Mutation Research-Reviews in Mutation Research最新文献

{"title":"Role of methylglyoxal protein modifications in DNA damage and chromosomal instability: Emerging molecular mechanisms.","authors":"Leigh Donnellan, Michael Fenech, Varinderpal S Dhillon, Clifford Young, Peter Hoffmann, Permal Deo","doi":"10.1016/j.mrrev.2025.108558","DOIUrl":"https://doi.org/10.1016/j.mrrev.2025.108558","url":null,"abstract":"<p><p>Methylglyoxal (MGO) is a highly reactive metabolite formed from glycolysis that can form advanced glycation endproducts (AGEs) on proteins and DNA. It has been well established that MGO induces DNA double strand breaks as a result of modifications on deoxyguanosine residues. However, recent studies shed new light on the genotoxic properties of MGO by its ability to cause chromosomal mis-segregation events, and other forms of chromosomal instability. These outcomes open a new avenue in which protein modifications, rather than DNA modifications, result in DNA damage. Herein, we present several hypotheses on how modification of proteins by MGO might cause these chromosome mis-segregation events based on identified protein modification sites from proteomic studies. These include various cell cycle proteins, such as those involved in sister chromatid cohesion, centrosome formation and histone proteins. Overall, recent studies implicate MGO in whole chromosome loss events, amongst other chromosomal instability events, suggesting it as a key player in cancer development and progression.</p>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"108558"},"PeriodicalIF":4.2,"publicationDate":"2025-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144805125","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"All roads lead to mitosis: A common requirement for DNA replication stress-dependent and -independent killing of BRCA-deficient cells.","authors":"Sebastian Omar Siri, Ariel Abramovici Blasco, Ginette Moyano, María Candelaria Mares Ahlers, Vanesa Gottifredi","doi":"10.1016/j.mrrev.2025.108557","DOIUrl":"10.1016/j.mrrev.2025.108557","url":null,"abstract":"<p><p>The deficiency in breast cancer associated proteins 1 and 2 (BRCA1 and 2) causes an early and more frequent onset of tumor genesis and progression. Poly (ADP-ribose) polymerase inhibitors (PARPi) are selectively toxic towards BRCA1 and 2-deficient tumors, sparing the healthy cells from patients from side effects. In BRCA1 and 2 deficient tumors, PARPi-mediated cell death is characterized by the augmentation of replication stress (RS) and chromosome instability (CIN) including micronuclei (MN) accumulation, a source of swift genomic rearrangements. PARPi also cause resistance to treatments which indicates the need of treatment alternatives. In this review, we discuss potential options that, similarly to PARPi, selectively kill BRCA1 and/or 2 deficient tumors. Remarkably, while many of those alternatives also upregulate MN and other CIN variables, others cause a RS-independent and MN-independent cell killing. This is the case of the inhibitors of Rho-kinase (ROCK) and, potentially, mitotic kinase Polo like kinase 1 (PLK1). Such a mode of cell killing could be advantageous if attempting to either prevent or postpone the rise of resistance clones in the tumor population that survives the treatment.</p>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":" ","pages":"108557"},"PeriodicalIF":4.2,"publicationDate":"2025-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144765736","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genotype-phenotype correlations in biallelic carriers of FANCM protein truncating variants: A systematic literature review","authors":"Gisella Figlioli ,&nbsp;Amandine Billaud ,&nbsp;Paolo Peterlongo","doi":"10.1016/j.mrrev.2025.108559","DOIUrl":"10.1016/j.mrrev.2025.108559","url":null,"abstract":"<div><div>The <em>FANCM</em> gene is involved in the Fanconi Anemia (FA) DNA repair pathway. Although germline biallelic pathogenic variants in genes of this pathway cause the recessive FA syndrome, the role of <em>FANCM</em> in FA or FA-like has been questioned. Biallelic <em>FANCM</em> protein truncating variants (PTVs) have been primarily linked to infertility and cancer, suggesting the gene causes a clinically distinct phenotype. Four literature databases were systematically searched from inception to June 2024 to identify published articles describing individuals carrying biallelic