Molecular Diagnosis & Therapy最新文献

{"title":"Afamitresgene Autoleucel: First Approval.","authors":"Susan J Keam","doi":"10.1007/s40291-024-00749-3","DOIUrl":"10.1007/s40291-024-00749-3","url":null,"abstract":"<p><p>Afamitresgene autoleucel (TECELRA^®), a genetically modified human leukocyte antigen (HLA)-restricted autologous melanoma-associated antigen 4 (MAGE-A4)-directed T cell immunotherapy, is being developed by Adaptimmune Therapeutics plc, for the treatment of solid tumours expressing the MAGE-A4 antigen. In August 2024, afamitresgene autoleucel was approved in the USA under accelerated approval for the treatment of adults with unresectable or metastatic synovial sarcoma who have received prior chemotherapy, are HLA-A*02:01P, -A*02:02P, -A*02:03P or -A*02:06P positive and whose tumour expresses the MAGE-A4 antigen as determined by FDA-approved or cleared companion diagnostic devices. This article summarizes the milestones in the development of afamitresgene autoleucel leading to this first approval for the treatment of advanced synovial sarcoma.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"861-866"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142479160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Performance of a Rapid Digital PCR Test for the Detection of Non-Small Cell Lung Cancer (NSCLC) Variants.","authors":"Abdulaziz F Al Mana, Kristen Culp, Abby Keeler, Orlando Perrera, Malini Rajagopalan, Lucien Jacky, Brad Brown, Bharat Thyagarajan","doi":"10.1007/s40291-024-00732-y","DOIUrl":"10.1007/s40291-024-00732-y","url":null,"abstract":"<p><strong>Background: </strong>Next-generation sequencing is widely used for comprehensive molecular profiling for many cancers including lung cancer. However, the complex workflows and long turnaround times limit its access and utility. ChromaCode's High Definition PCR Non-Small Cell Lung Cancer Panel (HDPCR™ NSCLC Panel) is a low-cost, rapid turnaround, digital polymerase chain reaction assay that is designed to detect variants in nine NSCLC genes listed in National Comprehensive Cancer Network guidelines.</p><p><strong>Methods: </strong>This assay uses TaqMan^® probe limiting chemistry and proprietary analysis software to enable multi-target detection within a single-color channel. We compared the performance of the HDPCR™ NSCLC Panel against an in-house, laboratory-developed, targeted next-generation sequencing panel used in the Molecular Diagnostics Laboratory at the University of Minnesota Medical Center to detect biomarkers for NSCLC.</p><p><strong>Results: </strong>The overall accuracy of the HDPCR panel was 99.48% (95% confidence interval 99.01-99.76) with a sensitivity of 95.35% (95% confidence interval 88.52-98.72) and a specificity of 99.69% (95% confidence interval 99.29-99.90). The HDPCR wet lab workflow was 4 h, and the time to generate variant calls from raw data using the ChromaCode Cloud was 2 minutes.</p><p><strong>Conclusions: </strong>We demonstrated that the HDPCR™ NSCLC Panel provides timely, comprehensive, and sensitive mutation detection in NSCLC samples with results in less than 24 h.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"791-802"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mycobacterium tuberculosis Detection Using CRISPR Technology: An Updated Systematic Review and Meta-analysis.","authors":"Mohammad Abavisani, Sobhan Karbas Foroushan, Reza Khayami, Amirhossein Sahebkar","doi":"10.1007/s40291-024-00741-x","DOIUrl":"10.1007/s40291-024-00741-x","url":null,"abstract":"<p><strong>Background: </strong>Rapid and precise detection of Mycobacterium tuberculosis (MTB) is paramount for effective management and control of tuberculosis. Clustered regularly interspaced short palindromic repeats (CRISPR) technology has emerged as a promising tool for pathogenic diagnosis owing to its specificity and adaptability. This systematic review and meta-analysis aimed to appraise the diagnostic accuracy of CRISPR-based techniques in identifying MTB.</p><p><strong>Methods: </strong>A meticulous search was conducted in Medline, Scopus, Embase, and ISI Web of Science to retrieve relevant studies, adhering to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Quality was assessed using the Joanna Briggs Institute checklist. Data synthesis and analyses, including subgroup analyses, were performed with R v 4.3.1, examining variables like CRISPR variants, gene targets, pre-amplification techniques, and signal readout methods.