Missense WT 5C 1 Fibrous Parasagital NF2 c.1499T > C p.(Leu500Pro) VUS Missense C/T 5D 1 Meningothelial Clinoid no variant observed C/T 5E 2 Atypical Sphenoid Wing KLF4 c.1225A > C p.(Lys409Gln) Oncogenic Missense C/T 2 Atypical Sphenoid Wing TRAF7 c.1559A > G p.(Asn520Ser) Likely Oncogenic Missense 5F 1 Meningothelial Petroclival AKT1 c.49G > A p.(Glu17Lys) Oncogenic Missense C/T 5G 1 Transitional Sphenoid Wing NF2 c.517-1G > A p.? Likely Oncogenic Splice Aceptor WT 5H 1 Meningothelial Foramen Magnum AKT1 c.49G > A p.(Glu17Lys) Oncogenic Missense WT 5I 1 Meningothelial Convexity SMO c.1604G > T p.(Trp535Leu) Likely Oncogenic Missense C/T 7B 1 Meningothelial Sellar Tubercle NF2 c.810 + 1G > A p.? Likely Oncogenic Splice Donor T/T 7C 1 Meningothelial Ethmoidal NF2 c.497del p.(Glu166GlyfsTer8) Likely Oncogenic Frameshift C/T NF2 c.889C > T p.(Leu297Phe) VUS Missense 7D 1 Transitional Sphenoid Wing SMO c.1234C > T p.(Leu412Phe) Oncogenic Missense WT 7F 1 Meningothelial Cavernous sinus no variant observed C/T 7G 1 Transitional Olfactory Groove no variant observed 7H 1 Transitional Cerebelar NF2 c.889C > T p.(Leu297Phe) VUS Missense WT 9A 1 Meningothelial Olfactory Groove SMO c.1234C > T p.(Leu412Phe) Oncogenic Missense C/T 9B 1 Transitional Cerebelar NF2 c.1499T > C p.(Leu500Pro) VUS Missense C/T 9C 1 Meningothelial Clinoid AKT1 c.49G > A p.(Glu17Lys) Oncogenic Missense WT 9D 1 Meningothelial Sphenoid Wing TRAF7 c.1559A > G p.(Asn520Ser) Likely Oncogenic Missense C/T 9E 1 Meningothelial Sphenoid Wing NF2 c.889C > T p.(Leu297Phe) VUS Missense C/T 9F 1 Meningothelial Anterior Petrous Crest AKT1 c.49G > A p.(Glu17Lys) Oncogenic Missense WT TRAF7 c.1922G > T p.(Arg641Leu) VUS Missense 9G 1 Transitional Sphenoid Wing NF2 c.1563dup p.(Glu522ArgfsTer20) Likely Oncogenic Frameshift WT 9H 1 Meningothelial Clinoid TRAF7 c.1958G > A p.(Arg653Gln) VUS Missense T/T * ARMC5 c.1864 + 250C > T intronic variant. Somatic variants were classified based on clinical significance using two categories of databases: variant catalogs (e.g., COSMIC) and variant interpretive databases (e.g., ClinVar, My Cancer Genome), which provide curated information regarding the functional and therapeutic implications of tumor-specific alterations. Variants of uncertain significance (VUS) were noted but not used to define positive cases. Samples were considered positive if they harbored at least one candidate variant with evidence supporting an association with meningioma pathogenesis. Variants failing default sequencing quality control parameters were excluded from analysis. According to the World Health Organization (WHO) histological classification, the vast majority of tumors were classified as Grade 1 meningiomas, with only one case identified as Grade 2 (atypical). The predominant histological subtype was meningothelial (24/41, 58.5%), followed by transitional (13/41, 31.7%). A summary of histological subtypes and tumor locations is presented in Table 2 . No pathogenic candidate variants were identified in the coding region of ARMC5 . However, the intronic allelic variant c.1864 + 250C > T (NM_001105247.2) was detected in most cases, present in 24 out of 41 meningioma samples (58.5%) (Table 2 ). In contrast, variants in non- ARMC5 genes were commonly observed. A total of 82.9% of samples (34/41) harbored at least one somatic variant classified as likely oncogenic or oncogenic. In several cases, multiple alterations were detected, yielding a total of 40 occurrences across 20 distinct somatic variants. Table 2 summarizes these findings, including the identified mutations, associated alleles, and their predicted oncogenic potential. NF2 was the most frequently altered gene, with 10 distinct variants observed across 14 samples (34.1%), totaling 16 variant occurrences. Among these, five were classified as missense variants of uncertain significance (VUS), two as likely oncogenic frameshift variants, two as likely oncogenic splicing variants, and one as an oncogenic stop-gain variant. Notably, 11 of the 14 NF2 -mutant samples (78.6%) also harbored the ARMC5 c.1864 + 250C > T intronic variant (Table 2 ), suggesting a potential pattern of co-occurrence. Six distinct missense variants and one splice donor variant in TRAF7 were identified, totaling seven variant occurrences across 11 of the 41 meningioma samples (26.8%). Among these, three variants were classified as likely oncogenic, while the remaining four were considered variants of uncertain significance (VUS). The ARMC5 c.1864 + 250C > T intronic variant was concurrently detected in six of the 11 TRAF7 -mutated cases (Table 2 ). A single oncogenic missense variant in AKT1 was observed in five samples (12.2%). Of these, two also carried the ARMC5 intronic variant. Likewise, one recurrent oncogenic missense variant in KLF4 was identified in five cases, with three of these also harboring the ARMC5 c.1864 + 250C > T variant (Table 2 ). For SMO , two distinct missense variants — one oncogenic and one likely oncogenic — were detected in three samples (7.3%). The ARMC5 intronic variant co-occurred in two of these cases (Table 2 ). 4. DISCUSSION Absence of Pathogenic ARMC5 Coding Variants in Sporadic Meningiomas Intracranial meningiomas have been documented in patients with bilateral macronodular adrenal disease (BMAD) carrying ARMC5 variants, which encode the armadillo repeat-containing protein 5. Interestingly, meningiomas have also been observed in BMAD patients with wild-type ARMC5 , indicating that the genotype-phenotype correlation may be incomplete[ 10 , 12 , 17 ]. Nevertheless, prior studies have implicated ARMC5 as a potential contributor to meningioma development, suggesting a possible role in tumor predisposition beyond the adrenal phenotype[ 18 – 20 ]. Contrary to our initial hypothesis — based on the observed frequency of ARMC5 variants in BMAD-associated meningiomas (unpublished data) — comprehensive molecular analysis of our well-defined cohort of 41 sporadic meningiomas did not identify any pathogenic variants within the coding region of the ARMC5 gene. This finding highlights a potentially distinct genetic landscape in sporadic meningiomas compared to those arising in the context of BMAD. Although both germline and somatic ARMC5 mutations are firmly established in the pathogenesis of corticotropin-independent macronodular adrenal hyperplasia[ 9 ], our data indicate that such alterations do not appear to play a major role in sporadic meningioma tumorigenesis. These findings add to the growing body of evidence supporting the molecular heterogeneity of meningiomas and emphasize the importance of considering clinical context — such as syndromic or endocrine associations — when exploring their genetic architecture. Noteworthy Prevalence of the ARMC5 Intronic Variant c.1864 + 250C > T Although no pathogenic coding variants in ARMC5 were detected, a notably high prevalence (58.5%) of the intronic allelic variant c.1864 + 250C > T (NM_001105247.2) was observed in our cohort of patients with sporadic meningiomas. The potential functional relevance of intronic variants is increasingly acknowledged, as they may influence pre-mRNA splicing, mRNA stability, or gene expression through regulatory mechanisms[ 21 ]. While this particular variant did not fulfill the criteria for pathogenicity based on current bioinformatic predictions[ 22 ] and available literature, its frequent occurrence across our series merits further attention. Notably, this variant often co-occurred with pathogenic or likely pathogenic mutations in well-established meningioma driver genes, raising the possibility that it may act as a genetic modifier or contribute to tumorigenesis through complex epistatic interactions. Given these observations, further investigation into the biological significance of this variant is warranted. Functional studies, including splicing assays and regulatory impact analyses, will be essential to determine whether the ARMC5 c.1864 + 250C > T variant contributes to meningioma development or progression, despite its current classification as a variant of uncertain significance. Recurrent Pathogenic and Likely Pathogenic Variants in Established Meningioma Genes Our findings reinforce the central role of established meningioma driver genes in the tumorigenesis of sporadic cases. Among these, the tumor suppressor gene NF2 — that encodes the merlin protein — was the most frequently altered, with potentially oncogenic variants identified in 34.1% of samples. This observation is consistent with prior large-scale genomic studies that have highlighted NF2 as a key tumor suppressor frequently inactivated in sporadic meningiomas[ 7 , 23 ]. The spectrum of NF2 alterations observed in our cohort, including frameshift, splicing, and stop-gain mutations, supports its canonical role in tumor suppression through loss of functional merlin protein[ 23 ]. Recurrent pathogenic or likely pathogenic variants were also identified in TRAF7 (26.8%), AKT1 (12.2%), KLF4 (12.2%), and SMO (7.3%). The high prevalence of TRAF7 mutations — encoding the tumor necrosis factor receptor-associated factor 7 protein — is consistent with prior reports indicating its enrichment in meningiomas