PTVs in <em>FANCM</em>. Twenty articles describing 40 carriers of biallelic <em>FANCM</em> PTVs were identified. We established genotype-phenotype correlations and found that women carrying biallelic combinations of the C-terminal p.Gln1701* and p.Gly1906Alafs*12 PTVs showed infertility, chromosome fragility, breast cancer, and chemotoxicity. Men carrying the same PTVs combinations showed infertility only. Carriers of biallelic combinations including a single N-terminal PTV showed chromosome fragility, infertility, and early onset breast cancer and/or squamous cell carcinoma, and pediatric hematological cancers, often associated with severe chemotoxicity. Our findings indicate that <em>FANCM</em> biallelic PTVs may cause a novel recessive syndrome which is distinct from FA and characterized by infertility, chromosome fragility, cancer and chemotoxicity. While infertility is always observed, the severity of chromosome fragility, cancer predisposition and chemotoxicity seem to depend on <em>FANCM</em> PTVs position and the sex of the carrier. Larger analyses are warranted to consolidate these findings.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108559"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144852994","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanistic roles of long non-coding RNAs in DNA damage response and genome stability","authors":"Li Wu ,&nbsp;Lingli Wang ,&nbsp;Jingyu Hou ,&nbsp;Zhengping Shao ,&nbsp;Jun Yang ,&nbsp;Xiangwei Gao","doi":"10.1016/j.mrrev.2025.108562","DOIUrl":"10.1016/j.mrrev.2025.108562","url":null,"abstract":"<div><div>To maintain genomic stability, cells have evolved complex mechanisms collectively known as the DNA damage response (DDR), which includes DNA repair, cell cycle checkpoints, apoptosis, and gene expression regulation. Recent studies have revealed that long non-coding RNAs (lncRNAs) are pivotal regulators of the DDR. Beyond their established roles in recruiting repair proteins and modulating gene expression, emerging evidence highlights two particularly intriguing functions. First, some lncRNAs contain small open reading frames (sORFs) encoding functional micropeptides that actively participate in DDR pathways. Second, lncRNAs regulate R-loop homeostasis, a key mechanism for preserving genome integrity. Together, these findings expand our understanding of lncRNAs in the DDR, positioning them as both key mechanistic players and promising therapeutic targets.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108562"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145026489","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The intracellular and extracellular fate of DNA and chromatin from micronuclei determines their pathogenicity","authors":"Micheline Kirsch-Volders ,&nbsp;Michael Fenech ,&nbsp;Miroslav Mišík ,&nbsp;Paul Van Hummelen","doi":"10.1016/j.mrrev.2025.108561","DOIUrl":"10.1016/j.mrrev.2025.108561","url":null,"abstract":"<div><div>Circulating cell-free DNA (cfDNA), particularly in blood, is emerging as a critical non-invasive biomarker for the prediction, diagnosis, and monitoring of human diseases. Additionally, cytoplasmic DNA has been implicated in promoting genetic aberrations, genome instability, and inflammation—factors that can contribute to the development of various diseases, including cancer. However, the heterogeneous nature of both intra- and extracellular DNA presents a significant challenge. This review synthesizes current evidence on the origin, composition, and fate of micronuclei (MN) and their derived DNA/chromatin, highlighting their potential as active participants in genomic instability and immune activation. We examine the molecular characteristics of MN, including their formation from acentric fragments, whole chromosomes, or double minutes, and their dynamic intracellular outcomes, such as reintegration, degradation, or extrusion. A major focus is placed on the consequences of micronuclear envelope rupture, including chromothripsis and cGAS-STING–mediated inflammation. We explore the emerging evidence for the extrusion of MN or MN-derived DNA via direct extrusion or packaging in extracellular vesicles, and discuss their implications for cfDNA composition, detection, and biomarker development. The review also underscores the relevance of MN in disease pathogenesis and senescence, and concludes by outlining critical knowledge gaps, particularly concerning the mechanisms of MN clearance, their tissue origin, and their survival and detectability in plasma. In conclusion, by elucidating the mechanistic link between MN biology and cfDNA, we propose that MN-derived DNA and chromatin may serve as informative indicators of genomic instability and disease progression, and offer valuable insights for future diagnostic and therapeutic strategies.