</p><p><strong>Results: </strong>From 389 identified studies, 14 met the inclusion criteria, encompassing 2175 MTB strains. The pooled sensitivity and specificity of CRISPR-based techniques were 0.93 (95% CI 0.85-0.99) and 0.97 (95% CI 0.94-0.99), respectively. The pooled diagnostic odds ratio was 273.4379 (95% CI 103.3311-723.5794), with an area under the curve of 0.97 for the summary receiver operating characteristic (SROC) curve, denoting excellent diagnostic accuracy. Subgroup analyses illustrated variations in diagnostic metrics based on factors like CRISPR variant utilized, target gene, and pre-amplification methods. For instance, CRISPR-Cas12 exhibited a sensitivity and specificity of 0.93 (95% CI 0.78-0.98) and 0.98 (95% CI 0.93-1), respectively. Moreover, this technology showed a sensitivity of 96% and specificity of 100% in detecting resistant MTB.</p><p><strong>Conclusion: </strong>CRISPR-based methods exhibit substantial diagnostic sensitivity and specificity for detecting MTB, with notable variances across different CRISPR variants and methodological approaches. Further studies must be conducted to optimize CRISPR's potential as a diagnostic tool for MTB in a variety of clinical and research settings.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"777-790"},"PeriodicalIF":4.1,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142114126","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumour Marker Expression in Head and Neck Malignancies to Identify Potential Targets for Intraoperative Molecular Near-Infrared Imaging","authors":"Lorraine J. Lauwerends, Bo E. Zweedijk, Hidde A. Galema, Lisanne K. A. Neijenhuis, Neeltje G. Dekker-Ensink, Robert J. Baatenburg de Jong, Cornelis Verhoef, Shadhvi S. Bhairosingh, Peter J. K. Kuppen, Alexander L. Vahrmeijer, Tessa M. van Ginhoven, Senada Koljenović, Sjors A. Koppes, Denise E. Hilling, Stijn Keereweer","doi":"10.1007/s40291-024-00742-w","DOIUrl":"https://doi.org/10.1007/s40291-024-00742-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Oral and laryngeal squamous cell carcinoma (OSCC and LSCC) and papillary thyroid carcinoma (PTC) are common head and neck cancers (HNCs) typically treated surgically. Challenges in tumour delineation often lead to inadequate resection margins in OSCC and LSCC, and missed multifocality in PTC. Fluorescence imaging (FLI) using near-infrared tumour-targeting tracers may improve intraoperative identification of malignancy, facilitating precise excision. This study evaluates six potential FLI targets in OSCC, LSCC and PTC.</p><h3 data-test=\"abstract-sub-heading\">Materials and methods</h3><p>Immunohistochemical staining was performed on OSCC (<i>n</i> = 20), LSCC (<i>n</i> = 10) and PTC (<i>n</i> = 10), assessing CEA, c-Met, EpCAM, EGFR, integrin αvβ6 and VEGF-α. Expression was scored (0–12) using the total immunostaining score (TIS) system, and categorized into absent (TIS 0), low (TIS 1–5), moderate (TIS 6–8) or high (TIS 9–12).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Integrin αvβ6 showed significant overexpression in OSCC (TIS: 12; <i>p</i> &lt; 0.001) and LSCC (TIS: 8; <i>p</i> = 0.002), with 80% of OSCC and 90% of LSCC exhibiting moderate-high expression. Similarly, EGFR expression was moderate-high in most OSCC (87.5%; TIS: 8) and universally high in LSCC (100%; TIS: 12). In PTC, EGFR and VEGF-α expressions were low-moderate, but significantly higher than in healthy tissue (TIS: 6; <i>p</i> &lt; 0.006).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>This study highlights integrin αvβ6 and EGFR as viable FLI targets in OSCC and LSCC, especially integrin αvβ6 for tumour margin delineation. In PTC, despite lower expressions, the significant overexpression of VEGF-α, c-MET, and EGFR suggests their potential as FLI targets. Our findings support the development of tumour-targeted FLI tracers to improve surgical precision in HNC.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":"14 1","pages":""},"PeriodicalIF":4.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142190172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Therapies in Clinical Development to Treat Retinal Disorders.","authors":"Michelle E McClements, Maram E A Abdalla Elsayed, Lauren Major, Cristina Martinez-Fernandez de la Camara, Robert E MacLaren","doi":"10.1007/s40291-024-00722-0","DOIUrl":"10.1007/s40291-024-00722-0","url":null,"abstract":"<p><p>Gene therapies have emerged as promising treatments in clinical development for various retinal disorders, offering hope to patients with inherited degenerative eye conditions. Several gene therapies have already shown remarkable success in clinical trials, with significant improvements observed in visual acuity and the preservation of retinal function. A multitude