located at the skull base[ 8 ], a common anatomical site within our surgically treated cohort. The detection of oncogenic AKT1 and KLF4 missense mutations, although observed in smaller subsets, further supports their role in meningioma biology. AKT1, encoding the RAS-alpha serine/threonine-protein kinase, is implicated in proliferative signaling pathways, while KLF4, encoding the Krüppel-like factor 4 transcription factor, is thought to influence differentiation. These findings align with previous studies suggesting a correlation between these mutations and specific histological features or clinical behavior [ 8 , 24 – 27 ]. In addition, co-occurring mutations in TRAF7 and SMO , the latter encoding the Smoothened homolog protein, were detected in a subset of samples, concordant with their established association with the secretory histological subtype (WHO grade I)[ 28 , 29 ]. The functional implications of TRAF7 and KLF4 mutations remain incompletely understood, underscoring the need for further mechanistic studies to evaluate their potential as therapeutic targets. Finally, consistent with literature reports, SMO and AKT1 mutant meningiomas in our cohort displayed a predilection for the anterior skull base and were frequently associated with the meningothelial histological subtype (WHO grade I), reflecting known genotype–phenotype correlations in meningioma subgroups[ 30 ]. High Prevalence of ARMC5 Intronic Variant c.1864 + 250C > T in Sporadic Intracranial Meningiomas: Evidence of Co-Occurrence with Canonical Driver Mutations A notable observation in our sporadic meningioma cohort was the frequent co-occurrence of the ARMC5 intronic variant c.1864 + 250C > T with pathogenic or likely pathogenic mutations in established meningioma driver genes, including NF2 , TRAF7 , AKT1 , KLF4 , and SMO . While the independent roles of these genes in meningioma pathogenesis are well-established[ 8 , 21 , 31 – 34 ], the biological significance of their co-occurrence with the ARMC5 variant remains unclear. Some studies have suggested that interactions between distinct genetic alterations may contribute to tumor development or progression in meningiomas[ 8 , 21 , 23 , 29 ]. Whether this observed co-occurrence reflects independent mutational events or points to a functional relationship, such as genetic modification, synergistic interaction, or epistasis, requires further investigation. Limitations and Future Research Imperatives The interpretation of our findings must consider several limitations. First, this study was conducted at a single institution and involved a modest sample size (n = 41), which may limit the detection of rare variants and constrain the statistical power for genotype–phenotype correlation analyses. Second, the absence of patients with BMAD precludes direct comparative analyses with this endocrine condition and limits the generalizability of our findings to broader clinical contexts. Additionally, our study employed a targeted gene panel, which, while appropriate for detecting known driver mutations, does not capture the full spectrum of genetic alterations that may be involved in sporadic meningioma pathogenesis. Future studies employing whole-exome or whole-genome sequencing in larger, multi-institutional cohorts are needed to expand our understanding of the genetic architecture of these tumors and to uncover novel candidate genes. Importantly, functional studies exploring the biological impact of the ARMC5 c.1864 + 250C > T variant, especially in the context of co-occurring mutations, are warranted to clarify its potential role as a genetic modifier or contributor to tumorigenesis. Furthermore, integrating genetic findings with clinically relevant outcomes, such as recurrence rates, progression-free survival, and response to neurosurgical intervention, will be critical to translating molecular insights into clinically actionable biomarkers that can inform prognosis and guide therapeutic decision-making in meningioma management. 5. CONCLUSION In summary, our comprehensive molecular analysis of a well-characterized cohort of sporadic meningiomas surgically treated at our institution reveals a distinct ARMC5 genetic profile compared to previously observed BMAD-associated cases. While no pathogenic coding variants in ARMC5 were identified, a high prevalence of the intronic variant c.1864 + 250C > T was observed, suggesting a potential, yet currently undefined, role in tumor biology that merits further investigation. Our findings also reaffirm the frequent involvement of established meningioma driver genes, particularly NF2 and TRAF7 , and uncover a pattern of co-occurrence between these mutations and the ARMC5 intronic variant. This observation may reflect underlying molecular interactions that contribute to tumor development or progression. Collectively, these results enhance our understanding of the molecular heterogeneity of sporadic meningiomas and emphasize the importance of continued research into both well-established and emerging genetic alterations. Such efforts are essential to refine diagnostic classifications, improve prognostic stratification, and guide the development of personalized therapeutic strategies for this common and diverse group of central nervous system tumors. Declarations Funding : This work was supported in part by the São Paulo Research Foundation (FAPESP 2015/50192-9)and was granted to MCBVF. Acknowledgments: We thank everyone who supported this study or helped with the manuscript but did not meet the criteria for authorship. Their contributions are greatly appreciated. Disclosure Statement: The authors have nothing to disclose. * Leonardo JTA and Arthur AMS contributed equally to this work and both are considered first authors. Authors’ contributions: * LJTA : biostatistical analysis/technical/experimental advisor and manuscript writer; * AAMS : provided the tumor samples and participant data for the validation cohort and manuscript reviewer; HLC : clinical management; BMPM, LMS, MYM, FRM : technical/experimental analysts and manuscript reviewers; AML : biostatistical analysis advisor and manuscript reviewer; FLL: histopathology analysis; MQA, BBM , EGF : manuscript reviewer; MCBVF : project mentor and advisor, clinical management and manuscript reviewer. Clinical trial number: not applicable. 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Accessed November 9 (2023) https://franklin.genoox.com Ritter DI, Roychowdhury S, Roy A et al (2016) Somatic cancer variant curation and harmonization through consensus minimum variant level data. Genome Med 8(1):117. 10.1186/s13073-016-0367-z Arrivé F, Coudroy R, Thille AW (2021) Early identification and diagnostic approach in acute respiratory distress syndrome (ARDS). Diagnostics (Basel) 11(12):2307. 10.3390/diagnostics11122307 Elbelt U, Trovato A, Kloth M et al (2015) Molecular and clinical evidence for an ARMC5 tumor syndrome: Concurrent inactivating germline and somatic mutations are associated with both primary macronodular adrenal hyperplasia and meningioma. J Clin Endocrinol Metab 100(1):E119–E128. 10.1210/jc.2014-2648 Liu Q, Tong D, Xu J et al (2018) A novel germline ARMC5 mutation in a patient with bilateral macronodular adrenal hyperplasia: A case report. BMC Med Genet 19(1):49. 10.1186/s12881-018-0564-2 Jojima T, Kogai T, Iijima T et al (2020) Genetic alteration of ARMC5 in a patient diagnosed with meningioma and primary macronodular adrenal hyperplasia: A case report. Eur J Endocrinol 183(6):K7–K12. 10.1530/EJE-20-0014 Zhang P, Philippot Q, Ren W et al (2022) Genome-wide detection of human variants that disrupt intronic branchpoints. Proc Natl Acad Sci U S A 119(44):e2211194119. 10.1073/pnas.2211194119 Horak P, Griffith M, Danos AM et al (2022) Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of ClinGen, CGC, and VICC. Genet Med 24(5):986–998. 10.1016/j.gim.2022.01.001 Riemenschneider MJ, Perry A, Reifenberger G (2006) Histological classification and molecular genetics of meningiomas. Lancet Neurol 5(12):1045–1054 Sahm F, Bissel J, Koelsche C et al (2013) AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry. Acta Neuropathol 126(5):757–762. 10.1007/s00401-013-1187-5 John P, Waldt N, Liebich J et al (2022) AKT1 E17K-mutated meningioma cell lines respond to treatment with the AKT inhibitor AZD5363. Neuropathol Appl Neurobiol 48(2):e12780. 10.1111/nan.12780 Yesilöz Ü, Kirches E, Hartmann C et al (2017) Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro Oncol 19(8):1088–1096. 10.1093/neuonc/nox018 Reuss DE, Piro RM, Jones DTW et al (2013) Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125(3):351–358. 10.1007/s00401-013-1093-x Wardaningsih BKSS (2020) Case report. Can Fam Physician 47(10):788–789. 10.21037/cco-20-168 Wang JZ, Nassiri F, Landry AP et al (2023) The multiomic landscape of meningiomas: A review and update. J Neurooncol 161(2):405–414. 10.1007/s11060-023-04253-2 Boetto J, Bielle F, Sanson M, Peyre M, Kalamarides M (2017) SMO mutation status defines a distinct and frequent molecular subgroup in olfactory groove meningiomas. Neuro Oncol 19(4):576–583. 10.1093/neuonc/now276 Stratakis CA, Berthon A (2019) Molecular mechanisms of ARMC5 mutations in adrenal pathophysiology. Curr Opin Endocr Metab Res 8:104–111. 