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108561"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144925136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mortality rate and causes of death in inborn errors of immunity: A systematic review and meta-analysis","authors":"Saba Fekrvand ,&nbsp;Zahra Hamidi Esfahani ,&nbsp;Mohammadmehdi Yarahmadi ,&nbsp;Ali Saeedi-Boroujeni ,&nbsp;Helia Salehi ,&nbsp;Ali Hakimelahi ,&nbsp;Amir Almasi-Hashiani ,&nbsp;Mahshid Rahmati ,&nbsp;Sanaz Afshar-Ghasemlou ,&nbsp;Najmeh Nameh Goshay Fard ,&nbsp;Fateme Tarighat Monfared ,&nbsp;Ehsan Khoshnezhad Afkham ,&nbsp;Nazanin Fathi ,&nbsp;Tannaz Moeini Shad ,&nbsp;Fateme Babaha ,&nbsp;Farzad Nazari ,&nbsp;Matineh Nirouei ,&nbsp;Amir Salehi Farid ,&nbsp;Negin Sanadgol ,&nbsp;Hosein Rafiemanesh ,&nbsp;Reza Yazdani","doi":"10.1016/j.mrrev.2025.108564","DOIUrl":"10.1016/j.mrrev.2025.108564","url":null,"abstract":"<div><h3>Background</h3><div>Patients with inborn errors of immunity (IEI) experience severe infectious and non-infectious complications, leading to an increased risk of mortality. Delayed diagnosis or misdiagnosis significantly contributes to the heightened mortality rates observed in IEI patients.</div></div><div><h3>Objectives</h3><div>This study systematically reviews the causes of mortality in IEI patients with a meta-analysis to determine the mortality rate among patients with various IEI.</div></div><div><h3>Methods</h3><div>Embase, ISI Web of Science, PubMed, and Scopus were searched (up to July 2024) using terms related to IEI and mortality.</div></div><div><h3>Results</h3><div>A total of 12,581 deceased IEI patients were included, with an overall reported mortality rate of 24.0 % (95 % confidence interval: 23.0–26.0 %) among all published IEI cases. This represents an approximately 27-fold higher mortality rate among IEI patients compared to the mean global mortality rate (24 % vs. 0.874 %). Severe combined immunodeficiency, chronic granulomatous disease, and ataxia-telangiectasia had the highest numbers of reported deceased cases (2304, 962, and 820 cases, respectively). However, familial hemophagocytic lymphohistiocytosis exhibited the highest mortality rate (49.0 %). The most common causes of death were infections, transplant-related mortality and non-infectious pulmonary complications, (3429, 2749, and 1141 cases), respectively. Among infectious causes of death, COVID-19 infection accounted for 10.8 % (370 cases).</div></div><div><h3>Conclusion</h3><div>This study identifies specific types of IEI with the highest mortality rates and numbers, alongside immune component defects most strongly associated with increased mortality. Patients with immune dysregulation, defects in cellular immunity, and phagocyte function were particularly linked to higher mortality rates, underscoring the urgent need for improved management strategies for these IEIs.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108564"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145187346","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular insights and emerging therapeutic perspectives of the lncRNA GAS5/miR-21 axis in cancer, fibrosis, cardiovascular, and immune disorders","authors":"Salma M.S. Ahmad ,&nbsp;Fatemeh Abdullah M. Ahmadi ,&nbsp;Roberta Giordo ,&nbsp;Gavino Casu ,&nbsp;Gheyath K. Nasrallaha ,&nbsp;Hatem Zayed ,&nbsp;Gianfranco Pintus","doi":"10.1016/j.mrrev.2025.108551","DOIUrl":"10.1016/j.mrrev.2025.108551","url":null,"abstract":"<div><div>Non-coding RNAs (ncRNAs) have redefined the complexity of gene regulation, with the long non-coding (lncRNA) GAS5/miR-21 axis emerging as a critical determinant of cell fate across diverse pathological contexts. This review examines the molecular mechanisms by which GAS5 regulates miR-21 activity, thereby restoring tumor suppressor networks and controlling key pathways, including the PI3K/AKT, MAPK/ERK, and Wnt/β-catenin pathways. We detail how dysregulation of this axis fuels cancer progression, metastasis, therapy resistance, fibrosis, cardiovascular