Human Mutation最新文献

Correction to “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity” 更正“卵巢癌泛素化相关基因的预后价值及其与肿瘤免疫的相关性”

IF 3.7 2区医学

Human Mutation Pub Date : 2025-10-04 DOI: 10.1155/humu/9879845

{"title":"Correction to “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity”","authors":"","doi":"10.1155/humu/9879845","DOIUrl":"https://doi.org/10.1155/humu/9879845","url":null,"abstract":"S. Zhao, X. Lin, Y. Huang, et al., “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity,” Human Mutation 2025 (2025): 8369299, https://doi.org/10.1155/humu/8369299.In the article titled “Prognostic Value of Ubiquitination-Related Genes in Ovarian Cancer and Their Correlation With Tumor Immunity,” there were errors in all the affiliations. The corrected affiliation list appears below:Shu Zhao,1,2,3,4 Xiaojing Lin,1,3 Yuying Huang,2 Zhongmin Kang,5 Huali Luo,2 Qizhu Zhang,1,3 Qinshan Li,1,2,3 and Mengxing Li51Department of Obstetrics and Gynecology, Institute of Precision Medicine of Guizhou Province, Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, China2Department of Clinical Biochemistry, School of Medical Laboratory Science, Guizhou Medical University, Guiyang, Guizhou, China3Clinical Medical College, Guizhou Medical University, Guiyang, Guizhou, China4Department of Obstetrics, Guizhou Provincial People’s Hospital, Guiyang, Guizhou, China5Department of Hematology, Guizhou Province Institute of Hematology, Guizhou Province Laboratory of Hematopoietic Stem Cell Transplantation Centre, Affiliated Hospital of Guizhou Medical University Guiyang, Guizhou, ChinaWe apologize for this error.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9879845","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224354","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Complementary Roles of Structure and Variant Effect Predictors in RyR1 Clinical Interpretation 结构和变异效应预测因子在RyR1临床解释中的互补作用

IF 3.7 2区医学

Human Mutation Pub Date : 2025-10-03 DOI: 10.1155/humu/1834898

Rolando Hernández Trapero, Mihaly Badonyi, Lukas Gerasimavicius, Joseph A. Marsh

{"title":"Complementary Roles of Structure and Variant Effect Predictors in RyR1 Clinical Interpretation","authors":"Rolando Hernández Trapero, Mihaly Badonyi, Lukas Gerasimavicius, Joseph A. Marsh","doi":"10.1155/humu/1834898","DOIUrl":"https://doi.org/10.1155/humu/1834898","url":null,"abstract":"RyR1-related disorders, arising from variants in the RYR1 gene encoding the skeletal muscle ryanodine receptor, encompass a wide range of dominant and recessive phenotypes. The extensive length of RyR1 and diverse mechanisms underlying disease variants pose significant challenges for clinical interpretation, exacerbated by the limited performance and biases of current variant effect predictors (VEPs). This study evaluates the efficacy of 70 VEPs for distinguishing pathogenic RyR1 missense variants from putatively benign variants derived from population databases. Existing VEPs show variable performance. Those trained on known clinical labels show greater classification performance, but this is likely inflated by data circularity. In contrast, VEPs using methodologies that avoid or minimise training bias show limited performance, likely reflecting difficulty in identifying gain-of-function variants. Leveraging protein structural information, we introduce Spatial Proximity to Disease Variants (SPDV), a novel metric based solely on three-dimensional clustering of pathogenic mutations. We determine ACMG/AMP PP3/BP4 classification thresholds for our method and top-performing VEPs, allowing us to assign PP3/BP4 evidence levels to all RyR1 missense variants of uncertain significance. Thus, we suggest that our protein structure–based approach represents an orthogonal strategy over existing computational tools for aiding in the diagnosis of RyR1-related diseases.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1834898","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224022","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma ets1驱动的核仁应激协调OLR1+巨噬细胞串扰维持透明细胞肾细胞癌的免疫抑制微环境