10.1016/j.coemr.2019.07.010 Youngblood M, Miyagishima D, Jin L et al (2020) PATH-39. Associations of genomic subgroup with recurrence in low-grade meningiomas. Neuro Oncol 22(suppl2):ii172–ii173. 10.1093/neuonc/noaa215.720 AlSahlawi A, Aljelaify R, Magrashi A et al (2019) New insights into the genomic landscape of meningiomas identified FGFR3 in a subset of patients with favorable prognoses. Oncotarget 10(53):5549–5559. 10.18632/oncotarget.27178 He WT, Wang X, Song W et al (2021) A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia. BMC Med Genomics 14(1):88. 10.1186/s12920-021-00896-0 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 06 Dec, 2025 Reviewers agreed at journal 10 Nov, 2025 Reviews received at journal 28 Aug, 2025 Reviewers agreed at journal 28 Aug, 2025 Reviewers invited by journal 28 Aug, 2025 Editor assigned by journal 28 Aug, 2025 Submission checks completed at journal 16 Jul, 2025 First submitted to journal 15 Jul, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7134493","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":507965232,"identity":"3e708655-382c-4e54-b5dd-7a6d4a71d6bf","order_by":0,"name":"Leonardo J. T. Araújo","email":"","orcid":"","institution":"IAMSPE","correspondingAuthor":false,"prefix":"","firstName":"Leonardo","middleName":"J. T.","lastName":"Araújo","suffix":""},{"id":507965233,"identity":"0c9a3a5d-dc1e-46ca-88a8-091e8ec8ff59","order_by":1,"name":"Arthur A. M. Salame","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9UlEQVRIiWNgGAWjYHACNjDJByI+NoBIxsYD+HUws8E1Ms5sYJAAUg3Ea2HmBWthYMCrhX/2+WOPeffUybOxn058bLvDpk63/TDQlhqbaFxaJM4lsxvzPDts2MaTu9k490yahNmZRKCWY2m5Dbj0nGFmk+Y5cICxjSF3m3Ru22EJswNALYwNh3FqkYdoqbNv43+7/bclSMv5h/i1GEC0MCe2SeRuY2YEablBwBbDM8xmknMOHE5uk3i7WbK3LU1y2w2gLQl4/CJ3hvGZxJsDdbb9/LkbP/xss+E3O5/+8MGHGhvc3scOEkhTPgpGwSgYBaMADQAA5f9dUxrn0hsAAAAASUVORK5CYII=","orcid":"","institution":"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":true,"prefix":"","firstName":"Arthur","middleName":"A. M.","lastName":"Salame","suffix":""},{"id":507965234,"identity":"ee35b880-c327-41df-8349-498385546dc0","order_by":2,"name":"Helaine L. Charchar","email":"","orcid":"","institution":"Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Helaine","middleName":"L.","lastName":"Charchar","suffix":""},{"id":507965235,"identity":"1c55700f-c9b2-400d-90ee-4998faf56a00","order_by":3,"name":"Flávia R. Mangone","email":"","orcid":"","institution":"Universidade de São Paulo","correspondingAuthor":false,"prefix":"","firstName":"Flávia","middleName":"R.","lastName":"Mangone","suffix":""},{"id":507965236,"identity":"33165725-8595-4531-9f74-f3cb8bdfe239","order_by":4,"name":"Beatriz M. P. Mariani","email":"","orcid":"","institution":"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Beatriz","middleName":"M. P.","lastName":"Mariani","suffix":""},{"id":507965237,"identity":"4f4d8e9f-576f-4c9b-a6a0-27503aed9e2e","order_by":5,"name":"Leandro M. Souza","email":"","orcid":"","institution":"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Leandro","middleName":"M.","lastName":"Souza","suffix":""},{"id":507965238,"identity":"d649e98c-5901-4b2b-b1f8-5a4bf86d59e1","order_by":6,"name":"Felipe L. Ledesma","email":"","orcid":"","institution":"Divisão de Anatomia Patológica do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Felipe","middleName":"L.","lastName":"Ledesma","suffix":""},{"id":507965239,"identity":"74a97d5f-0cde-4703-9689-9f1ad21ba7a8","order_by":7,"name":"Mirian Y. Nishi","email":"","orcid":"","institution":"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Mirian","middleName":"Y.","lastName":"Nishi","suffix":""},{"id":507965240,"identity":"30dda46f-60d8-44c8-904c-4f8e83e661ad","order_by":8,"name":"Madson Q. Almeida","email":"","orcid":"","institution":"Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Madson","middleName":"Q.","lastName":"Almeida","suffix":""},{"id":507965241,"identity":"a804407c-4ecc-433a-a724-f7e2f0c09ad8","order_by":9,"name":"Antônio M. Lerário","email":"","orcid":"","institution":"University of Michigan","correspondingAuthor":false,"prefix":"","firstName":"Antônio","middleName":"M.","lastName":"Lerário","suffix":""},{"id":507965242,"identity":"c1f3924d-37e7-4d38-896f-466ebc025d22","order_by":10,"name":"Berenice B. Mendonça","email":"","orcid":"","institution":"Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Berenice","middleName":"B.","lastName":"Mendonça","suffix":""},{"id":507965243,"identity":"152911ce-2958-473b-bda4-685d914913b1","order_by":11,"name":"Eberval G. Figueiredo","email":"","orcid":"","institution":"Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Eberval","middleName":"G.","lastName":"Figueiredo","suffix":""},{"id":507965245,"identity":"fa810d42-1495-4d86-b96c-9ed61fbf07f1","order_by":12,"name":"Maria Candida B. V. Fragoso","email":"","orcid":"","institution":"Disciplina de Endocrinologia e Metabologia da Faculdade de Medicina da Universidade de São Paulo (HCFMUSP)","correspondingAuthor":false,"prefix":"","firstName":"Maria","middleName":"Candida B. V.","lastName":"Fragoso","suffix":""}],"badges":[],"createdAt":"2025-07-16 00:38:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7134493/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7134493/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90593832,"identity":"3107fa5b-abf4-4c41-b7ab-7ca103957c9a","added_by":"auto","created_at":"2025-09-04 13:11:02","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1208449,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7134493/v1/e72641a5-08a7-47f2-92b6-9a764b990d1a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"\u003cp\u003eRevealing Hidden Drivers: \u003cem\u003eARMC5 \u003c/em\u003eIntronic Variant Coexists with \u003cem\u003eNF2\u003c/em\u003e,\u003cem\u003e TRAF7\u003c/em\u003e and \u003cem\u003eAKT1\u003c/em\u003e Mutations in Sporadic Meningiomas\u003c/p\u003e","fulltext":[{"header":"1. INTRODUCTION","content":"\u003cp\u003eIntracranial meningiomas are the most prevalent primary tumors of the central nervous system, characterized by a wide range of histopathological subtypes and clinical outcomes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. While many cases follow an indolent course, a significant proportion exhibit aggressive behavior, necessitating multidisciplinary management and often leading to substantial morbidity[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. As neurosurgery advances toward a precision medicine framework, understanding the molecular underpinnings of meningiomas is essential for refining diagnosis, risk stratification, and therapeutic decision-making.\u003c/p\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e inactivation is the most established genetic alteration in meningiomas, found in both sporadic and familial forms, especially among neurofibromatosis type 2 (NF2) patients[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. More recently, somatic mutations in \u003cem\u003eTRAF7, KLF4, AKT1\u003c/em\u003e, and \u003cem\u003eSMO\u003c/em\u003e have been identified, particularly in skull base tumors, forming non-NF2 meningioma subgroups with distinct molecular signatures and clinical profiles[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cem\u003eARMC5\u003c/em\u003e is implicated in bilateral macronodular adrenal disease (BMAD), where both germline and somatic mutations have been linked to adrenal hyperplasia and, in some cases, meningiomas[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Notably, intronic variants are emerging as potentially functional genomic elements capable of influencing splicing and gene regulation[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Previous case reports and familial studies have hinted at a role for ARMC5 in meningioma development, yet its significance in sporadic cases remains uncertain[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThis study aims to comprehensively evaluate the prevalence and distribution of \u003cem\u003eARMC5\u003c/em\u003e variants, especially intronic alterations, in a cohort of patients with surgically treated sporadic meningiomas. We also characterize co-occurrence patterns with canonical driver mutations, alongside the established meningioma-associated genes (\u003cem\u003eNF2, TRAF7, SMO, KLF4\u003c/em\u003e, and \u003cem\u003eAKT1\u003c/em\u003e), to elucidate potential genetic interactions relevant to tumor biology.\u003c/p\u003e"},{"header":"2. MATERIALS AND METHODS","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003e2.1. Cohort and Ethics Statement\u003c/h2\u003e\u003cp\u003e This study was approved by the local institutional review board (CAAE 25627919.1.0000.0068), and all procedures were conducted in accordance with the principles of the Declaration of Helsinki. All participants were fully informed about the study objectives and procedures, and written informed consent was obtained from each participant and/or their legal guardians.