diseases, osteoporosis, osteoarthritis, and autoimmune conditions like systemic lupus erythematosus. Beyond its role as a master regulator of apoptosis, proliferation, and EMT, the GAS5/miR-21 interaction holds immense promise as a therapeutic target and a liquid biopsy biomarker. However, clinical translation demands solutions to major challenges, including RNA delivery barriers, context-dependent effects, and adaptive resistance. Leveraging multi-omics integration, gene-editing technologies, and personalized RNA therapeutics will be pivotal to overcoming these obstacles. By critically integrating current knowledge and outlining future directions, this review positions the GAS5/miR-21 axis at the forefront of next-generation ncRNA therapeutics. Harnessing its full potential could not only revolutionize treatment paradigms but also transform our understanding of RNA-driven disease networks.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108551"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144548777","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of resveratrol on neutrophil extracellular traps","authors":"Mahboobeh Ghasemzadeh Rahbardar ,&nbsp;Prashant Kesharwani ,&nbsp;Amirhossein Sahebkar","doi":"10.1016/j.mrrev.2025.108550","DOIUrl":"10.1016/j.mrrev.2025.108550","url":null,"abstract":"<div><div>Neutrophil extracellular traps (NETs) and the process of NETosis have emerged as critical participants in various pathological conditions. Resveratrol, a natural polyphenol found in several plants, has received significant attention due to its potential therapeutic properties. The purpose of this review is to investigate how resveratrol affects NETs and NETosis. The molecular mechanisms underlying NET formation and its role in disease pathogenesis are discussed, highlighting the involvement of various cellular and molecular factors. Moreover, the effects of resveratrol on NET formation, release, and stability are reported, focusing on its potential as a modulator of NET-associated diseases. Studies investigating the effect of resveratrol on NETosis in different disease models, including lung injury, COVID-19, cancer, and hepatic ischemia-reperfusion injury, are also summarized. Furthermore, the potential mechanisms through which resveratrol exerts its effects on NETosis, including anti-inflammatory, antioxidant, and immunomodulatory properties, are elucidated. The review also addresses the challenges and future perspectives in the field, emphasizing the need for further research to fully understand the therapeutic potential of resveratrol in targeting NET-associated disorders. Generally, this review provides a comprehensive analysis of the impact of resveratrol on NETs and NETosis, shedding light on its potential as a therapeutic intervention in various pathological conditions characterized by excessive NET formation. However, further research is essential to clarify the detailed mechanisms through which resveratrol exerts its effects on NETosis and to determine optimal dosages and treatment procedures.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108550"},"PeriodicalIF":6.4,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144534366","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single nucleotide variants associated with colorectal cancer among Saudi patients: A systematic review","authors":"Ahmad M. Alamri ,&nbsp;Abdullah A. Assiri ,&nbsp;Najeeb Ullah Khan","doi":"10.1016/j.mrrev.2025.108563","DOIUrl":"10.1016/j.mrrev.2025.108563","url":null,"abstract":"<div><h3>Objective</h3><div>To assess the variations in Single Nucleotide Polymorphisms (SNPs) that affect susceptibility of CRC in Saudi patients.</div></div><div><h3>Methods</h3><div>A systematic literature review was conducted following PRISMA guidelines. Electronic databases were searched from inception up to March 2025 using MeSH terms and keywords related to SNPs, Colorectal Cancer (CRC), and Saudi Arabia. Eligibility criteria mandated studies conducted on Saudi populations, including confirmed CRC cases and healthy controls (≥18 years), investigating SNP-CRC associations, and reporting risk estimates. Data on study characteristics, gene/SNP details, participant numbers, genotyping methods, risk estimates, p-values, and pathway categorization were extracted by two independent reviewers. The Newcastle-Ottawa Scale was used to assess the risk of bias in included case-control studies.