Hum. Mutat. [JOURNAL]
Sun
200 papers
Integrated Radiomics Model Combining Diffusion Kurtosis Imaging and Dynamic Contrast-Enhanced MRI for Predicting TERT Promoter Mutation Status in Gliomas.
Gao S, Zhang S, Wang Y … +3 more , Chen L, Cao A, Du P
Hum Mutat · 2026 · PMID 41953399 · Full text
PURPOSE: The purpose of this study is to investigate the value of a radiomics model based on diffusion kurtosis imaging (DKI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for preoperative prediction...
PURPOSE: The purpose of this study is to investigate the value of a radiomics model based on diffusion kurtosis imaging (DKI) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for preoperative prediction of telomerase reverse transcriptase (TERT) promoter mutation status in gliomas. METHODS: This retrospective study included 126 patients with pathologically confirmed gliomas who underwent TERT promoter mutation testing between January 2020 and June 2025. All patients underwent preoperative multiparametric MRI including DKI and DCE-MRI sequences. Patients were randomly divided into training ( = 88) and validation ( = 38) cohorts at a 7:3 ratio. Radiomics features were extracted from DKI parameter maps (mean kurtosis, mean diffusivity, axial kurtosis, radial kurtosis, axial diffusivity, and radial diffusivity) and DCE-MRI parameter maps (volume transfer constant [Ktrans], extravascular extracellular volume fraction [Ve], rate constant [Kep], and plasma volume fraction [Vp]). Feature selection was performed using the least absolute shrinkage and selection operator (LASSO) regression. DKI-based, DCE-MRI-based, and combined radiomics models were constructed using logistic regression. Model performance was evaluated using receiver operating characteristic (ROC) curve analysis, and comparison between models was performed using the DeLong test. Decision curve analysis was conducted to assess clinical utility. RESULTS: Significant differences in DKI and DCE-MRI parameters were observed between TERT promoter mutant and wild-type gliomas ( < 0.05). LASSO regression selected 12 optimal features (five from DKI and seven from DCE-MRI) for the combined model. In the training cohort, the DKI-based model, the DCE-MRI-based model, and the combined model achieved areas under the curve (AUCs) of 0.847 (95% confidence interval [CI]: 0.768-0.926), 0.892 (95% CI: 0.821-0.963), and 0.961 (95% CI: 0.927-0.995), respectively. In the validation cohort, the corresponding AUCs were 0.823 (95% CI: 0.691-0.955), 0.869 (95% CI: 0.752-0.986), and 0.943 (95% CI: 0.871-1.000). The combined model demonstrated significantly superior performance compared to single-modality models ( < 0.05), with sensitivity, specificity, and accuracy of 88.9%, 95.0%, and 92.1% in the validation cohort. Decision curve analysis indicated that the combined model provided greater clinical net benefit across threshold probabilities ranging from 0.15 to 0.85. CONCLUSION: The integrated multiparametric radiomics model combining DKI and DCE-MRI enables noninvasive preoperative prediction of TERT promoter mutation status in gliomas with high accuracy. The combined approach demonstrates superior predictive performance and clinical utility compared to single-modality imaging, providing valuable imaging biomarkers for molecular stratification and personalized treatment planning in glioma patients.
Macrophages as a Critical Node Linking Ferroptosis and Immunosuppression: A Multiomics Framework for Prognosis and Therapy in High-Grade Serous Ovarian Cancer.
Zhou J, Zeng T, Liu Y … +4 more , Ye M, Li M, Zhang Z, Meng Y
Hum Mutat · 2026 · PMID 41953398 · Full text
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is characterized by a complex tumor microenvironment and poor prognosis, yet the roles of specific tumor-associated macrophages (TAMs) subpopulations in driving diseas...
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is characterized by a complex tumor microenvironment and poor prognosis, yet the roles of specific tumor-associated macrophages (TAMs) subpopulations in driving disease progression remain elusive. METHODS: This study evaluated the prognostic relevance of in HGSOC. Single-cell RNA sequencing identified TAMs as a distinct macrophage subpopulation with unique transcriptional features. Integrative analyses combining single-cell and bulk differentially expressed genes, macrophage-associated modules, and ferroptosis-related gene sets identified 26 candidate prognostic genes, from which a four-gene signature (, , , and ) was derived to construct the prognostic risk model. The model was validated in an independent cohort. Immune infiltration, single-cell trajectory, copy number variation, and drug-gene associations were analyzed to explore the molecular and therapeutic implications of risk stratification. RESULTS: HGSOC patients classified as high risk exhibited poorer survival outcomes, increased infiltration of M2-like macrophages, elevated expression of immune checkpoints, and enrichment of immune- and ferroptosis-related pathways. Trajectory and copy number variation analyses revealed stage-specific gene expression patterns and amplification-associated regulation. Drug-gene association analyses further suggested that high-risk patients may be more responsive to targeted therapies and proteasome inhibitors, whereas low-risk patients may benefit from conventional chemotherapy. CONCLUSION: TAMs are closely linked to HGSOC progression, and the proposed prognostic model based on TAMs provides predictive value and potential therapeutic insights for patient stratification.
Peripheral Immune and Metabolic Dysregulation in Migraine, Ménière's Disease, and Vestibular Migraine: A Single-Cell Atlas Study.