\u003c/p\u003e\u003cp\u003eA total of 41 adult patients (mean age: 56.7 years; range: 23\u0026ndash;77 years) diagnosed with sporadic intracranial meningioma were enrolled. The cohort was predominantly female (87.8%). All participants underwent brain magnetic resonance imaging (MRI) and had clinical indications for surgical intervention. Patients were followed at the Neurosurgery Outpatient Clinic and had no prior genetic or molecular investigations related to meningioma. None of the participants reported a family history of tumors. Meningioma diagnosis and grading were based on the 2016 World Health Organization (WHO) classification of central nervous system tumors. Histopathological evaluation included assessment of brain invasion, mitotic index, necrosis, prominent nucleoli, and high cellularity as key diagnostic criteria.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Clinical and laboratory evaluations\u003c/h2\u003e\u003cp\u003eAll participants underwent clinical and laboratory evaluations to assess the presence of subclinical hypercortisolism and/or metabolic syndrome. Abdominal imaging was performed to exclude the presence of bilateral macronodular adrenal disease (BMAD). Blood pressure, weight, and height were recorded, and body mass index (BMI) was calculated accordingly.\u003c/p\u003e\u003cp\u003eTo evaluate autonomous cortisol secretion, participants underwent an overnight dexamethasone suppression test (DST), in which 1 mg of oral dexamethasone (or 10 \u0026micro;g/kg for individuals weighing up to 40 kg) was administered at midnight. Serum cortisol was measured the following morning, with post-suppression values\u0026thinsp;\u0026lt;\u0026thinsp;1.8 \u0026micro;g/dL considered indicative of appropriate suppression. Values above this threshold were interpreted as consistent with autonomous adrenal cortisol secretion. The presence of suppressed ACTH levels in the context of elevated cortisol was considered suggestive of endogenous glucocorticoid production rather than exogenous corticosteroid use.\u003c/p\u003e\u003cp\u003e In addition, participants provided 24-hour urine samples for urinary free cortisol measurement and underwent midnight salivary cortisol testing. Saliva samples were collected using Salivette\u0026reg; collection devices (Catalog #51.1534; SARSTEDT AG \u0026amp; Co, Sarstedtstra\u0026szlig;e, NRW, Germany), stored under refrigeration, and processed according to standardized protocols.\u003c/p\u003e\u003cp\u003e\u003cb\u003e2.3 Targeted panel investigation\u003c/b\u003e Paired genomic DNA (gDNA) samples from fresh-frozen tumor tissue and peripheral blood leukocytes were obtained from all 41 participants and submitted for targeted next-generation sequencing (NGS) analysis using a custom gene panel.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section3\"\u003e\u003ch2\u003e2.3.1 DNA extraction from fresh-frozen meningioma tissue\u003c/h2\u003e\u003cp\u003eIntracranial meningioma specimens were collected intraoperatively during tumor resection and preserved in RNAlater\u0026reg; (Catalog #AM7021; Thermo Scientific, Waltham, MA, USA) at \u0026minus;\u0026thinsp;80\u0026deg;C until DNA extraction. Genomic DNA was isolated from approximately 30 mg of each frozen tumor sample using the AllPrep DNA/RNA Mini Kit (Catalog #80204; Qiagen, Germantown, MD, USA), in accordance with the manufacturer\u0026rsquo;s protocol. DNA integrity was evaluated by 0.8% agarose gel electrophoresis, and DNA concentration was quantified using the Qubit\u0026trade; Broad Range fluorometric assay (Catalog #Q32850; Thermo Scientific, Waltham, MA, USA).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section3\"\u003e\u003ch2\u003e2.3.2 DNA extraction from peripheral blood\u003c/h2\u003e\u003cp\u003ePeripheral venous blood was collected from each participant in EDTA-containing tubes. Leukocyte gDNA was extracted using the salting-out method, which includes red blood cell lysis, leukocyte lysis, and protein precipitation, followed by ethanol precipitation and washing steps. The DNA pellet was resuspended in buffer, and DNA concentration and purity were assessed using both the Qubit\u0026trade; Broad Range fluorometric method (Catalog #Q32850; Thermo Scientific, Waltham, MA, USA) and spectrophotometric analysis with the NanoDrop\u0026trade; One (Thermo Scientific, Waltham, MA, USA).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section3\"\u003e\u003ch2\u003e2.3.3 Custom panel for NGS\u003c/h2\u003e\u003cp\u003eA custom amplicon panel was designed using the Illumina Design Studio platform to enable targeted mutation profiling of six genes: \u003cem\u003eARMC5\u003c/em\u003e (Gene ID: 79798; ENST00000268314.9), \u003cem\u003eNF2\u003c/em\u003e (Gene ID: 4771), \u003cem\u003eAKT1\u003c/em\u003e (Gene ID: 207), \u003cem\u003eSMO\u003c/em\u003e (Gene ID: 6608), \u003cem\u003eTRAF7\u003c/em\u003e (Gene ID: 84231), and \u003cem\u003eKFL4\u003c/em\u003e (Gene ID: 9314). A total of 199 primers were designed to cover 90.8% of the complete coding region of these six genes.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section3\"\u003e\u003ch2\u003e2.3.4 DNA library preparation and sequencing\u003c/h2\u003e\u003cp\u003eLibrary preparation was performed using the AmpliSeq\u0026trade; for Illumina Custom Panels Kit (Catalog #20020495; Illumina, San Diego, CA, USA) with 50 ng of intact genomic DNA per sample. Fragment size and integrity were assessed using the Agilent TapeStation 2200 system with D1000 ScreenTape and reagents (Catalog #5067\u0026ndash;5584 and #5067\u0026ndash;5585; Agilent Technologies, Santa Clara, CA, USA). DNA library quantification was conducted using the Qubit\u0026trade; dsDNA Broad Range Assay Kit (Catalog #Q32853; Thermo Fisher Scientific, Waltham, MA, USA). Sequencing was carried out on the Illumina MiSeq platform using the MiSeq Micro Kit v2 (300 cycles; Catalog #MS-102-2002; Illumina, San Diego, CA, USA).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section3\"\u003e\u003ch2\u003e2.3.5 Variant calling and classification workflow\u003c/h2\u003e\u003cp\u003eThe bioinformatic workflow for variant analysis consisted of multiple stages, each incorporating specialized analytical tools, including:\u003c/p\u003e\u003cp\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eQuality Control\u003c/b\u003e: Evaluation of raw sequencing data for base quality, read length, and coverage using FastQC and the Illumina platform's native metrics.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAlignment and Variant Calling\u003c/b\u003e: High-quality reads were aligned to the human reference genome (hg19 UCSC | b37 GRC/NCBI) using the Burrows-Wheeler Aligner (BWA), and variant calling was performed using GATK or a platform-optimized variant caller.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eAnnotation and Filtering\u003c/b\u003e: Identified variants were annotated using ANNOVAR and filtered based on allele frequency, predicted pathogenicity, and coverage thresholds.\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003e\u003cb\u003eClassification\u003c/b\u003e: Variants were interpreted and classified according to the American College of Medical Genetics and Genomics (ACMG) guidelines, integrating information from databases such as ClinVar[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], dbSNP, gnomAD, and COSMIC[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003c/p\u003e\u003cp\u003eThis multi-step analytical framework enabled the identification and prioritization of potentially pathogenic variants in both tumor and matched germline samples.\u003c/p\u003e\u003cp\u003eSamples harboring at least one candidate variant associated with meningioma development were considered positive. Variants that failed to meet standard sequencing quality control thresholds were excluded from further analysis.\u003c/p\u003e\u003cp\u003eCandidate variants were selected based on a comprehensive set of criteria, including: absence from population frequency databases (e.g., gnomAD), location within coding regions or canonical splice sites, predicted nonsynonymous effects or splicing alterations (as determined by SpliceAI), presence in the Catalogue of Somatic Mutations in Cancer (COSMIC)\u003csup\u003e14\u003c/sup\u003e, variant allele frequency (VAF)\u0026thinsp;\u0026gt;\u0026thinsp;10%, and lack of strand bias.\u003c/p\u003e\u003cp\u003eSomatic variants were subsequently classified according to their potential clinical relevance using two categories of reference databases: (1) variant catalogs, such as COSMIC, which catalog somatic mutations observed in cancer; and (2) interpretive databases, including ClinVar[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], Franklin by Genoox[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and My Cancer Genome[\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. These databases integrate expert-curated information regarding the functional and therapeutic implications of tumor-specific variants, particularly their potential to guide targeted treatment strategies.