</div></div><div><h3>Results</h3><div>Twenty-three case-control studies met the inclusion criteria, encompassing 2521 CRC cases and 2236 healthy controls. These studies investigated SNPs within 46 different genes. Significant associations (p &lt; 0.05) with CRC risk were identified across various biological pathways. SNPs in inflammation/immune response genes (e.g., <em>TNF-α</em>, <em>IL-17A</em>, <em>PD-1</em>, <em>CTLA-4</em>, <em>IL-10</em>, <em>TGFβ1</em>) showed both increased and decreased risk associations. Variations in DNA repair (<em>PARP-1, XRCC1, TP53</em>) and cellular protection/drug metabolism genes (<em>ABCC1, MDR1, GSTM1</em>) also modulated susceptibility. Furthermore, SNPs in signaling pathways (<em>VDR, MMP-2, NOTCH</em>) and membrane/RNA-related genes (<em>HER1, HER2, RETN, PRNCR1, HOTAIR</em>) were significantly associated with CRC risk. Some allele frequencies (CYP19A) appeared distinct in the Saudi population compared to others. Most studies (77 %) were assessed as having a low risk of bias, though hospital-based control recruitment was a common limitation.</div></div><div><h3>Conclusion</h3><div>This systematic review confirms that numerous SNPs are significantly associated with altered CRC susceptibility in the Saudi population. These findings highlight a complex genetic landscape and underscore the potential value of identified SNPs for developing population-specific CRC risk assessment tools and targeted screening programs in Saudi Arabia.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108563"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145118009","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neurogenetic biomarkers in epilepsy: A comprehensive narrative review of progression and therapeutic approaches","authors":"Ramandeep Kaur Sidhu ,&nbsp;Kousik Maparu ,&nbsp;Khadga Raj Aran","doi":"10.1016/j.mrrev.2025.108556","DOIUrl":"10.1016/j.mrrev.2025.108556","url":null,"abstract":"<div><div>Epilepsy is a multifaceted and heterogenous neurological disorder that affects an estimated 70 million people worldwide and is identified by recurrent or unprovoked seizure activity. Although there have been advances in pharmacotherapeutic treatments, approximately one-third of patients with epilepsy remain drug resistant, highlighting the need for personalised and mechanism-based strategies. Neurogenetic biomarkers are emerging as valuable instruments for translating the genetic findings to the bedside and may provide new opportunities within a more precise treatment paradigm in epilepsy. Neurogenetic biomarkers include single-nucleotide polymorphisms (SNPs), copy number variants (CNVs), and mutations in disease-specific genes that inform our knowledge about the genetic architecture of seizure susceptibility, seizure progression and therapeutic response. The main genes, such as SCN1A, KCNQ2, GRIN2A, LGI1, GABRA1, and CHRNA4, impact neuronal excitability, ion channel dynamics, and synaptic interactions. Variations of mTOR signaling pathways (TSC1, TSC2, DEPDC5) and mutations in epigenetic regulators (MECP2, CDKL5) implicated a multilayered structure in the mechanistic underpinnings of epileptogenesis. Neurogenetic biomarkers are increasingly relevant to clinical practice for refining diagnosis, predicting seizure onset, guiding drug selection, and determining surgical intervention. The integration of neurogenetic sampling with neuroimaging, electrophysiological, inflammatory, and molecular signatures can improve diagnostic precision and provide an evidence-based framework towards therapeutic stratification. Although challenges remain-such as genetic heterogeneity, variant interpretation, cost barriers, and ethical considerations, advances in next-generation sequencing, pharmacogenomics, and artificial intelligence are rapidly transforming these limitations into opportunities. Neurogenetic biomarkers hold transformative potential to redefine epilepsy care, enabling earlier diagnosis, individualized therapy, and improved long-term outcomes. As the field advances, they are poised to shift epilepsy management from reactive to predictive, and from generalized to precision-driven, initiating a new era of neurology.</div></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":"796 ","pages":"Article 108556"},"PeriodicalIF":4.2,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144772249","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}