Pan M, Lu L, Song W … +10 more , Xie Y, Liang G, Wei Q, Huang Q, Zeng J, Lan Y, Zou C, Zou D, Su L, Wan Q
Hum Mutat · 2026 · PMID 41953397 · Full text
BACKGROUND: Migraine (MI), Ménière's disease (MD), and vestibular migraine (VM) share significant clinical and pathological similarities, particularly their link to neurological dysfunction and immune cell activity, thou...
BACKGROUND: Migraine (MI), Ménière's disease (MD), and vestibular migraine (VM) share significant clinical and pathological similarities, particularly their link to neurological dysfunction and immune cell activity, though mechanisms remain poorly understood. METHODS: We utilized a single-cell RNA sequencing dataset of peripheral blood mononuclear cells from eight patients with MD, five patients with MI, five patients with VM, and six healthy controls. A cross-disease cell atlas was constructed via cellular heterogeneity and dynamic cell abundance analysis. Further studies analyzed metabolic heterogeneity and performed differential expression analysis across all groups. The core regulatory pathways were identified using gene set enrichment and pathway analyses. Additionally, herbal and compound screenings related to targets in MI were performed. Pseudotime analysis was then employed to infer the evolutionary trajectories, identifying key genes associated with differentiation. RESULTS: We identified 42,198 cells grouped into 16 clusters and classified into five cell types: T cells, B cells, dendritic cells, natural killer cells, and monocytes. Among these, T cell abundance significantly increased, whereas monocytes were essential for metabolic reprogramming. Notably, the upregulated MAPK signaling pathway was identified as the core regulatory pathway. A total of 1571 interaction pairs were screened between matched targets for herbs and compounds. T cell trajectory analysis revealed two differentiation pathways originating from CD8 T cells that diverged into CD4 T cells and naïve T cells. was significantly upregulated during differentiation, being highly expressed in the disease groups. CONCLUSIONS: This study identified distinct immune cell patterns in MI, MD, and VM, with notable T cell imbalances. was highlighted as a core regulator of disease mechanisms via the MAPK pathway, laying the groundwork for future research into therapies and disease understanding.
Immunomodulatory Roles and Clinical Significance of GZMM and DDX24 in Sepsis: A Multiomics Integrative Analysis With Experimental Validation.
Zhang Y, Tang L, Wu J … +6 more , Yang L, Liu W, Liang Y, Han J, He S, Yang Y
Hum Mutat · 2026 · PMID 41948606 · Full text
Sepsis is a systemic inflammatory response syndrome caused by an infection featuring high morbidity and mortality due to complex mechanisms underlying immune dysfunction. In this study, based on the sepsis transcriptome...
Sepsis is a systemic inflammatory response syndrome caused by an infection featuring high morbidity and mortality due to complex mechanisms underlying immune dysfunction. In this study, based on the sepsis transcriptome profiles from the GEO datasets (GSE65682, GSE28750, GSE95233, and GSE167363), we used the machine learning method and other computational algorithms, such as differential gene expression analysis, weighted gene coexpression network analyses (WGCNA), and the building of PPI networks to identify four hub genes (DDX24, GZMM, KCNA3, and NCL). The quantitative reverse transcription PCR performed preliminary validation that all four hub genes were significantly downregulated in patients with sepsis. DDX24 had the highest diagnostic performance (AUC > 0.8) for discriminating patients from normal subjects. GZMM was found to be significantly related to the prognoses of patients as well as APACHE II scores, and the downregulated expression pattern might represent T cell and NK cell exhaustion. Analysis based on single-cell RNA sequencing showed that DDX24 and GZMM were mainly expressed in T cells and NK cells, and the expression trends strongly correlate with patient survival. Functional enrichment analysis suggested that the hub genes likely participate in regulation of immune responses, especially those pertaining to T cells. Drug prediction found 25 candidate drugs that will serve as new therapeutic targets for precision medicine to treat sepsis. Overall, the multifaceted study shed light on key roles played by these hub genes (especially DDX24 and GZMM) in the development of sepsis and will be useful references in diagnosing patients and estimating prognosis.
SELL Marks an Effector-Deficient CD8 T Cell Subset That Promotes Intracerebral Hemorrhage and Responds to Rutin Therapy.
Huang Y, Xu H, Bai C … +3 more , Liu J, Sun Y, Chen J
Hum Mutat · 2026 · PMID 41937927 · Full text
BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and limited therapeutic options. While neuroinflammation contributes to secondary brain injury, the role of peripheral CD8 T...