of gene therapies have now been delivered safely in human clinical trials for a wide range of inherited retinal disorders but there are some gaps in the reported trial data. Some of the most exciting treatment options are not under peer review and information is only available in press release form. Whilst many trials appear to have delivered good outcomes of safety, others have failed to meet primary endpoints and therefore not proceeded to phase III. Despite this, such trials have enabled researchers to learn how best to assess and monitor patient outcomes, which will guide future trials to greater success. In this review, we consider recent and ongoing clinical trials for a variety of potential retinal gene therapy treatments and discuss the positive and negative issues related to these trials. We discuss the treatment potential following clinical trials as well as the potential risks of some treatments under investigation. As these therapies continue to advance through rigorous testing and regulatory approval processes, they hold the potential to revolutionise the landscape of retinal disorder treatments, providing renewed vision and enhancing the quality of life for countless individuals worldwide.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"575-591"},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Immunodominant Epitopes of Dengue Virus 2 Envelope and NS1 Proteins: Evaluating the Diagnostic Potential of a Synthetic Peptide.","authors":"Sushmita Singha, Neena Nath, Vaishali Sarma, Kangkana Barman, Gurumayum Chourajit Sharma, Lahari Saikia, Shashi Baruah","doi":"10.1007/s40291-024-00728-8","DOIUrl":"10.1007/s40291-024-00728-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Dengue is a major infectious disease with potential for outbreaks and epidemics. A specific and sensitive diagnosis is a prerequisite for clinical management of the disease. We designed our study to identify epitopes on the Dengue virus (DENV) envelope (E) and non-structural protein 1 (NS1) with potential for diagnosis.</p><p><strong>Methods: </strong>Serology and immunoinformatic approaches were employed. We collected DENV-positive, DENV-negative and Japanese encephalitis virus-positive samples from collaborating hospitals in 2019 and 2022-2023. Seropositive peptides in 15-18 mer peptide arrays of E and NS1 proteins of DENV2 were determined by an indirect enzyme-linked immunosorbent assay. B-cell linear and conformational epitopes were predicted using BepiPred2.0 and ElliPro, respectively. A consensus recombinant peptide was designed, synthesised and evaluated for its diagnostic potential using patient sera.</p><p><strong>Results: </strong>Eight peptides of E protein and six peptides of NS1 protein were identified to be the most frequently recognised by Dengue-positive patients. These peptide sequences were compared with B-cell epitope regions and found to be overlapped with predicted B-cell linear and conformational epitopes. EP11 and NSP15 showed a 100% amino acid sequence overlap with B-cell epitopes. EP1 and NSP15 had 14 whereas EP28, EP31, EP60 16, NSP12 and NSP32 had more than 15 interacting interface residues with a neutralising antibody, suggesting a strength of interaction. Interestingly, potential epitopes identified were localised on the surface of proteins as visualised by PyMOL. Validation with a recombined synthetic peptide yielded 92.3% sensitivity and 91.42% specificity.</p><p><strong>Conclusions: </strong>Immunodominant regions identified by serology and computationally predicted epitopes overlapped, thereby showing the robustness of the methodology and the peptide designed for diagnosis.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"633-643"},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Central Nervous System Infections: Advances and Challenges.","authors":"LingHui David Su, Charles Y Chiu, David Gaston, Catherine A Hogan, Steve Miller, Dennis W Simon, Kiran T Thakur, Shangxin Yang, Anne Piantadosi","doi":"10.1007/s40291-024-00727-9","DOIUrl":"10.1007/s40291-024-00727-9","url":null,"abstract":"<p><p>Central nervous system (CNS) infections carry a substantial burden of morbidity and mortality worldwide, and accurate and timely diagnosis is required to optimize management. Metagenomic next-generation sequencing (mNGS) has proven to be a valuable tool in detecting pathogens in patients with suspected CNS infection. By sequencing microbial nucleic acids present in a patient's cerebrospinal fluid, brain tissue, or samples collected outside of the CNS, such as plasma, mNGS can detect a wide range of pathogens, including