\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"3. RESULTS","content":"\u003cp\u003eClinical and laboratory evaluations did not identify evidence of autonomous cortisol secretion. All participants demonstrated adequate suppression following the dexamethasone suppression test (DST), and no abnormalities were observed in midnight salivary cortisol or 24-hour urinary free cortisol levels (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eClinical data of meningioma patients\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eParticipants N (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFemale N (%)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMale N (%)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eMean age (yrs)\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e57\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e54\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e60\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eObesity\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (26.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e10 (90.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (9.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eBlood hypertention\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e10 (24.4)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e9 (90.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (10.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDiabetes\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (9.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3 (75.0)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1 (25.0)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eDyslipidemia\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19 (43.3)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e15 (78.9)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e4 (21.1)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e\u003cb\u003eTotal\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41 (100)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36 (87.8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e5 (12.2)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"BlockQuote\"\u003e\u003cp\u003eObesity classification: BMI\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026ge;\u003c/span\u003e\u0026thinsp;30 cm/kg\u003csup\u003e2\u003c/sup\u003e. All participants received medical care, and their other medical conditions/comorbidities were well-managed.\u003c/p\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eRegarding metabolic comorbidities, 11 participants (26.8%) met the criteria for obesity (BMI\u0026thinsp;\u0026gt;\u0026thinsp;30 kg/m\u0026sup2;), 10 (24.4%) had systemic arterial hypertension, four (9.8%) had diabetes mellitus, and 19 (46.3%) had dyslipidemia. The prevalence and sex-based distribution of these comorbid conditions are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eThe most frequent anatomical locations of the surgically resected meningiomas were the sphenoid wing (n\u0026thinsp;=\u0026thinsp;13), clinoid region (n\u0026thinsp;=\u0026thinsp;7), and olfactory groove (n\u0026thinsp;=\u0026thinsp;4), as detailed in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSomatic variants from each meningioma sample, according to their topography.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"10\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSample\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eGrade\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eHistology\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTopography\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003eGene\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eVariant(s)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenicity\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eConsequence\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003eARMC5*\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePetroclival\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c6\" namest=\"c5\"\u003e\u003cp\u003e\u003cem\u003eAKT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003ec.49G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu17Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eForamen Magnum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c10\" namest=\"c5\"\u003e\u003cp\u003e\u003cem\u003eno variant observed\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePetroclival\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1499T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Leu500Pro)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eT/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1935T\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Ser645Arg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.889C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu297Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1633G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu545Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"2\" rowspan=\"3\"\u003e\u003cp\u003eT/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1639G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu547Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1559A\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Asn520Ser)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOlfactory Groove\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c9\" namest=\"c5\"\u003e\u003cp\u003e\u003cem\u003eno variant observed\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eCT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.227A\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Lys76Arg)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eAnterior Petrous Crest\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c10\" namest=\"c5\"\u003e\u003cp\u003e\u003cem\u003eno variant observed\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.784C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Arg262)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eStop-gain\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePetroclival\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eKLF4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1225A\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Lys409Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePsammomatous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOptic Nerve Sheath\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c9\" namest=\"c5\"\u003e\u003cp\u003e\u003cem\u003eno variant observed\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSellar Tubercle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.475\u0026thinsp;+\u0026thinsp;2T\u0026thinsp;\u0026gt;\u0026thinsp;A p.?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSplice Donor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAngiomatous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eKLF4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1225A\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Lys409Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e3F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eKLF4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1225A\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Lys409Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1559A\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Asn520Ser)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1559A\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Asn520Ser)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1958G\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Arg653Pro)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e3l\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eTentorial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.889C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu297Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eKLF4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1225A\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Lys409Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOlfactory Groove\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1958G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Arg653Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eFibrous\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eParasagital\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1499T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Leu500Pro)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c9\" namest=\"c5\"\u003e\u003cp\u003eno variant observed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e5E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAtypical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eKLF4\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1225A\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Lys409Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eAtypical\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1559A\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Asn520Ser)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePetroclival\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eAKT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.49G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu17Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.517-1G\u0026thinsp;\u0026gt;\u0026thinsp;A p.?