BACKGROUND: Intracerebral hemorrhage (ICH) is a devastating stroke subtype with high mortality and limited therapeutic options. While neuroinflammation contributes to secondary brain injury, the role of peripheral CD8 T cell dysfunction in ICH pathogenesis remains poorly characterized. This study is aimed at identifying disease-associated CD8 T cell subpopulations and potential therapeutic targets through integrative multiomics analysis. METHODS: We performed bulk RNA sequencing on peripheral blood from 130 patients (66 ICH and 64 hypertension controls) across two independent cohorts, combined with single-cell RNA sequencing of 13 patients. The scPAS algorithm integrated bulk and single-cell data to identify phenotype-associated cells. Five machine learning algorithms (LASSO, random forest, XGBoost, SVM, and Boruta) were employed for biomarker discovery. The therapeutic efficacy of rutin was evaluated in murine hypertensive ICH models. RESULTS: We identified a distinct SELL-high CD8 T cell subpopulation (scPAS cells) exhibiting comprehensive effector dysfunction, characterized by downregulation of cytotoxicity genes (GZMA, GZMB, GNLY, NKG7, and CCL5). Pseudotime trajectory analysis revealed progressive differentiation toward this dysfunctional phenotype. SELL emerged as a consensus diagnostic biomarker across all five algorithms, demonstrating excellent discriminative performance (AUC: 0.876-0.936). In vivo, rutin treatment reduced SELL expression, restored CD8 T cell cytotoxicity, decreased hemorrhage incidence, and attenuated neuroinflammation and oxidative stress. CONCLUSIONS: This study identifies SELL-marked effector-deficient CD8 T cells as a hallmark of ICH and establishes SELL as a robust diagnostic biomarker. Rutin represents a promising therapeutic candidate targeting peripheral immune dysfunction in hypertensive ICH.
A Comprehensive Review of Gene Mutations in Inherited Blood Disorders Among the Saudi Population.
Younis NS, Alkabsh RM, Nasser Alqahtani SM … +9 more , Aljuail H, Alhashim MA, Bokhamsin SA, Albaqshi LJ, Alqadhib SF, Aldandan JA, Alshakhs ZA, Altaweel MH, Mohamed ME
Hum Mutat · 2026 · PMID 41929524 · Full text
BACKGROUND: Inherited blood disorders (IBDs) are a major health concern in the Kingdom of Saudi Arabia (KSA), largely due to the high prevalence of consanguineous marriages. OBJECTIVES: This review is aimed at summarizin...
BACKGROUND: Inherited blood disorders (IBDs) are a major health concern in the Kingdom of Saudi Arabia (KSA), largely due to the high prevalence of consanguineous marriages. OBJECTIVES: This review is aimed at summarizing gene mutations and variants associated with IBDs in the Saudi population to enhance diagnosis and personalized care. METHODS: Published studies on IBD-related genetic mutations in Saudis were systematically retrieved from PubMed, Web of Science, Google Scholar, and EGEMS database using keywords "gene," "Saudi," "polymorphism," and "the different inherited blood disorders." A total of 118 studies published between 2015 and 2024 met the inclusion criteria. RESULTS: The -globin () gene showed the greatest mutational diversity, with over 60 -thalassemia variants identified. The -globin genes (, , and the unique ) were frequently involved in -thalassemia, with the - deletion predominating. In sickle cell disease, the mutation (>) is the most common, primarily linked to the Arab-Indian haplotype, whereas polymorphisms in , , and influenced fetal hemoglobin levels. Frequent thrombophilia-related variants occurred in , , , and , and inherited thrombocytopenias were linked to , , , , and . Rare disorders such as Wiskott-Aldrich syndrome (WAS) and coagulation factor deficiencies (e.g., FX, F7, and F8) were also reported. CONCLUSION: The Saudi population exhibits a distinct and diverse spectrum of IBD-related mutations. Understanding these genetic patterns can enhance diagnostic precision, guide genetic counseling, and advance personalized medicine initiatives across the Kingdom.
ALOX5 Expression and Pathomics Features Reveal New Insights Into Lung Adenocarcinoma Prognosis: Model Construction and Functional Validation.
Hu P, Huang C, Liu X … +3 more , Li Q, Xiang R, Liang X
Hum Mutat · 2026 · PMID 41809565 · Full text
BACKGROUND: Arachidonic acid 5-lipoxygenase (ALOX5) is a biomarker of lung adenocarcinoma (LUAD). This research seeks to establish a prognostic model for LUAD by examining ALOX5 expression. METHODS: The Cancer Genome Atl...
BACKGROUND: Arachidonic acid 5-lipoxygenase (ALOX5) is a biomarker of lung adenocarcinoma (LUAD). This research seeks to establish a prognostic model for LUAD by examining ALOX5 expression. METHODS: The Cancer Genome Atlas database provided the pathological images and transcriptome data. To determine the prognostic value of ALOX5, survival analysis and Cox regression (univariate and multivariate) were conducted, along with subgroup analysis and interaction tests. The OTSU algorithm and the PyRadiomics package were used to segment the pathological images of patients with LUAD and extract pathological features. The gradient-enhanced model algorithm was used to construct the pathological omics model. The prognostic value of pathomics mechanism analysis was confirmed using the pathomics score (PS) output from the model. Cell experiments were used to verify gene function. RESULTS: A total of 327 samples and seven best pathological features were included in the analysis. In LUAD, elevated levels of ALOX5 and PS were associated with improved overall survival. The gradient boosting machine (GBM) pathomics model demonstrated strong predictive performance and clinical applicability, achieving an area under the curve (AUC) of 0.786 in the training set ( = 230) and 0.741 in the validation set ( = 97). According to the model, samples with elevated ALOX5 expression exhibited higher PS values. Moreover, macrophage infiltration was significantly increased in groups with high PS expression. Gene set enrichment analysis (GSEA) indicated that genes differentially expressed between PS subgroups were involved in apoptosis and inflammatory-response pathways. Apoptosis-related genes were positively correlated with PS values ( < 0.001), and 63 hub genes associated with the inflammatory response were enriched in cytokine-mediated signaling pathways. In vitro experiments showed that ALOX5 knockdown in lung cancer cells enhanced tumor cell proliferation and migration. CONCLUSIONS: There was a strong link between ALOX5 expression levels and OS in LUAD patients. A pathomics-based model can effectively predict the expression level of ALOX5; as a result, LUAD patients' prognoses can be predicted.
