bims-tubesc 2021-10-31 papers

bims-tubesc

Biomed News

on Molecular mechanisms in tuberous sclerosis

Issue of 2021–10–31
twelve papers selected by

Lipomatous Infiltration in Tuberous Sclerosis Complex - A Case Series and Literature Review.
Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex.
Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3.
Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.
Multivariate data analysis identifies natural clusters of Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND).
Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy.
Electroconvulsive seizure inhibits the mTOR signaling pathway via AMPK in the rat frontal cortex.
Vacuolar localization via the N-terminal domain of Sch9 is required for TORC1-dependent phosphorylation and downstream signal transduction.
The Potential and Limitations of Precision Oncology: Lessons Learned from Whole-Exome Sequencing in an Exceptional Response to Everolimus in Advanced Renal Cell Carcinoma.
Sin1-mediated mTOR signaling in cell growth, metabolism and immune response.
Hyperin Alleviates Triptolide-Induced Ovarian Granulosa Cell Injury by Regulating AKT/TSC1/mTORC1 Signaling.
Frequency of Specific Genes in Different Types of Epilepsy.

Child Neurol Open. 2021 Jan-Dec;8:8 2329048X211048065

Lipomatous Infiltration in Tuberous Sclerosis Complex - A Case Series and Literature Review.

Mohammed Ilyas, Julio Quezada, Erin K Opfer.

  Diffuse Lipomatosis is a dermatological lesion consisting of a poorly circumscribed, infiltrative overgrowth of mature adipose tissue that usually affects the trunk and the extremities. The lesions in the Tuberous Sclerosis Complex (TSC) are usually hamartomatous in nature, but lesions arising from adipocytes are rare. There are only three previous reports of association of TSC with diffuse lipomatosis. Herein we present a case series of diffuse lipomatosis in three subjects with TSC and proceed to review the literature for any other reported cases. On the basis of the three index cases and identification of three more cases in the literature, we believe that there is an association of diffuse lipomatosis with TSC that has not been appreciated until now. We believe that this association in some selected cases will serve to improve diagnosis, surveillance, and management..

Keywords:  dermatological lesion; diffuse lipomatosis; lipoma; tuberous sclerosis; tuberous sclerosis complex; tuberous sclerosis surveillance

DOI:  https://doi.org/10.1177/2329048X211048065
Respir Med Case Rep. 2021 ;34 101526

Resolution of multifocal micronodular pneumocyte hyperplasia with everolimus in a patient with tuberous sclerosis complex.

Tetsuaki Shoji, Yo Niida, Takahiro Osawa, Ryuji Matsumoto, Kotaro Sakurai, Masaru Suzuki, Yoshihiro Matsuno, Satoshi Konno.

  A woman with a diagnosis of tuberous sclerosis complex (TSC) presented with TSC2 gene mutation and various manifestations, including epilepsy, renal angiomyolipomas (AML), and pathologically confirmed multifocal micronodular pneumocyte hyperplasia (MMPH). With oral administration of everolimus, a mammalian target of rapamycin (mTOR) inhibitor, MMPH and AML were markedly reduced. Further, after starting treatment with everolimus, serum levels of surfactant protein (SP)-A and SP-D, which reflect type II pneumocyte hyperplasia, decreased to the normal range. At the time of writing of this manuscript, 6 years after starting everolimus, MMPH lesions did not relapse and SP-A/D remained the low levels. This is the first case of everolimus efficacy shown for histologically confirmed MMPH in genetically determined TSC patient, with time course of serum SP-A and SP-D.

Keywords:  Everolimus; Multifocal micronodular pneumocyte hyperplasia; Surfactant Protein-A (SP-A); Surfactant protein-B (SP–B); Tuberous sclerosis complex

DOI:  https://doi.org/10.1016/j.rmcr.2021.101526
Epilepsia. 2021 Oct 25.

Adjunctive everolimus therapy for tuberous sclerosis complex-associated refractory seizures: Results from the postextension phase of EXIST-3.