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSplice Aceptor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eForamen Magnum\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eAKT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.49G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu17Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e5I\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eConvexity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eSMO\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1604G\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Trp535Leu)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSellar Tubercle\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.810\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;A p.?\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eSplice Donor\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eT/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e7C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eEthmoidal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.497del p.(Glu166GlyfsTer8)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFrameshift\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.889C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu297Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eSMO\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1234C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu412Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCavernous sinus\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c9\" namest=\"c5\"\u003e\u003cp\u003eno variant observed\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOlfactory Groove\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"6\" nameend=\"c10\" namest=\"c5\"\u003e\u003cp\u003eno variant observed\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e7H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCerebelar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.889C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu297Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9A\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eOlfactory Groove\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eSMO\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1234C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu412Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9B\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eCerebelar\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1499T\u0026thinsp;\u0026gt;\u0026thinsp;C p.(Leu500Pro)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9C\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eAKT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.49G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu17Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9D\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1559A\u0026thinsp;\u0026gt;\u0026thinsp;G p.(Asn520Ser)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9E\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.889C\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Leu297Phe)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eC/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e9F\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eAnterior Petrous Crest\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eAKT1\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.49G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Glu17Lys)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eOncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1922G\u0026thinsp;\u0026gt;\u0026thinsp;T p.(Arg641Leu)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9G\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eTransitional\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eSphenoid Wing\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1563dup p.(Glu522ArgfsTer20)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eLikely Oncogenic\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eFrameshift\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eWT\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e9H\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003eMeningothelial\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eClinoid\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eTRAF7\u003c/em\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003ec.1958G\u0026thinsp;\u0026gt;\u0026thinsp;A p.(Arg653Gln)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003eVUS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003eMissense\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003eT/T\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e*\u003cem\u003eARMC5\u003c/em\u003e c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T intronic variant. Somatic variants were classified based on clinical significance using two categories of databases: variant catalogs (e.g., COSMIC) and variant interpretive databases (e.g., ClinVar, My Cancer Genome), which provide curated information regarding the functional and therapeutic implications of tumor-specific alterations. Variants of uncertain significance (VUS) were noted but not used to define positive cases. Samples were considered positive if they harbored at least one candidate variant with evidence supporting an association with meningioma pathogenesis. Variants failing default sequencing quality control parameters were excluded from analysis.\u003c/p\u003e\u003cp\u003eAccording to the World Health Organization (WHO) histological classification, the vast majority of tumors were classified as Grade 1 meningiomas, with only one case identified as Grade 2 (atypical). The predominant histological subtype was meningothelial (24/41, 58.5%), followed by transitional (13/41, 31.7%). A summary of histological subtypes and tumor locations is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003eNo pathogenic candidate variants were identified in the coding region of \u003cem\u003eARMC5\u003c/em\u003e. However, the intronic allelic variant c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T (NM_001105247.2) was detected in most cases, present in 24 out of 41 meningioma samples (58.5%) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). In contrast, variants in non-\u003cem\u003eARMC5\u003c/em\u003e genes were commonly observed.\u003c/p\u003e\u003cp\u003eA total of 82.9% of samples (34/41) harbored at least one somatic variant classified as likely oncogenic or oncogenic. In several cases, multiple alterations were detected, yielding a total of 40 occurrences across 20 distinct somatic variants. Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e summarizes these findings, including the identified mutations, associated alleles, and their predicted oncogenic potential.\u003c/p\u003e\u003cp\u003e\u003cem\u003eNF2\u003c/em\u003e was the most frequently altered gene, with 10 distinct variants observed across 14 samples (34.1%), totaling 16 variant occurrences. Among these, five were classified as missense variants of uncertain significance (VUS), two as likely oncogenic frameshift variants, two as likely oncogenic splicing variants, and one as an oncogenic stop-gain variant. Notably, 11 of the 14 \u003cem\u003eNF2\u003c/em\u003e-mutant samples (78.6%) also harbored the \u003cem\u003eARMC5\u003c/em\u003e c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T intronic variant (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e), suggesting a potential pattern of co-occurrence.\u003c/p\u003e\u003cp\u003eSix distinct missense variants and one splice donor variant in \u003cem\u003eTRAF7\u003c/em\u003e were identified, totaling seven variant occurrences across 11 of the 41 meningioma samples (26.8%). Among these, three variants were classified as likely oncogenic, while the remaining four were considered variants of uncertain significance (VUS). The \u003cem\u003eARMC5\u003c/em\u003e c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T intronic variant was concurrently detected in six of the 11 \u003cem\u003eTRAF7\u003c/em\u003e-mutated cases (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eA single oncogenic missense variant in \u003cem\u003eAKT1\u003c/em\u003e was observed in five samples (12.2%). Of these, two also carried the \u003cem\u003eARMC5\u003c/em\u003e intronic variant.