IF 3.7 2区医学

Human Mutation Pub Date : 2025-10-03 DOI: 10.1155/humu/8856239

Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Jia Wang, Wei Tang

{"title":"ETS1-Driven Nucleolar Stress Orchestrates OLR1+ Macrophage Crosstalk to Sustain Immunosuppressive Microenvironment in Clear Cell Renal Cell Carcinoma","authors":"Lei Xiao, Zicheng Zhang, Tong Li, Yuyin Jiang, Yuanxin Liu, Jia Wang, Wei Tang","doi":"10.1155/humu/8856239","DOIUrl":"https://doi.org/10.1155/humu/8856239","url":null,"abstract":"While hypoxia-driven nucleolar stress (NS) has been recognized as a critical modulator of the immunosuppressive tumor microenvironment in clear cell renal cell carcinoma (ccRCC), its mechanistic contribution to disease progression remains poorly defined. To address this gap, we systematically mapped NS-associated molecular landscapes through integrated spatial transcriptomics and single-cell RNA sequencing of ccRCC specimens. Our analysis stratified tumors into two distinct NS subtypes, revealing that high-NS tumors exhibit aggressive clinical behavior, elevated expression of immunosuppressive checkpoints, and significantly reduced survival. At single-cell resolution, high-NS malignant cells displayed enhanced proliferative activity, glycolytic metabolic reprograming, and marked chromosomal instability. Mechanistic investigations demonstrated that hypoxia-induced ETS1 activation orchestrates NS via the MYC/NPM1/DDX17 signaling axis, directly promoting tumor proliferation and metabolic adaptation in preclinical models. Spatial multiomics further uncovered coordinated niche formation between high-NS cells and OLR1+ macrophages, with ligand–receptor profiling identifying the EDN1–EDNRA–OLR1 axis as a central mediator of this immunosuppressive crosstalk. Functional validation in syngeneic mouse models confirmed that ETS1 overexpression accelerates tumor growth while enriching OLR1+ macrophages with immunosuppressive phenotypes. Clinically, high OLR1+ macrophage infiltration correlated with shorter survival across independent cohorts. These findings establish a hypoxia–ETS1–NS–macrophage axis as a key mechanism sustaining ccRCC progression and highlight actionable targets for disrupting protumorigenic immune niches through modulation of the NS pathway.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/8856239","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Vimentin Regulates Alternative Polyadenylation and mTOR Signaling via ARVCF to Promote B Cell Lymphoma Progression Vimentin通过ARVCF调节选择性聚腺苷化和mTOR信号传导促进B细胞淋巴瘤进展

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-28 DOI: 10.1155/humu/1463685