David N Franz, John A Lawson, Zuhal Yapici, Hiroko Ikeda, Tilman Polster, Rima Nabbout, Paolo Curatolo, Petrus J de Vries, Dennis J Dlugos, Fabian Herbst, Severine Peyrard, Diana Pelov, Jacqueline A French.

   OBJECTIVE: Epilepsy is highly prevalent in patients with tuberous sclerosis complex (TSC). Everolimus showed higher efficacy than placebo for seizures in the primary analysis of the EXIST-3 study. Here, we present the long-term outcomes of everolimus at the end of the postextension phase (PEP; data cutoff date: October 25, 2017).
METHODS: After completion of the extension phase, patients were invited to continue everolimus in the PEP with everolimus (targeted trough concentration = 5-15 ng/ml, investigator-judged). Efficacy assessments included changes in seizure status during the PEP collected at 12-week intervals as parent/caregiver-reported data through a structured questionnaire.
RESULTS: Among 361 patients, 343 entered the extension phase and 249 entered the PEP. After 12 weeks in the PEP, 18.9% (46/244) of patients were seizure-free since the last visit of the extension phase and 64.8% (158/244) had a stable/improved seizure status. At 24 weeks, the corresponding percentages were 18.2% (42/231) and 64.5% (149/231). Among 244 patients, the response rate was 32.8% (80/244) during the 12-week maintenance period of the core phase and 63.9% (156/244) at the end of the extension phase. Of the 149 responders at the end of the extension phase, 70.5% were seizure-free or had stable/improved seizure status. Long-term efficacy data showed persistent responses were observed in 183 of 361 patients (50.7%); 63.9% of these patients had a response that lasted at least 48 weeks. The most frequent Grade 3-4 adverse events (≥2% incidence) reported throughout the study were pneumonia, status epilepticus, seizure, stomatitis, neutropenia, and gastroenteritis. Four patients died during the study.
SIGNIFICANCE: The final analysis of EXIST-3 demonstrated the sustained efficacy of everolimus as adjunctive therapy in patients with TSC-associated treatment-refractory seizures, with a tolerable safety profile.

Keywords:  EXIST-3; epilepsy; everolimus; postextension phase; tuberous sclerosis complex

DOI:  https://doi.org/10.1111/epi.17099
Cell Mol Neurobiol. 2021 Oct 28.

Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.

Anika Bongaarts, Caroline Mijnsbergen, Jasper J Anink, Floor E Jansen, Wim G M Spliet, Wilfred F A den Dunnen, Roland Coras, Ingmar Blümcke, Werner Paulus, Victoria E Gruber, Theresa Scholl, Johannes A Hainfellner, Martha Feucht, Katarzyna Kotulska, Sergiusz Jozwiak, Wieslawa Grajkowska, Anna Maria Buccoliero, Chiara Caporalini, Flavio Giordano, Lorenzo Genitori, Figen Söylemezoğlu, José Pimentel, David T W Jones, Brendon P Scicluna, Antoinette Y N Schouten-van Meeteren, Angelika Mühlebner, James D Mills, Eleonora Aronica.

  Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response.

Keywords:  Low-grade glioma; Methylation; RNA-sequencing; SEGA; TSC

DOI:  https://doi.org/10.1007/s10571-021-01157-5
Orphanet J Rare Dis. 2021 10 24. 16(1): 447

Multivariate data analysis identifies natural clusters of Tuberous Sclerosis Complex Associated Neuropsychiatric Disorders (TAND).

Petrus J de Vries, Loren Leclezio, Sugnet Gardner-Lubbe, Darcy Krueger, Mustafa Sahin, Steven Sparagana, Liesbeth De Waele, Anna Jansen.