Recognition of a Critical Functional Domain and Improved Missense Variant Interpretation by Utilization of In Silico Prediction Tools.
Drackley A, Skol AD, Rand CM … +2 more , Weese-Mayer DE, Yap KL
Hum Mutat · 2026 · PMID 41809564 · Full text
Pathogenic heterozygous variants in are associated with congenital central hypoventilation syndrome (CCHS), which is characterized by autonomic nervous system dysregulation severely affecting respiratory control. The in...
Pathogenic heterozygous variants in are associated with congenital central hypoventilation syndrome (CCHS), which is characterized by autonomic nervous system dysregulation severely affecting respiratory control. The interpretation of missense variation is challenging due to their rarity and the lack of available functional evidence. Consequently, most missense variants are classified as variants of uncertain significance (VUSs), complicating the timely diagnosis and clinical management of the condition. To generate an improved model for assessments of missense variants, a methodology was derived to evaluate all missense variants in the literature and public/private databases according to a consensus classification framework and assigned pathogenicity classifications. Pathogenicity prediction scores from the in silico prediction tools CADD, REVEL, BayesDel, and AlphaMissense were obtained for all variants. A weighted logistic regression in a multiple imputation framework was performed to assess the strength of evidence supporting application of ACMG/AMP guidelines' PP3/BP4 criteria. CADD, REVEL, and BayesDel meet the predictive strengths for PP3/BP4 recommended by the Clinical Genome Resource (ClinGen). Based on their areas under the curve and low proportions of variants with indeterminate pathogenicity predictions, BayesDel and REVEL were the strongest predictive tools and should be utilized for routine missense variant assessment with this study's calculated score thresholds for PP3/BP4 strength levels. Furthermore, the positional distribution of pathogenic and benign variants was analyzed to assess potential hotspots or critical functional domains in , and pathogenic variants were found to cluster in the homeodomain. The enrichment of pathogenic variation was substantiated by the prediction tools, supporting the use of the PM1 criterion for variants in the homeodomain. This calibration of existing computational prediction tools for missense variant classification and recognition of the homeodomain variants will enable fewer VUS classifications in favor of conclusive results, aiding in these individuals' care.
Oncological Genetic Counseling in Hereditary Breast and Ovarian Cancers and Lynch Syndrome High-Risk Subjects: Evaluation of Efficacy and Outcomes Using the Genomics Outcome Scale.
Maccaroni E, Chiariotti R, Giampieri R … +21 more , Bianchi F, Brugiati C, Belvederesi L, Ambrosini E, Chiodi N, Serritelli EN, Morgese F, Agostinelli V, Mentrasti G, Copparoni C, Magnarini A, De Filippis C, Burattini E, Bracci R, Chiari R, Del Prete M, Bisonni R, Faloppi L, Battelli N, Silva RR, Berardi R
Hum Mutat · 2026 · PMID 41809563 · Full text
BACKGROUND: Validated tools assessing oncological genetic counseling (OGC) quality are lacking. METHODS: We assessed OCG effectiveness using italian-translated version of the Genomics Outcome Scale (GOS) questionnaire. C...
BACKGROUND: Validated tools assessing oncological genetic counseling (OGC) quality are lacking. METHODS: We assessed OCG effectiveness using italian-translated version of the Genomics Outcome Scale (GOS) questionnaire. Clinical variables were collected and their association with different answers was assessed by Fisher's exact test or Chi-square test for either dichotomous or other categorical variables, respectively, with level of statistical significance = 0.05. RESULTS: Between November 2024 and February 2025, 209 subjects who received the complete OGC program at Our Center responded to the questionnaire; median age was 56 years (25-81). Most (76%) had breast cancer, 72% received a negative test, 15% positive test, and 13% noninformative test with variant of unknown significance (VUS). Most patients answered affirmatively to Question 1, focused on OGC understanding: age ( = 0.0181) and education ( = 0.0028) yielded different answers. Question 2, assessing relatives risk understanding, was answered completely/partially affirmative by 94% of subjects: test result (negative noninformative vs. positive vs. VUS) was associated ( = 0.0175) with different answers. To Question 3, related to concern, 65% confirmed their worry: education ( = 0.0392) and cancer type ( = 0.0128) yielded different answers. In Question 4, focused on surveillance understanding, 77% declared full or partial awareness, regardless of examined factors. In Question 5, enquiring decisional ability for themselves or family members, 72% stated they were completely/partially able to make decisions. Education ( = 0.0287) and genetic test result ( = 0.0090) yielded different answers. In Question 6, reflecting future planning, 69% responded completely/almost completely affirmatively, 17% were uncertain, and 14% responded partially/completely negatively, regardless of examined clinical factors. CONCLUSIONS: GOS questionnaire confirms that OGC is useful and effective to inform patients about their condition, surveillance, and prevention. Higher levels of empowerment were seen in younger patients and those with higher education.