Lujing Shao, Qianke Xing, Yao Xiong, Kaidi Jin, Qi Li, Chunyan Dong, Qianling Ye

{"title":"Vimentin Regulates Alternative Polyadenylation and mTOR Signaling via ARVCF to Promote B Cell Lymphoma Progression","authors":"Lujing Shao, Qianke Xing, Yao Xiong, Kaidi Jin, Qi Li, Chunyan Dong, Qianling Ye","doi":"10.1155/humu/1463685","DOIUrl":"https://doi.org/10.1155/humu/1463685","url":null,"abstract":"Background: Vimentin (VIM), a cytoskeletal protein implicated in tumor progression, has been associated with poor prognosis in B cell lymphomas. Alternative polyadenylation (APA), a posttranscriptional mechanism that modulates mRNA isoforms via 3 ′UTR length changes, is frequently dysregulated in cancer. The interaction between VIM and APA in B cell lymphoma remains poorly understood.Methods: We performed RNA-seq, APA analysis (DaPars), and proteomic profiling in wild-type and VIM-knockout (VIM-KO) B cell lymphoma cells (A20 and M12). Functional assays including CCK-8, EdU, Western blot, and ARVCF overexpression were used to explore the regulatory axis involving APA and mTOR signaling.Results: VIM deletion in B cell lymphoma cells triggered widespread transcriptome remodeling, inducing 4089 APA shortening events that preferentially targeted prosurvival pathways, for example, mTORC1, G2-M checkpoint. Strikingly, RRAGA—a critical mTOR activator—underwent 3 ′UTR shortening, concomitant with ARVCF downregulation in proteomic profiles. Functional rescue experiments demonstrated ARVCF’s dual role in maintaining RRAGA 3 ′UTR length and suppressing mTOR-EIF4G1 signaling, ultimately inhibiting lymphoma proliferation.Conclusion: This study reveals a novel VIM–ARVCF–RRAGA–mTOR axis in B cell lymphoma, linking cytoskeletal disruption to APA-mediated oncogenic signaling. VIM loss drives APA shortening and mTOR activation via ARVCF downregulation, promoting lymphoma progression. These findings offer mechanistic insight and potential targets for therapeutic intervention.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/1463685","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145224443","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The Role of NOL3 in Colon Adenocarcinoma Metastasis and Its Association With DNA Methylation NOL3在结肠癌转移中的作用及其与DNA甲基化的关系

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-24 DOI: 10.1155/humu/9983517

Li Hong, Hao Zhang, Ruipeng Wang, Zirui Zhuang, Jinjing Xu, Youyuan Tang

{"title":"The Role of NOL3 in Colon Adenocarcinoma Metastasis and Its Association With DNA Methylation","authors":"Li Hong, Hao Zhang, Ruipeng Wang, Zirui Zhuang, Jinjing Xu, Youyuan Tang","doi":"10.1155/humu/9983517","DOIUrl":"https://doi.org/10.1155/humu/9983517","url":null,"abstract":"Colon adenocarcinoma (COAD) is a particularly aggressive cancer type, frequently identified at a later stage. Thus, it is crucial to enhance our understanding of the fundamental mechanisms that govern COAD cellular behavior and to perform extensive research into the biological foundations underlying its development, progression, invasion, and metastasis. We initially discovered NOL3 as a significant gene influencing COAD metastasis through the application of the weighted gene coexpression network analysis algorithm using the TCGA-COAD dataset. This was succeeded by an assessment of NOL3’s expression levels and prognostic significance. Moreover, we investigated the biological roles of NOL3 utilizing transcriptomic data. Our results demonstrate significant associations between NOL3 and immune infiltration in COAD, as well as sensitivity to chemotherapy. Furthermore, we utilized the tumor immune dysfunction and exclusion (TIDE) algorithm to evaluate how various cohorts responded to immune checkpoint therapies. Ultimately, the influence of NOL3 on the metastasis of COAD cells was confirmed through in vitro experiments. Our results indicate that NOL3 can promote COAD metastasis, and its underlying mechanism may be associated with DNA methylation. In summary, NOL3 has been identified by us as a key biomarker for COAD metastasis.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9983517","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145146397","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Metabolic Reprogramming in Colorectal Cancer: The Impact of Fatty Acid Metabolism 结直肠癌的代谢重编程：脂肪酸代谢的影响

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-22 DOI: 10.1155/humu/9567214