   BACKGROUND: Tuberous Sclerosis Complex (TSC), a multi-system genetic disorder, is associated with a wide range of TSC-Associated Neuropsychiatric Disorders (TAND). Individuals have apparently unique TAND profiles, challenging diagnosis, psycho-education, and intervention planning. We proposed that identification of natural TAND clusters could lead to personalized identification and treatment of TAND. Two small-scale studies showed cluster and factor analysis could identify clinically meaningful natural TAND clusters. Here we set out to identify definitive natural TAND clusters in a large, international dataset.
METHOD: Cross-sectional, anonymized TAND Checklist data of 453 individuals with TSC were collected from six international sites. Data-driven methods were used to identify natural TAND clusters. Mean squared contingency coefficients were calculated to produce a correlation matrix, and various cluster analyses and exploratory factor analysis were examined. Statistical robustness of clusters was evaluated with 1000-fold bootstrapping, and internal consistency calculated with Cronbach's alpha.
RESULTS: Ward's method rendered seven natural TAND clusters with good robustness on bootstrapping. Cluster analysis showed significant convergence with an exploratory factor analysis solution, and, with the exception of one cluster, internal consistency of the emerging clusters was good to excellent. Clusters showed good clinical face validity.
CONCLUSIONS: Our findings identified a data-driven set of natural TAND clusters from within highly variable TAND Checklist data. The seven natural TAND clusters could be used to train families and professionals and to develop tailored approaches to identification and treatment of TAND. Natural TAND clusters may also have differential aetiological underpinnings and responses to molecular and other treatments.

Keywords:  Autism spectrum disorder; Cluster analysis; Factor analysis; Natural TAND clusters; Neuropsychiatric; Precision medicine; TAND; Tuberous Sclerosis Complex

DOI:  https://doi.org/10.1186/s13023-021-02076-w
J Hepatol. 2021 Oct 25. pii: S0168-8278(21)02151-6. [Epub ahead of print]

Hepatocytic p62 suppresses ductular reaction and tumorigenesis in mouse livers with mTORC1 activation and defective autophagy.

Xiaojuan Chao, Shaogui Wang, Sam Fulte, Xiaowen Ma, Forkhan Ahamed, Wei Cui, Zhipeng Liu, Thomas Rülicke, Kurt Zatloukal, Wei-Xing Zong, Wanqing Liu, Hong-Min Ni, Wen-Xing Ding.

   BACKGROUND & AIMS: Either activation of mTORC1 due to loss of Tsc1 (Tuberous Sclerosis Complex 1) or defective hepatic autophagy due to loss of Atg5 leads to spontaneous liver tumorigenesis in mice. The purpose of this study was to investigate the mechanisms of how autophagy impacts mTORC1 activation-mediated liver metabolic changes and tumorigenesis.
METHODS: Atg5 Flox/Flox (Atg5F/F) and Tsc1F/F mice were crossed with albumin Cre mice to generate liver-specific Atg5 knockout (L-Atg5 KO), L-Tsc1 KO and L-Atg5/Tsc1 double KO (DKO) mice. These mice were crossed with p62/Sqstm1F/F (p62) and whole body Nrf2 KO mice to generate L-Atg5/Tsc1/p62 and L-Atg5/Tsc1, Nrf2 triple KO (TKO) mice. These mice were housed for various time points up to 12 months, and blood and liver tissues were harvested for biochemical and histological analysis RESULTS: Deletion of Atg5 in L-Tsc1 KO mice inhibited liver tumorigenesis, but increased mortality of L-Tsc1 KO mice accompanied by drastically enhanced hepatic ductular reaction (DR), hepatocyte degeneration and metabolic reprogramming. Deletion of p62 reversed DR, hepatocyte degeneration and metabolic reprogramming as well as the mortality of L-Atg5/Tsc1 DKO mice, but unexpectedly promoted liver tumorigenesis via activation of a group of oncogenic signaling pathways. Nrf2 ablation markedly improved DR with increased hepatocyte population and improved metabolic reprogramming and survival of the L- Atg5/Tsc1 DKO mice without tumor formation. Decreased p62 and increased mTOR activity was also found in a subset of human hepatocellular carcinoma.
CONCLUSIONS: These results reveal previously undescribed functions of hepatic p62 in suppressing tumorigenesis and regulating liver cell repopulation and metabolic reprogramming resulting from persistent mTORC1 activation and defective autophagy.
LAY SUMMARY: Metabolic liver disease and viral hepatitis are common chronic liver diseases and risk factors of hepatocellular carcinoma, which are often associated with impaired hepatic autophagy with increased mTOR activation. Using multiple genetic engineered mice that are defective of hepatic autophagy with persistent mTOR activation, we dissected the complex interplay among mTOR, autophagy, p62 and Nrf2 on liver cell repopulation, metabolic reprogramming and redox homeostasis in liver tumorigenesis. Our results uncovered an unexpected novel tumor suppressor function of p62/Sqstm1 by regulating liver cell repopulation, ductular reaction and metabolic reprogramming in liver tumorigenesis.