GGPS1 Promoter Variant (rs3806394) Is Associated With Larger Simple Renal Cysts via Reduced GGPPS Expression.
Wang K, Tang T, Xu T … +8 more , Chen Z, Gou L, Wang Y, Wang D, Wu J, Wang X, Xue B, Xu X
Hum Mutat · 2026 · PMID 41800173 · Full text
OBJECTIVE: We are aimed at investigating the association between the size of simple renal cyst (SRC) and the expression of geranylgeranyl pyrophosphate synthase (GGPPS), which can induce renal cyst formation after its de...
OBJECTIVE: We are aimed at investigating the association between the size of simple renal cyst (SRC) and the expression of geranylgeranyl pyrophosphate synthase (GGPPS), which can induce renal cyst formation after its deletion. METHODS: Seventy-seven patients who received renal cyst decortication were enrolled. Clinical characteristics and tissue sections were collected. We used immunohistochemistry and immunofluorescence to detect the expression and location of GGPPS in SRC tissues. The relationship between GGPPS expression and renal cyst size was evaluated by multivariate linear regression analysis. The tagging SNPs located in GGPS1 promoter were identified and the effect of the rs3806394 locus variant on GGPS1 promoter activity was assessed. RESULTS: Immunohistochemistry and Western blot analysis revealed that GGPPS expression was downregulated in SRC tissues and that the larger the renal cyst volume was, the lower the expression of GGPPS in the cyst lining epithelial. Multivariate linear regression analysis indicated that low GGPPS levels in SRCs were independently related to large SRC size. Additionally, we reported that the frequency of the rs3806394 variant located in the GGPS1 promoter increased in SRC patients. The variant of the rs3806394 locus could decrease the activity of the GGPS1 promoter. CONCLUSION: A reduction in GGPPS expression in the cyst lining epithelium was associated with a risk of larger SRC size. The variant of the rs3806394 locus may be one of the reasons for the differential GGPPS expression in SRC tissues among the patients. These findings offer novel insights into the pathological mechanisms of SRC development.
Assessment of In-Frame Indel Variants in an Unsolved Cohort of Inherited Retinal Diseases Using Machine Learning.
Rauch DE, Wang M, Hafiz MJH … +11 more , Brock DC, Li Y, Marra M, Pennesi ME, Yang P, Lesley E, Lopez I, Koenekoop R, Collantes ER, Bolinao J, Chen R
Hum Mutat · 2026 · PMID 41777615 · Full text
The standard for in silico pathogenicity prediction of in-frame insertions and deletions (indels) is less established compared to other types of variations. We aimed to systematically assess the performance of in silico...
The standard for in silico pathogenicity prediction of in-frame insertions and deletions (indels) is less established compared to other types of variations. We aimed to systematically assess the performance of in silico machine learning (ML) tools on a patient cohort with inherited retinal diseases (IRDs). The performance of four ML tools (CADD, FATHMM-indel, VEST4, and MetaRNN-indel) was compared. Among them, MetaRNN-indel showed the best overall results. MetaRNN-indel was then applied to 1013 unsolved IRD patients, identifying two likely pathogenic causal variants in two unrelated IRD patients by confirming clinical phenotypes. Hence, our findings indicate that reliable prediction of the pathogenicity of in-frame indels can be achieved using existing ML tools with proper evaluation and tuning.
Analyses of mRNA in Nasopharyngeal Swab Samples Increase Yields of Wilson Disease Molecular Genetic Diagnostics.
Steiner Mrázová L, Vrbacká A, Majer F … +17 more , Stránecký V, Nosková L, Záhoráková D, Májovská J, Bitar I, Klempíř J, Šaligová J, Majlingová S, Giertlová M, Drenčáková P, Harvanová D, Solařová P, Brůha R, Dušek P, Kmoch S, Sikora J, Jedličková I
Hum Mutat · 2026 · PMID 41756680 · Full text
Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by bi-allelic pathogenic variants in the ATPase copper transporting beta gene (). Results of standard genetic diagnostics remain inconclus...
Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by bi-allelic pathogenic variants in the ATPase copper transporting beta gene (). Results of standard genetic diagnostics remain inconclusive in 3%-20% of WD patients in part due to problematic assessment of variants of unknown or conflicting pathogenicity (synonymous variants included). Correct interpretation of potential effects of such variants can be substantially enhanced by RNA analyses. This strategy is, however, of limited utility in WD patients because of predominant liver expression of . To avoid invasive bioptic liver collection and increase WD diagnostic yields, we searched for a surrogate tissue sample and identified profiles of transcripts in nasopharyngeal swabs that were comparable to liver. Amplicons spanning Exons 3-21 were prepared from the swab material and analysed by long-read nanopore sequencing to enable the detection of splicing changes and variant phasing. Diagnostic utility of this novel methodology was demonstrated by characterization of mRNA splicing abnormalities caused by synonymous variants c.1488C>T (p.(Gly496=)), c.2241C>T (p.(Ile747=)), c.2292C>T (p.(Phe764=)), and a nonsense variant c.2336G>A (p.(Trp779Ter)) in four WD patients, who were not genetically resolved by standard techniques. Nasopharyngeal swab sampling is minimally invasive and allows effective analyses of mRNA to detect and/or validate effects of variants in WD patients. Conclusive genetic diagnosis attained by this novel technique may facilitate family counselling and substantiate initiation of copper-chelation therapy in presymptomatic individuals.