rare, unexpected, and/or fastidious organisms. Furthermore, its target-agnostic approach allows for the identification of both known and novel pathogens. This is particularly useful in cases where conventional diagnostic methods fail to provide an answer. In addition, mNGS can detect multiple microorganisms simultaneously, which is crucial in cases of mixed infections without a clear predominant pathogen. Overall, clinical mNGS testing can help expedite the diagnostic process for CNS infections, guide appropriate management decisions, and ultimately improve clinical outcomes. However, there are key challenges surrounding its use that need to be considered to fully leverage its clinical impact. For example, only a few specialized laboratories offer clinical mNGS due to the complexity of both the laboratory methods and analysis pipelines. Clinicians interpreting mNGS results must be aware of both false negatives-as mNGS is a direct detection modality and requires a sufficient amount of microbial nucleic acid to be present in the sample tested-and false positives-as mNGS detects environmental microbes and their nucleic acids, despite best practices to minimize contamination. Additionally, current costs and turnaround times limit broader implementation of clinical mNGS. Finally, there is uncertainty regarding the best practices for clinical utilization of mNGS, and further work is needed to define the optimal patient population(s), syndrome(s), and time of testing to implement clinical mNGS.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"513-523"},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11660858/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Future of CAR T Therapeutics to Treat Autoimmune Disorders.","authors":"Ann-Christin Pecher, Luca Hensen, Claudia Lengerke, Jörg Henes","doi":"10.1007/s40291-024-00730-0","DOIUrl":"10.1007/s40291-024-00730-0","url":null,"abstract":"<p><p>The concept of chimeric antigen receptor (CAR) T cell therapy emerged from cancer immunotherapy and has been rapidly adapted and developed for the treatment of autoimmune, especially B-cell-driven, diseases since the first publication of an article featuring a patient with systemic lupus erythematosus in 2021. Phase II studies are about to start, but up to now, only case reports and small series have been published. In contrast to hemato-oncological diseases, where an aggressive response to malignant cells and long-lasting persistence of CAR T cells has been aimed at and observed in many patients, this is not the case with autoimmune diseases but might not be necessary to control disease. Future studies will focus on the optimal target but also on the optimal level of immunogenicity. The latter can be influenced by numerous modulations that affect not only cytokine release but also regulation. In addition, there are potential applications in regulatory cells such as CAR regulatory T cells (Treg). The question of toxicity reduction must also be addressed, as long-term complications such as the potential development of malignant diseases, infections, or cytopenia must be considered even more critically in the area of autoimmune diseases than is the case for patients with oncologic diseases. Alternative antibody-based therapies using the same target (e.g., CD3/CD19 bispecific targeting antibodies) have not been used in these patients and might also be considered in the future. In conclusion, CAR T cell therapy represents a promising therapeutic approach for autoimmune diseases, offering a targeted strategy to modulate immune responses and restore immune tolerance.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"593-600"},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Papillary Thyroid Carcinoma: Correlation Between Molecular and Clinical Features.","authors":"Qiang Wang, Bo Yu, Shuilong Zhang, Dongliang Wang, Zhifu Xiao, Hongjing Meng, Lingxiang Dong, Yuhang Zhang, Jie Wu, Zebin Hou, Yunji Zhu, Dewei Li","doi":"10.1007/s40291-024-00721-1","DOIUrl":"10.1007/s40291-024-00721-1","url":null,"abstract":"<p><strong>Background: </strong>Thyroid cancer is prevalent worldwide, including in China, where its incidence is on the rise. Papillary thyroid carcinoma (PTC) is the predominant subtype. Investigating the relationship between clinical data associated with PTC and gene mutations is crucial for improving detection and treatment.</p><p><strong>Patients and methods: </strong>We collected samples and associated clinical data from 700 PTC patients at Shanxi Provincial People's Hospital. Using a panel of 57 genes linked to thyroid cancer, we sequenced the samples to determine the mutation frequency of thyroid cancer-associated genes in PTC. We further analyzed the correlation between gene variants and clinical information.