Keywords:  Atg5; HCC; Nrf2; Tsc1; fibrosis; p62

DOI:  https://doi.org/10.1016/j.jhep.2021.10.014
Psychopharmacology (Berl). 2021 Oct 30.

Electroconvulsive seizure inhibits the mTOR signaling pathway via AMPK in the rat frontal cortex.

Se Hyun Kim, Hyun Sook Yu, Seonghoo Huh, Ung Gu Kang, Yong Sik Kim.

   RATIONALE: Accumulating evidence indicates critical involvement of mammalian target of rapamycin (mTOR) in the treatment of depressive disorders, epilepsy, and neurodegenerative disorders through its signal transduction mechanisms related to protein translation, autophagy, and synaptic remodeling. Electroconvulsive seizure (ECS) treatment is a potent antidepressive, anti-convulsive, and neuroprotective therapeutic modality; however, its effects on mTOR signaling have not yet been clarified.
METHODS: The effect of ECS on the mTOR complex 1 (mTORC1) pathway was investigated in the rat frontal cortex. ECS or sham treatment was administered once per day for 10 days (E10X or sham), and compound C was administered through the intracerebroventricular cannula. Changes in mTORC1-associated signaling molecules and their interactions were analyzed.
RESULTS: E10X reduced phosphorylation of mTOR downstream substrates, including p70S6K, S6, and 4E-BP1, and increased inhibitory phosphorylation of mTOR at Thr2446 compared to the sham group in the rat frontal cortex, indicating E10X-induced inhibition of mTORC1 activity. Akt and ERK1/2, upstream kinases that activate mTORC1, were not inhibited; however, AMPK, which can inhibit mTORC1, was activated. AMPK-responsive phosphorylation of Raptor at Ser792 and TSC2 at Ser1387 inhibiting mTORC1 was increased by E10X. Moreover, intrabrain inhibition of AMPK restored E10X-induced changes in the phosphorylation of S6, Raptor, and TSC2, indicating mediation of AMPK in E10X-induced mTOR inhibition.
CONCLUSIONS: Repeated ECS treatments inhibit mTORC1 signaling by interactive crosstalk between mTOR and AMPK pathways, which could play important roles in the action of ECS via autophagy induction.

Keywords:  AMP-activated protein kinase; Electroconvulsive therapy; Mammalian target of rapamycin

DOI:  https://doi.org/10.1007/s00213-021-06015-2
J Mol Biol. 2021 Oct 22. pii: S0022-2836(21)00563-5. [Epub ahead of print] 167326

Vacuolar localization via the N-terminal domain of Sch9 is required for TORC1-dependent phosphorylation and downstream signal transduction.

Daniele Novarina, Paolo Guerra, Andreas Milias-Argeitis.