Analysis of Mutations Reveals Domain-Specific Impacts on Cardiovascular Disorders Among Patients With Rare Diseases.
Novillo A, Ysbert M, Brea R … +3 more , Hidalgo-Estévez AM, El Abdellaoui-Soussi F, Gómez-Del Arco P
Hum Mutat · 2026 · PMID 41756679 · Full text
Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a critical ATP-dependent chromatin remodeler that plays fundamental roles in transcriptional repression, DNA damage repair, and lineage specification, making it indis...
Chromodomain-helicase-DNA-binding protein 4 (CHD4) is a critical ATP-dependent chromatin remodeler that plays fundamental roles in transcriptional repression, DNA damage repair, and lineage specification, making it indispensable for cardiovascular development and function. Pathogenic mutations are linked to syndromic and nonsyndromic conditions, often presenting with severe cardiac and vascular anomalies. However, most of these mutations are unique and nonrecurrent, complicating variant classification. In this study, we establish a connection between recent advances in CHD4 structure and function and 36 pathogenic mutations associated with rare diseases, including Sifrim-Hitz-Weiss syndrome, moyamoya angiopathy, and childhood idiopathic epilepsy with sinus arrhythmia, all of which exhibited cardiomyopathy, congenital heart defects, and/or vascular abnormalities. Among these mutations, 33 were missense variants, one was an in-frame small insertion, one, an in-frame small deletion, and one, a splice-site variant. Variants were classified according to the ACMG guidelines and subsequent refinements, integrating clinical, functional, population, and (REVEL-based PP3/BP4) evidence, and cross-referenced with the ClinVar database to prioritize candidates for further association and functional studies. We classified the missense variants as follows: seven as pathogenic (P), nineteen as likely pathogenic (LP), one as likely benign (LB), and six as variants of uncertain significance (VUS). The splice-site variant was predicted to cause nonsense-mediated decay and reduced CHD4 expression, whereas the structural variants were predicted to exert moderate effects on protein function. LP/P variants associated with congenital heart defects were significantly enriched within the ATPase/helicase domain ( = 0.027), suggesting impairing ATPase motor activity. Nevertheless, several severe heart malformations, including tetralogy of Fallot were linked to pathogenic or LP variants, such as C467Y (plant homeodomain [PHD]), M202I (high-mobility group [HMG]), and Y1345D (C-terminal domain). In contrast, other variants located in the N- and C-terminal regions were more often associated with vascular phenotypes, suggesting domain-specific roles of CHD4 in cardiovascular disease. These findings establish CHD4 as a key regulator of cardiovascular pathophysiology, though a clear genotype-phenotype correlation remains elusive. Further functional validation is essential to elucidate CHD4's molecular mechanisms, aiding in diagnostic and therapeutic developments.
P4HA2 Participates in Pathogenesis of Refractive Error by Regulating Collagen Posttranslational Modification and Extracellular Matrix Balance.
Liu Y, Dong S, Huang F … +14 more , Li R, He X, Jiang Y, Tian Q, Xiong H, Jin L, Wang Q, Xia L, Chen J, Wu H, Guo H, Zhou X, Xia K, Hu Z
Hum Mutat · 2026 · PMID 41756678 · Full text
Myopia represents a refractive anomaly characterized by impaired vision resulting from a misfocused image in front of the fovea. Although numerous genes linked to high myopia (HM) have been identified, the exact etiology...
Myopia represents a refractive anomaly characterized by impaired vision resulting from a misfocused image in front of the fovea. Although numerous genes linked to high myopia (HM) have been identified, the exact etiology and pathogenesis mechanisms of HM remain predominantly obscure. In a prior investigation, a mutation in the gene was identified in association with HM. To illuminate the potential mechanisms of action of in HM, we established a -knockout mouse line ( ) and a P4HA2-knockout HEK293 cell line for this study. mice exhibited compromised visual acuity and altered light transmission pathways as evidenced by multiple biometric assessments. Furthermore, we observed a time-dependent disruption in the arrangement of collagen fibrils in the sclera and cornea of the mice, attributed to diminished thermal stability due to decreased collagen hydroxylation. Our findings also revealed elevated fibronectin levels and reduced Collagen I expression in the sclera and cornea of the mice, as well as in P4HA2-knockout HEK293 cells, suggesting an imbalance in extracellular matrix (ECM) components that could further perturb light transmission pathways, which induced HM-associated refractive error. In summary, contributes significantly to the pathogenesis and progressive deterioration of refractive error by accelerating collagen degeneration via reduced collagen hydroxylation.
Unraveling Signaling Pathways in Immune Microenvironment Crosstalk to Overcome Immunotherapy Resistance in Colorectal Cancer.
Zhang H, Shao J, Zhao T … +5 more , Wang Y, Shao L, Zhu H, Liu J, Zhang L
Hum Mutat · 2026 · PMID 41693728 · Full text
As a major cause of cancer-related death globally, colorectal cancer (CRC) remains largely refractory to immunotherapy outside the context of microsatellite instability-high (MSI-H). This limited efficacy stems largely f...