\u003c/p\u003e\u003cp\u003eLikewise, one recurrent oncogenic missense variant in \u003cem\u003eKLF4\u003c/em\u003e was identified in five cases, with three of these also harboring the \u003cem\u003eARMC5\u003c/em\u003e c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T variant (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eFor \u003cem\u003eSMO\u003c/em\u003e, two distinct missense variants \u0026mdash; one oncogenic and one likely oncogenic \u0026mdash; were detected in three samples (7.3%). The \u003cem\u003eARMC5\u003c/em\u003e intronic variant co-occurred in two of these cases (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e"},{"header":"4. DISCUSSION","content":"\u003cp\u003e\u003cb\u003eAbsence of Pathogenic\u003c/b\u003e \u003cb\u003eARMC5\u003c/b\u003e \u003cb\u003eCoding Variants in Sporadic Meningiomas\u003c/b\u003e\u003c/p\u003e\u003cp\u003eIntracranial meningiomas have been documented in patients with bilateral macronodular adrenal disease (BMAD) carrying \u003cem\u003eARMC5\u003c/em\u003e variants, which encode the armadillo repeat-containing protein 5. Interestingly, meningiomas have also been observed in BMAD patients with wild-type \u003cem\u003eARMC5\u003c/em\u003e, indicating that the genotype-phenotype correlation may be incomplete[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Nevertheless, prior studies have implicated \u003cem\u003eARMC5\u003c/em\u003e as a potential contributor to meningioma development, suggesting a possible role in tumor predisposition beyond the adrenal phenotype[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eContrary to our initial hypothesis \u0026mdash; based on the observed frequency of \u003cem\u003eARMC5\u003c/em\u003e variants in BMAD-associated meningiomas (unpublished data) \u0026mdash; comprehensive molecular analysis of our well-defined cohort of 41 sporadic meningiomas did not identify any pathogenic variants within the coding region of the \u003cem\u003eARMC5\u003c/em\u003e gene. This finding highlights a potentially distinct genetic landscape in sporadic meningiomas compared to those arising in the context of BMAD.\u003c/p\u003e\u003cp\u003eAlthough both germline and somatic \u003cem\u003eARMC5\u003c/em\u003e mutations are firmly established in the pathogenesis of corticotropin-independent macronodular adrenal hyperplasia[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e], our data indicate that such alterations do not appear to play a major role in sporadic meningioma tumorigenesis. These findings add to the growing body of evidence supporting the molecular heterogeneity of meningiomas and emphasize the importance of considering clinical context \u0026mdash; such as syndromic or endocrine associations \u0026mdash; when exploring their genetic architecture.\u003c/p\u003e\u003cp\u003e\u003cb\u003eNoteworthy Prevalence of the\u003c/b\u003e \u003cb\u003eARMC5\u003c/b\u003e \u003cb\u003eIntronic Variant c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAlthough no pathogenic coding variants in \u003cem\u003eARMC5\u003c/em\u003e were detected, a notably high prevalence (58.5%) of the intronic allelic variant c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T (NM_001105247.2) was observed in our cohort of patients with sporadic meningiomas. The potential functional relevance of intronic variants is increasingly acknowledged, as they may influence pre-mRNA splicing, mRNA stability, or gene expression through regulatory mechanisms[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eWhile this particular variant did not fulfill the criteria for pathogenicity based on current bioinformatic predictions[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] and available literature, its frequent occurrence across our series merits further attention. Notably, this variant often co-occurred with pathogenic or likely pathogenic mutations in well-established meningioma driver genes, raising the possibility that it may act as a genetic modifier or contribute to tumorigenesis through complex epistatic interactions.\u003c/p\u003e\u003cp\u003eGiven these observations, further investigation into the biological significance of this variant is warranted. Functional studies, including splicing assays and regulatory impact analyses, will be essential to determine whether the \u003cem\u003eARMC5\u003c/em\u003e c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T variant contributes to meningioma development or progression, despite its current classification as a variant of uncertain significance.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRecurrent Pathogenic and Likely Pathogenic Variants in Established Meningioma Genes\u003c/b\u003e\u003c/p\u003e\u003cp\u003eOur findings reinforce the central role of established meningioma driver genes in the tumorigenesis of sporadic cases. Among these, the tumor suppressor gene \u003cem\u003eNF2\u003c/em\u003e \u0026mdash; that encodes the merlin protein \u0026mdash; was the most frequently altered, with potentially oncogenic variants identified in 34.1% of samples. This observation is consistent with prior large-scale genomic studies that have highlighted \u003cem\u003eNF2\u003c/em\u003e as a key tumor suppressor frequently inactivated in sporadic meningiomas[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The spectrum of \u003cem\u003eNF2\u003c/em\u003e alterations observed in our cohort, including frameshift, splicing, and stop-gain mutations, supports its canonical role in tumor suppression through loss of functional merlin protein[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eRecurrent pathogenic or likely pathogenic variants were also identified in \u003cem\u003eTRAF7\u003c/em\u003e (26.8%), \u003cem\u003eAKT1\u003c/em\u003e (12.2%), \u003cem\u003eKLF4\u003c/em\u003e (12.2%), and \u003cem\u003eSMO\u003c/em\u003e (7.3%). The high prevalence of \u003cem\u003eTRAF7\u003c/em\u003e mutations \u0026mdash; encoding the tumor necrosis factor receptor-associated factor 7 protein \u0026mdash; is consistent with prior reports indicating its enrichment in meningiomas located at the skull base[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e], a common anatomical site within our surgically treated cohort.\u003c/p\u003e\u003cp\u003eThe detection of oncogenic AKT1 and KLF4 missense mutations, although observed in smaller subsets, further supports their role in meningioma biology. AKT1, encoding the RAS-alpha serine/threonine-protein kinase, is implicated in proliferative signaling pathways, while KLF4, encoding the Kr\u0026uuml;ppel-like factor 4 transcription factor, is thought to influence differentiation. These findings align with previous studies suggesting a correlation between these mutations and specific histological features or clinical behavior [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn addition, co-occurring mutations in \u003cem\u003eTRAF7\u003c/em\u003e and \u003cem\u003eSMO\u003c/em\u003e, the latter encoding the Smoothened homolog protein, were detected in a subset of samples, concordant with their established association with the secretory histological subtype (WHO grade I)[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. The functional implications of \u003cem\u003eTRAF7\u003c/em\u003e and \u003cem\u003eKLF4\u003c/em\u003e mutations remain incompletely understood, underscoring the need for further mechanistic studies to evaluate their potential as therapeutic targets.\u003c/p\u003e\u003cp\u003eFinally, consistent with literature reports, \u003cem\u003eSMO\u003c/em\u003e and \u003cem\u003eAKT1\u003c/em\u003e mutant meningiomas in our cohort displayed a predilection for the anterior skull base and were frequently associated with the meningothelial histological subtype (WHO grade I), reflecting known genotype\u0026ndash;phenotype correlations in meningioma subgroups[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e].\u003c/p\u003e\u003cp\u003e\u003cb\u003eHigh Prevalence of ARMC5 Intronic Variant c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T in Sporadic Intracranial Meningiomas: Evidence of Co-Occurrence with Canonical Driver Mutations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA notable observation in our sporadic meningioma cohort was the frequent co-occurrence of the \u003cem\u003eARMC5\u003c/em\u003e intronic variant c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T with pathogenic or likely pathogenic mutations in established meningioma driver genes, including \u003cem\u003eNF2\u003c/em\u003e, \u003cem\u003eTRAF7\u003c/em\u003e, \u003cem\u003eAKT1\u003c/em\u003e, \u003cem\u003eKLF4\u003c/em\u003e, and \u003cem\u003eSMO\u003c/em\u003e. While the independent roles of these genes in meningioma pathogenesis are well-established[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan additionalcitationids=\"CR32 CR33\" citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e], the biological significance of their co-occurrence with the \u003cem\u003eARMC5\u003c/em\u003e variant remains unclear.\u003c/p\u003e\u003cp\u003eSome studies have suggested that interactions between distinct genetic alterations may contribute to tumor development or progression in meningiomas[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Whether this observed co-occurrence reflects independent mutational events or points to a functional relationship, such as genetic modification, synergistic interaction, or epistasis, requires further investigation.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations and Future Research Imperatives\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe interpretation of our findings must consider several limitations. First, this study was conducted at a single institution and involved a modest sample size (n\u0026thinsp;=\u0026thinsp;41), which may limit the detection of rare variants and constrain the statistical power for genotype\u0026ndash;phenotype correlation analyses. Second, the absence of patients with BMAD precludes direct comparative analyses with this endocrine condition and limits the generalizability of our findings to broader clinical contexts.