  The budding yeast Sch9 kinase (functional orthologue of the mammalian S6 kinase) is a major effector of the Target of Rapamycin Complex 1 (TORC1) complex in the regulation of cell growth in response to nutrient availability and stress. Sch9 is partially localized at the vacuolar surface, where it is phosphorylated by TORC1. The recruitment of Sch9 on the vacuole is mediated by direct interaction between phospholipids of the vacuolar membrane and the region of Sch9 encompassing amino acid residues 1-390, which contains a C2 domain. Since many C2 domains mediate phospholipid binding, it had been suggested that the C2 domain of Sch9 mediates its vacuolar recruitment. However, the in vivo requirement of the C2 domain for Sch9 localization had not been demonstrated, and the phenotypic consequences of Sch9 delocalization remained unknown. Here, by examining cellular localization, phosphorylation state and growth phenotypes of Sch9 truncation mutants, we show that deletion of the N-terminal domain of Sch9 (aa 1-182), but not the C2 domain (aa 183-399), impairs vacuolar localization and TORC1-dependent phosphorylation of Sch9, while causing growth defects similar to those observed in sch9Δ cells. These defects can be reversed either via artificial tethering of the protein to the vacuole, or by introducing phosphomimetic mutations at the TORC1 target sites, suggesting that Sch9 localization on the vacuole is needed for the TORC1-dependent activation of the kinase. Our study uncovers a key role for the N-terminal domain of Sch9 and provides new mechanistic insight into the regulation of a major TORC1 signaling branch.

Keywords:  C2 domain; Cell growth; Saccharomyces cerevisiae; TOR signaling; kinase

DOI:  https://doi.org/10.1016/j.jmb.2021.167326
Case Rep Oncol. 2021 May-Aug;14(2):14(2): 1194-1200

The Potential and Limitations of Precision Oncology: Lessons Learned from Whole-Exome Sequencing in an Exceptional Response to Everolimus in Advanced Renal Cell Carcinoma.

Amanda Pilling, Christopher Wee, Eliezer Bar-Meir, Gregory Dyson, Ok Hwang, Nilesh Gupta, Dhananjay Chitale, Clara Hwang.

  Through elucidating the genetic mechanisms of drug sensitivity, precision medicine aims to improve patient selection and response to therapy. Exceptional responders are patients that exhibit exquisite and durable responses to targeted therapy, providing a rare opportunity to identify the molecular basis of drug sensitivity. We identified an exceptional responder to everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, in a patient with advanced renal cell carcinoma. Through whole-exome sequencing on pretreatment and metastatic tumor DNA, we identified alterations in several mTOR pathway genes, with several mutations implicated in mTOR activation. Importantly, these alterations are currently not included in commercially available next-generation sequencing panels, suggesting that precision medicine is still limited in its ability to predict responses to mTOR-targeted therapies. Further research to discover and validate predictive biomarkers of response to everolimus and other targeted therapies is urgently needed. Given the rarity of patients with exceptional responses to targeted agents, cooperative efforts to understand the molecular basis for these phenotypes are essential.

Keywords:  Biomarker; Durable response; Mammalian target of rapamycin inhibitor

DOI:  https://doi.org/10.1159/000516277
Natl Sci Rev. 2019 Nov;6(6): 1149-1162

Sin1-mediated mTOR signaling in cell growth, metabolism and immune response.

Chun Ruan, Xinxing Ouyang, Hongzhi Liu, Song Li, Jingsi Jin, Weiyi Tang, Yu Xia, Bing Su.

  The mammalian target of rapamycin (mTOR) is an evolutionarily conserved Ser/Thr protein kinase with essential cellular function via processing various extracellular and intracellular inputs. Two distinct multi-protein mTOR complexes (mTORC), mTORC1 and mTORC2, have been identified and well characterized in eukaryotic cells from yeast to human. Sin1, which stands for Sty1/Spc1-interacting protein1, also known as mitogen-activated protein kinase (MAPK) associated protein (MAPKAP)1, is an evolutionarily conserved adaptor protein. Mammalian Sin1 interacts with many cellular proteins, but it has been widely studied as an essential component of mTORC2, and it is crucial not only for the assembly of mTORC2 but also for the regulation of its substrate specificity. In this review, we summarize our current knowledge of the structure and functions of Sin1, focusing specifically on its protein interaction network and its roles in the mTOR pathway that could account for various cellular functions of mTOR in growth, metabolism, immunity and cancer.