As a major cause of cancer-related death globally, colorectal cancer (CRC) remains largely refractory to immunotherapy outside the context of microsatellite instability-high (MSI-H). This limited efficacy stems largely from the complex crosstalk within the tumor microenvironment (TME), which fosters immunosuppression and resistance. Our review analyzes the impact of dysregulated pathways-such as PD-1/PD-L1, cGAS/STING, Notch, and cytokine signaling-on the functional states of T cells, B cells, macrophages, dendritic cells, and NK cells in CRC. We investigate how these pathways underpin critical processes such as immune evasion, T cell exhaustion, and the protumor polarization of innate immune cells, thereby fostering a permissive niche for tumor growth and resistance to checkpoint inhibitors. The discussion also covers emerging biomarkers and innovative strategies, including combination therapies targeting pivotal signaling nodes, to reprogram the immune landscape. A deeper mechanistic understanding of these immunoregulatory pathways is essential for developing effective treatments to overcome resistance and improve patient prognosis.
TMEM106C, BSG, COPE, CDCA8, KPNA2, LIG1, UQCRH, and CCT5: Predictive of Survival and Immunotherapy Resistance in Hepatocellular Carcinoma.
Yu K, Chen M, Hou W … +8 more , Lu J, Liu Q, Zeng W, Du Z, Hou X, Hao E, Deng J, Gong P
Hum Mutat · 2026 · PMID 41674779 · Full text
INTRODUCTION: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with cellular senescence playing a context-dependent role in tumor progression and the immunosuppressive microen...
INTRODUCTION: Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with cellular senescence playing a context-dependent role in tumor progression and the immunosuppressive microenvironment. This study is aimed at identifying senescence-related gene signatures through integrated single-cell and transcriptomic analyses to construct a robust prognostic model for predicting survival and immunotherapy response in HCC patients. METHODS: We obtained single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database and transcriptomic data from The Cancer Genome Atlas (TCGA). The scRNA-seq data were processed using the Seurat and Harmony packages for cell clustering and batch correction. Senescence scores were calculated via the AUCell package, and differentially expressed genes were identified using the limma package. Prognostic genes were selected through univariate and LASSO Cox regression (glmnet package) to construct a risk model, which was validated in multiple independent cohorts. Immune infiltration was assessed with single-sample gene set enrichment analysis (ssGSEA), TIMER, and MCPCounter algorithms, and response to immune checkpoint blockade was predicted using the tumor immune dysfunction and exclusion (TIDE) platform. Experimental validation included qRT-PCR, Cell Counting Kit-8 (CCK-8), wound healing, and Transwell assays in HCC cell lines. RESULTS: A total of 80,997 identified cells were allocated to eight clusters, with an evidently higher percentage of natural killer (NK) cells in HCC samples. A higher senescence score was also seen in HCC samples, and poor prognosis was noticed in the patients of high senescence score group. Further, the DEGs were intersected with the genes highly expressed in Population 4 of NK cells to reveal their enrichment in cell cycle and cell division. Further, eight genes (, , , , , , , and ) with differential expression in HCC were applied to construct the risk model, which could stratify HCC patients into different risks and predict the prognosis. Besides, the high immune infiltration and expression levels of immune checkpoint-relevant genes yet poor immunotherapy response were noticed in HCC patients of high risk. Further validation tests have suggested that the knockdown of repressed the malignant phenotypes of HCC cells. DISCUSSION: This integrated analysis establishes a senescence-related gene signature as a robust tool for prognostic stratification and immunotherapy response prediction in HCC. The model highlights the complex interplay between cellular senescence and the immunosuppressive tumor microenvironment, offering insights for personalized treatment strategies. Furthermore, the identified biomarker represents a promising therapeutic target warranting further investigation. CONCLUSION: These discoveries provide novel evidence on senescence in HCC, which may tailor the pharmacological interventions to improve the clinical management.
Epithelial Cell-Specific Prognostic Signature (FTH1, RIT1, WASL, NDRG2, KIFC3) Stratifies Cervical Cancer Patients and Correlates With Immune Infiltration.
Wang X, Pan X, Li X … +5 more , Ding B, Jin Z, Wang X, Dou C, Nair S
Hum Mutat · 2026 · PMID 41660555 · Full text
BACKGROUND: Cervical cancer (CC) remains one of the leading female malignancies. Epithelial cells (EpCs), primarily derived from the cervical squamous and glandular epithelium, are targeted by human papillomavirus to dri...