\u003c/p\u003e\u003cp\u003eAdditionally, our study employed a targeted gene panel, which, while appropriate for detecting known driver mutations, does not capture the full spectrum of genetic alterations that may be involved in sporadic meningioma pathogenesis. Future studies employing whole-exome or whole-genome sequencing in larger, multi-institutional cohorts are needed to expand our understanding of the genetic architecture of these tumors and to uncover novel candidate genes.\u003c/p\u003e\u003cp\u003eImportantly, functional studies exploring the biological impact of the \u003cem\u003eARMC5\u003c/em\u003e c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T variant, especially in the context of co-occurring mutations, are warranted to clarify its potential role as a genetic modifier or contributor to tumorigenesis. Furthermore, integrating genetic findings with clinically relevant outcomes, such as recurrence rates, progression-free survival, and response to neurosurgical intervention, will be critical to translating molecular insights into clinically actionable biomarkers that can inform prognosis and guide therapeutic decision-making in meningioma management.\u003c/p\u003e"},{"header":"5. CONCLUSION","content":"\u003cp\u003eIn summary, our comprehensive molecular analysis of a well-characterized cohort of sporadic meningiomas surgically treated at our institution reveals a distinct \u003cem\u003eARMC5\u003c/em\u003e genetic profile compared to previously observed BMAD-associated cases. While no pathogenic coding variants in \u003cem\u003eARMC5\u003c/em\u003e were identified, a high prevalence of the intronic variant c.1864\u0026thinsp;+\u0026thinsp;250C\u0026thinsp;\u0026gt;\u0026thinsp;T was observed, suggesting a potential, yet currently undefined, role in tumor biology that merits further investigation.\u003c/p\u003e\u003cp\u003eOur findings also reaffirm the frequent involvement of established meningioma driver genes, particularly \u003cem\u003eNF2\u003c/em\u003e and \u003cem\u003eTRAF7\u003c/em\u003e, and uncover a pattern of co-occurrence between these mutations and the \u003cem\u003eARMC5\u003c/em\u003e intronic variant. This observation may reflect underlying molecular interactions that contribute to tumor development or progression.\u003c/p\u003e\u003cp\u003eCollectively, these results enhance our understanding of the molecular heterogeneity of sporadic meningiomas and emphasize the importance of continued research into both well-established and emerging genetic alterations. Such efforts are essential to refine diagnostic classifications, improve prognostic stratification, and guide the development of personalized therapeutic strategies for this common and diverse group of central nervous system tumors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This work was supported in part by the São Paulo Research Foundation (FAPESP 2015/50192-9)and was granted to MCBVF.\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u003c/strong\u003e We thank everyone who supported this study or helped with the manuscript but did not meet the criteria for authorship. Their contributions are greatly appreciated.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure Statement:\u003c/strong\u003e The authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e* Leonardo JTA and Arthur AMS contributed equally to this work and both are considered first authors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions:\u003c/strong\u003e*\u003cstrong\u003eLJTA\u003c/strong\u003e: biostatistical analysis/technical/experimental advisor and manuscript writer; *\u003cstrong\u003eAAMS\u003c/strong\u003e: provided the tumor samples and participant data for the validation cohort and manuscript reviewer; \u003cstrong\u003eHLC\u003c/strong\u003e: clinical management; \u003cstrong\u003eBMPM, LMS, MYM, FRM\u003c/strong\u003e: technical/experimental analysts and manuscript reviewers; \u003cstrong\u003eAML\u003c/strong\u003e: biostatistical analysis advisor and manuscript reviewer; \u003cstrong\u003eFLL:\u0026nbsp;\u003c/strong\u003ehistopathology analysis; \u003cstrong\u003eMQA,\u003c/strong\u003e \u003cstrong\u003eBBM\u003c/strong\u003e, \u003cstrong\u003eEGF\u003c/strong\u003e: manuscript reviewer; \u003cstrong\u003eMCBVF\u003c/strong\u003e: project mentor and advisor, clinical management and manuscript reviewer.\u003c/p\u003e\n\u003cp\u003e\u003cdel cite=\"mailto:Trinka\" datetime=\"2025-02-11T21:07\"\u003e\u003c/p\u003e\n\u003cp\u003eClinical trial number: not applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eBlack PM, Meningiomas (1993) Neurosurg Neurosurg 32(4):643\u0026ndash;657\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOstrom QT, Gittleman H, Truitt G et al (2018) CBTRUS Statistical Report: Primary brain and other central nervous system tumors diagnosed in the United States in 2011\u0026ndash;2015. 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Oncotarget 10(53):5549\u0026ndash;5559. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.18632/oncotarget.27178\u003c/span\u003e\u003cspan address=\"10.18632/oncotarget.27178\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eHe WT, Wang X, Song W et al (2021) A novel nonsense mutation in ARMC5 causes primary bilateral macronodular adrenocortical hyperplasia. BMC Med Genomics 14(1):88. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1186/s12920-021-00896-0\u003c/span\u003e\u003cspan address=\"10.1186/s12920-021-00896-0\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Meningioma, Sporadic, ARMC5, Intronic Variant, Molecular Genetics, Next-generation Sequencing","lastPublishedDoi":"10.21203/rs.3.rs-7134493/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7134493/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Sporadic intracranial meningiomas exhibit a diverse molecular landscape. While ARMC5 mutations are recognized in bilateral macronodular adrenal disease (BMAD)-associated meningiomas, their role in sporadic cases is uncertain. \u003cbr\u003e\n\u003cstrong\u003eObjective\u003c/strong\u003e: To determine the frequency and implications of ARMC5 variants, particularly intronic alterations, alongside canonical driver mutations in surgically treated sporadic meningiomas.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Forty-one patients undergoing surgical resection for sporadic meningiomas were analyzed. Tumor DNA was screened using targeted next-generation sequencing (NGS) for variants in ARMC5, NF2, TRAF7, AKT1, KLF4, and SMO. Patients were clinically and biochemically evaluated to exclude BMAD.\u003cbr\u003e\n\u003cstrong\u003eResults\u003c/strong\u003e: No pathogenic coding variants in ARMC5 were found. However, 58.5% of cases harbored the intronic variant c.1864+250C\u0026gt;T. This variant frequently co-occurred with driver mutations, notably in NF2 (34.1%), TRAF7, AKT1, KLF4, and SMO. Most tumors were WHO grade I and predominantly meningothelial in subtype.\u003cbr\u003e\n\u003cstrong\u003eConclusion\u003c/strong\u003e: Our findings identify a high prevalence of a specific ARMC5 intronic variant in sporadic meningiomas, co-occurring with key oncogenic mutations. These results suggest a potential modifying or synergistic role for this variant, warranting further functional investigation.\u003c/p\u003e","manuscriptTitle":"Revealing Hidden Drivers: ARMC5 Intronic Variant Coexists with NF2, TRAF7 and AKT1 Mutations in Sporadic Meningiomas","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-04 13:02:57","doi":"10.21203/rs.3.rs-7134493/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-12-07T02:55:41+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"111944859080953105358309038558436998916","date":"2025-11-10T08:55:20+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-08-28T14:21:38+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"28652713861513122382134765253707540094","date":"2025-08-28T13:38:32+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-28T08:08:35+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-28T08:07:49+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-07-16T06:00:13+00:00","index":"","fulltext":""},{"type":"submitted","content":"Neurosurgical Review","date":"2025-07-16T00:32:34+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"neurosurgical-review","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nrev","sideBox":"Learn more about [Neurosurgical Review](https://www.springer.com/journal/10143)","snPcode":"10143","submissionUrl":"https://submission.nature.com/new-submission/10143/3","title":"Neurosurgical Review","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b1c4fe5e-59b8-404c-aa6b-df4bf0674eea","owner":[],"postedDate":"September 4th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-13T13:54:39+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-04 13:02:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7134493","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7134493","identity":"rs-7134493","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}