Keywords:  AGC kinases; Akt; Sin1; mTOR complex; metabolism and immune response

DOI:  https://doi.org/10.1093/nsr/nwz171
Evid Based Complement Alternat Med. 2021 ;2021 9399261

Hyperin Alleviates Triptolide-Induced Ovarian Granulosa Cell Injury by Regulating AKT/TSC1/mTORC1 Signaling.

Fang You, Junyan Cao, Li Cheng, Xiaogu Liu, Li Zeng.

Premature ovarian insufficiency (POI) is characterized by the loss of ovarian function before 40 years of age and affects approximately 1% of women worldwide. Caragana sinica is a traditional Miao (a Chinese ethnic minority) medicine that improves ovarian function and follicular development. In the present study, we aimed to investigate the effect of active ingredients of C. sinica on POI and determine underlying mechanisms. Herein, the chemical composition of the C. sinica compound was analyzed using ultra-high-performance liquid chromatography, which identified hyperin (HR) as one of the main ingredients in C. sinica. Then, interaction targets of HR and POI were predicted and analyzed using network pharmacology and bioinformatics. The effect of HR on triptolide (TP)-induced granulosa cell injury was evaluated, and the underlying mechanism was explored based on bioinformatic results. A total of 100 interaction targets for POI and HR were obtained. The protein-protein interaction network of identified interaction targets emphasized the topological importance of AKT1. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that HR might regulate POI by modulating the mechanistic target of rapamycin (mTOR) signaling pathway. In addition, the KEGG graph of the mTOR signaling pathway revealed that AKT phosphorylation inhibits the TSC1/2, while TSC1/2 activation inhibits the expression of mTORC1. The fundamental experiment revealed that HR increased proliferation, progesterone receptor levels, and estradiol levels decreased by TP in KGN cells. Additionally, HR alleviated TP-induced apoptosis and G1/G1 phase arrest in KGN cells. Western blotting demonstrated that HR increased the phosphorylation of AKT and mTORC1 and decreased TSC1 expression in TP-induced KGN cells. Collectively, our findings revealed that HR alleviates TP-induced granulosa cell injury by regulating AKT/TSC1/mTORC1 signaling, providing insight into the treatment of POI.

DOI: https://doi.org/10.1155/2021/9399261
J Coll Physicians Surg Pak. 2021 Nov;31(11): 1296-1302

Frequency of Specific Genes in Different Types of Epilepsy.

Neslihan Duzkale, Rıdvan Akın.

OBJECTIVE: To determine the diagnostic importance of using an exome-based multigene panel in childhood epilepsy.
STUDY DESIGN: Observational study.
PLACE AND DURATION OF STUDY: Department of Medical Genetics, Diskapi Yildirim Beyazid Training and Research Hospital, from January 2017 to May 2020.
METHODOLOGY: The phenotype-genotype relationship was investigated in 35 pediatric patients (aged 18 years or younger) with epilepsy, using a large gene panel comprising 464 epilepsy-related genes. The exome-based panel was used to analyse secondary findings. Results: The diagnostic yield of the targeted multi-gene panel used was 20% (7/35). The causative genes identified in seven patients (5 boys, 2 girls) were CACNA1E, RELN, PRRT2, TSC1, GABRG2, SCN2A, and SHH. Four of the detected disease-related variants were defined as the novel. Secondary findings in various genes were detected in 19 of the patients. Seven patients with causal genes and the remaining 28 patients were compared in terms of parameters such as gender, mental retardation, developmental retardation, autism, hypotonia, seizure phenotype (only), seizure phenotype (plus), magnetic resonance imaging, degree of kinship of their parents and number of relatives with epilepsy. In addition, patients were evaluated statistically in terms of the same parameters by grouping them according to their gender. There was no statistically significant difference in either study (p >0.05).
CONCLUSION: Genetic testing is an important tool for clinicians in determining the diagnosis, management, and treatment strategies of epilepsy patients. Key Words: Epilepsy, Diagnostic yield, Exome-based multigene panel, Next-generation sequencing, Seconder findings.

DOI: https://doi.org/10.29271/jcpsp.2021.11.1296