</p><p><strong>Results: </strong>The mean age of patients in this study was 42.5 years. Females predominated, comprising 507 of the total patient population, resulting in a female-to-male ratio of 2.63 (507:193). Tumor distribution revealed 198, 257, and 142 cases on the left, right, and both sides, respectively. Among the 57 thyroid cancer-related genes analyzed, we identified at least one driver gene in 83.6% of patients. Notably, 76.4% had BRAF mutations, mainly BRAF^V600E, which constituted 90.9% of all BRAF mutations, with 535 cases exhibiting these mutations. Other significant driver genes included CHEK2 (n = 84), RET (n = 42), PIK3CA (n = 7), and EGFR (n = 7). RET fusions (n = 28) were also identified. Notably, patients under 55 years old exhibit a higher tendency towards advanced N staging, suggesting that younger individuals may be more prone to lymph node metastasis. Additionally, male patients were more likely to have advanced N stages. Importantly, a positive correlation was observed between higher BRAF allele frequencies and more advanced T and N stages. Similarly, correlation analysis revealed that a greater frequency of RET fusions correlated with later T and N stages.</p><p><strong>Conclusion: </strong>This study uncovered several significant insights. Younger PTC patients exhibited a higher propensity for lymph node metastasis. An elevated mutation frequency of BRAF was correlated with a higher occurrence of RET fusions, predisposing individuals to lymph node metastasis and potentially indicating a poorer prognosis.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"601-609"},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421645","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of 13 Novel Genetic Variants in Genes Associated with Epilepsy: Implications for Targeted Therapeutic Strategies.","authors":"Marina Andjelkovic, Kristel Klaassen, Anita Skakic, Irena Marjanovic, Ruzica Kravljanac, Maja Djordjevic, Biljana Vucetic Tadic, Bozica Kecman, Sonja Pavlovic, Maja Stojiljkovic","doi":"10.1007/s40291-024-00720-2","DOIUrl":"10.1007/s40291-024-00720-2","url":null,"abstract":"<p><strong>Background: </strong>Childhood epilepsies are caused by heterogeneous underlying disorders where approximately 40% of the origins of epilepsy can be attributed to genetic factors. The application of next-generation sequencing (NGS) has revolutionized molecular diagnostics and has enabled the identification of disease-causing genes and variants in childhood epilepsies. The objective of this study was to use NGS to identify variants in patients with childhood epilepsy, to expand the variant spectrum and discover potential therapeutic targets.</p><p><strong>Methods: </strong>In our study, 55 children with epilepsy of unknown etiology were analyzed by combining clinical-exome and whole-exome sequencing. Novel variants were characterized using various in silico algorithms for pathogenicity and structure prediction.</p><p><strong>Results: </strong>The molecular genetic cause of epilepsy was identified in 28 patients and the overall diagnostic success rate was 50.9%. We identified variants in 22 different genes associated with epilepsy that correlate well with the described phenotype. SCN1A gene variants were found in five unrelated patients, while ALDH7A1 and KCNQ2 gene variants were found twice. In the other 19 genes, variants were found only in a single patient. This includes genes such as ASH1L, CSNK2B, RHOBTB2, and SLC13A5, which have only recently been associated with epilepsy. Almost half of diagnosed patients (46.4%) carried novel variants. Interestingly, we identified variants in ALDH7A1, KCNQ2, PNPO, SCN1A, and SCN2A resulting in gene-directed therapy decisions for 11 children from our study, including four children who all carried novel SCN1A genetic variants.</p><p><strong>Conclusions: </strong>Described novel variants will contribute to a better understanding of the European genetic landscape, while insights into the genotype-phenotype correlation will contribute to a better understanding of childhood epilepsies worldwide. Given the expansion of molecular-based approaches, each newly identified genetic variant could become a potential therapeutic target.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"645-663"},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349789/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141604405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}