Zirui Zhuang, Yu Chen, Yizhou Yao, Xinguo Zhu

{"title":"Metabolic Reprogramming in Colorectal Cancer: The Impact of Fatty Acid Metabolism","authors":"Zirui Zhuang, Yu Chen, Yizhou Yao, Xinguo Zhu","doi":"10.1155/humu/9567214","DOIUrl":"https://doi.org/10.1155/humu/9567214","url":null,"abstract":"Colorectal cancer (CRC) ranks among the most common malignant tumors worldwide, with the metabolism of fatty acids being crucial for its development and progression. Altered fatty acid metabolism is a well-established metabolic characteristic of malignant tumors, including CRC. A complex and reciprocal relationship exists between fatty acid metabolism and CRC. On one side, the emergence and advancement of CRC can trigger a reprogramming of fatty acid metabolism. To fulfill the requirements of rapid cell division and survival, cancer cells increase both the synthesis and uptake of fatty acids while also suppressing their oxidation. Conversely, modifications in fatty acid metabolism can affect CRC, as abnormal fatty acid byproducts may activate signaling pathways that foster tumor cell proliferation, thus enhancing tumor progression. Understanding the interplay between fatty acid metabolism and the early stages and advancement of CRC, in conjunction with its relationship with the tumor microenvironment, is a vital area for future investigation. This article reviews the most recent discoveries concerning the impact of fatty acid metabolism on CRC progression, with the objective of supplying a solid theoretical framework and innovative perspectives for additional research and treatment of this condition.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/9567214","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145111173","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Identification of ARHGAP9 as a Key Diagnostic Marker for Abdominal Aortic Aneurysm by Multiomics and Experimental Validation ARHGAP9作为腹主动脉瘤关键诊断标志物的多组学鉴定及实验验证

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-16 DOI: 10.1155/humu/7230083

Zhe Peng, Kun Li, Shile Wu, Baozhang Chen, Xiaonan Wang, Liang Chen, Xinsheng Wang, Hao Zhang, Biao Wu

{"title":"Identification of ARHGAP9 as a Key Diagnostic Marker for Abdominal Aortic Aneurysm by Multiomics and Experimental Validation","authors":"Zhe Peng, Kun Li, Shile Wu, Baozhang Chen, Xiaonan Wang, Liang Chen, Xinsheng Wang, Hao Zhang, Biao Wu","doi":"10.1155/humu/7230083","DOIUrl":"https://doi.org/10.1155/humu/7230083","url":null,"abstract":"Abdominal aortic aneurysm (AAA) is a serious vascular condition that significantly endangers the lives of patients. Although there have been improvements in early detection and treatment methods, considerable challenges persist regarding the timely identification and evaluation of risk associated with this disease. Therefore, there is an immediate requirement for novel biomarkers that can enhance the early diagnosis and risk evaluation of AAA, thus allowing for more accurate and individualized medical interventions. In this study, we identified key diagnostic markers for AAA using various machine learning algorithms, and we explored the functions of these genes in AAA through gene enrichment analysis. A diagnostic model for AAA was constructed based on multiple machine learning algorithms, with the random forest algorithm highlighting the central role of ARHGAP9. In vitro experiments confirmed the influence of ARHGAP9 on vascular smooth muscle cells (VSMCs). Our findings indicate that the key genes identified are associated with the immune microenvironment and metabolism in AAA samples. The validated diagnostic model exhibited excellent predictive performance. Knockdown of ARHGAP9 significantly inhibited the proliferative capacity of VSMCs. In conclusion, our results suggest that ARHGAP9 may serve as a diagnostic and therapeutic marker for AAA.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/7230083","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145101121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PAQR4: A Critical Senescence-Related Gene Influencing Immune Evasion and Metastasis in Bladder Urothelial Carcinoma PAQR4：影响膀胱尿路上皮癌免疫逃避和转移的关键衰老相关基因

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-12 DOI: 10.1155/humu/2227219

Yizhang Sun, Xincheng Yi, Chenchao Zhou, Yuhua Huang

{"title":"PAQR4: A Critical Senescence-Related Gene Influencing Immune Evasion and Metastasis in Bladder Urothelial Carcinoma","authors":"Yizhang Sun, Xincheng Yi, Chenchao Zhou, Yuhua Huang","doi":"10.1155/humu/2227219","DOIUrl":"https://doi.org/10.1155/humu/2227219","url":null,"abstract":"Background: Bladder urothelial carcinoma (BLCA) is a prevalent malignant tumor known for its high recurrence rates and limited therapeutic efficacy. Cellular senescence has been extensively shown to inhibit tumorigenesis via cell cycle arrest. Consequently, the identification of senescence-associated biomarkers is essential for enhancing the diagnosis, prognosis, and immunotherapeutic outcomes of BLCA.Method: This study integrated the TCGA-BLCA and GSE13507 datasets to analyze senescence-related genes. ConsensusClusterPlus was employed for cluster analysis, while immune infiltration was assessed using CIBERSORT. A diagnostic and prognostic model for BLCA was developed and validated through the combination of various machine learning algorithms. Experimental validation was conducted using qRT-PCR, colony formation, and Transwell assays to evaluate the functional role of PAQR4.Result: Our study revealed that aging-related samples demonstrated improved survival rates and a lower incidence of high-grade tumors. Cluster analysis identified two distinct subgroups of BLCA characterized by unique immune infiltration profiles and varying responses to immune checkpoint blockade. The diagnostic and prognostic models developed from aging-related genes were subsequently validated. Notably, PAQR4 was identified as a critical aging-related gene linked to poor prognosis and an immunosuppressive microenvironment. The knockdown of PAQR4 significantly inhibited the proliferation and metastasis of BLCA cells.Conclusion: PAQR4 is a novel biomarker and therapeutic target for BLCA, influencing cellular senescence, immune evasion, and metastasis. This study provides insights into the senescence-related mechanisms and offers tools for precision diagnosis and the optimization of immunotherapy in BLCA.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/2227219","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145037731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Corrigendum to “Compendium of Clinical Variant Classification for 2,246 Unique ABCA4 Variants to Clarify Variant Pathogenicity in Stargardt Disease Using a Modified ACMG/AMP Framework” 《使用改良的ACMG/AMP框架阐明Stargardt病变异致病性的2246个独特ABCA4变异临床变异分类纲要》的更正

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-12 DOI: 10.1155/humu/9815325

引用次数: 0

A Cell-Based Functional Assay Calibrated for Analysis of MSH6 and MSH2 Mismatch Repair Gene Variants MSH6和MSH2错配修复基因变异的细胞功能分析校准

IF 3.7 2区医学

Human Mutation Pub Date : 2025-09-06 DOI: 10.1155/humu/3923193

Elizabeth Szabo, Emily Blackburn, Olivia N. Amodeo, Samantha Nadeau, Alexander A. Radecki, James P. Grady, Abhijit Rath, Christopher D. Heinen

{"title":"A Cell-Based Functional Assay Calibrated for Analysis of MSH6 and MSH2 Mismatch Repair Gene Variants","authors":"Elizabeth Szabo, Emily Blackburn, Olivia N. Amodeo, Samantha Nadeau, Alexander A. Radecki, James P. Grady, Abhijit Rath, Christopher D. Heinen","doi":"10.1155/humu/3923193","DOIUrl":"https://doi.org/10.1155/humu/3923193","url":null,"abstract":"Variants of uncertain significance (VUS) in the DNA mismatch repair (MMR) genes can confound the diagnosis and treatment of suspected Lynch syndrome (LS) patients. To aid the reclassification of VUS, we developed the in cellulo analysis of MMR variants (inCAMA) and used known control variants to calibrate this assay such that results can be readily applied as functional evidence by expert classification panels. We used CRISPR gene engineering to introduce known pathogenic and benign variants into the MSH6 or MSH2 loci in human embryonic stem cells and assessed their effects on cellular MMR repair and damage response functions. Our functional assay successfully discerned known pathogenic and benign variants. Using these results and performing a linear regression analysis with available odds of pathogenicity scores for the known calibration variants, we created equations that can generate a functional odds of pathogenicity score for any future MSH6 or MSH2 variant tested. In summary, inCAMA represents a new, calibrated assay for testing the function of virtually any MSH6 or MSH2 variant. The conversion of assay results directly into odds of pathogenicity scores makes it possible to use any PS3 or BS3 evidence strength level toward the reclassification of VUS.","PeriodicalId":13061,"journal":{"name":"Human Mutation","volume":"2025 1","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1155/humu/3923193","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144998908","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0