BACKGROUND: Cervical cancer (CC) remains one of the leading female malignancies. Epithelial cells (EpCs), primarily derived from the cervical squamous and glandular epithelium, are targeted by human papillomavirus to drive CC. Herein, we aimed to develop an EpC-specific risk model to improve clinical outcomes and unravel tumor immune microenvironment alterations in CC. METHODS: scRNA-seq data from GSE208653 were processed using Seurat (including SCTransform for normalization and Harmony for batch correction). EpC heterogeneity was analyzed via subclustering, pseudotime trajectory analysis with monocle2, and cell-cell communication inference with CellChat. The hdWGCNA package identified EpC-specific coexpression modules. Prognostic genes were screened by univariate Cox and LASSO regression, and a Riskscore model was built using multivariate Cox regression. Immune infiltration was assessed by ssGSEA, MCPCounter, and ESTIMATE algorithms. Drug sensitivity correlation was analyzed using pRRophetic. In vitro functional assays validated key gene roles in CC cells. RESULTS: Forty thousand four hundred fifty-seven cells were annotated into eight cell populations with a lower percentage of EpCs. Thereafter, EpCs were categorized into three subclusters with specifically highly expressed genes in peculiar biological pathways and with distinct trajectories of fate. A strong cell-cell communication network was observed, particularly involving Ep C3 and immune cells, via ligand-receptor pairs such as LGALS9-CD44 and HBEGF-EGFR. The hdWGCNA analysis revealed Ep C3-specific gene modules, from which a five-gene prognostic signature (, , , , and ) was constructed. The resulting risk model effectively stratified patients into high- and low-risk groups with significantly different overall survival in both TCGA-CESC and GSE52903 cohorts, supported by time-dependent ROC curves. The high-risk group exhibited lower immune/stromal scores and distinct immune cell infiltration patterns. The risk score significantly correlated with sensitivity to several chemotherapeutic agents. Crucially, in vitro experiments confirmed that knockdown inhibited the proliferation, migration, and invasion of CC cells while enhancing the level of apoptosis in cancer cells. CONCLUSION: A proposed EpC-specific gene signature for CC may be applicable to support clinical decision-making.
miR-221/222 Facilitate Pituitary Adenoma Progression Via PHACTR4 Downregulation.
Dong W, Yan S, Song L … +6 more , Wang W, Sun D, Pang P, Yang G, Gu W, Nair S
Hum Mutat · 2026 · PMID 41660554 · Full text
Most of pituitary adenomas are biologically benign, but some grow local-invasively and can invade important adjacent tissues, resulting in clinical symptoms such as hormone secretion disorders and visual field defects. M...
Most of pituitary adenomas are biologically benign, but some grow local-invasively and can invade important adjacent tissues, resulting in clinical symptoms such as hormone secretion disorders and visual field defects. MicroRNA-221/222 (miR-221/222) is tandemly encoded on the X chromosome in humans, mice and rats, and is highly conserved in vertebrates with the same seed sequence. To date, miR-221/222 has been reported as either a tumor suppressor or a tumor promoter in different tumors, however, its role in pituitary tumors has not been elucidated. Our study aimed to investigate the effect and mechanism of miRNA-221/222 in pituitary tumor cells. Results of real-time quantitative PCR showed that the expression level of miRNA-221/222 in plasma exosomes from patients with pituitary tumor was significantly higher than that from healthy people. Results of cell function experiments indicated that miRNA-221/222 significantly promoted cell proliferation and migration, inhibited apoptosis and significantly inhibited the expression of Cleaved-Caspase3 and E-cadherin, while promoted the expression level of N-cadherin. With transcriptome sequencing and comprehensive bioinformatics analysis, PHACTR4 was identified as the potential target gene of miRNA-221/222 in regulating biological functions of pituitary adenoma cells. Dual luciferase reporter assay confirmed that PHACTR4 was the direct target gene of miRNA-221/222 and overexpression of PHACTR4 gene reversed the regulatory effects of miRNA-221/222. In vivo experiment of subcutaneous tumor formation in nude mice verified that miRNA-221/222 promoted tumor growth by targeting PHACTR4. In conclusion, miRNA-221/222 played the role of proto-oncogene in the occurrence and development of pituitary tumors by targeting PHACTR4, which provided a new target for the diagnosis and molecular treatment of pituitary adenomas.
Buyang Huanwu Decoction Alleviates Chronic Intermittent Hypoxia-Induced Myocardial Inflammation and Fibrosis via the NF-B/LOX Signaling Pathway.
Ou L, Liu C, Zhao W … +3 more , Liu C, Ning Y, Ren M
Hum Mutat · 2026 · PMID 41660553 · Full text
OBJECTIVE: To investigate the protective effects of Buyang Huanwu decoction (BYHW) on myocardial injury induced by chronic intermittent hypoxia (CIH) in rats and to analyze its potential regulatory mechanism through the...
OBJECTIVE: To investigate the protective effects of Buyang Huanwu decoction (BYHW) on myocardial injury induced by chronic intermittent hypoxia (CIH) in rats and to analyze its potential regulatory mechanism through the NF-B/LOX signaling pathway. METHODS: Then, 36 adult male Sprague-Dawley (SD) rats (weighing 200-250 g) were randomly divided into six groups ( = 6): normal control (NC), CIH model, BYHW, BYHW + lipopolysaccharide (LPS), BYHW + pyrrolidinedithiocarbamate (PDTC), and LPS. Except for the NC group, all groups underwent 5 weeks of intermittent hypoxia (8 h/day) alongside their respective drug treatments. Postintervention, systolic blood pressure and heart rate were recorded. Cardiac function was evaluated by echocardiography to measure left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular internal dimension at end-diastole (LVDd) and left ventricular internal dimension at end-systole (LVDs). Myocardial sections were analyzed by HE and Sirius Red staining for quantitative assessment of inflammatory cell infiltration and collagen volume fraction (CVF). The protein and mRNA expression levels of NF-B, LOX, Collagen I, and Collagen III in cardiac tissue were analyzed by Western blot and qPCR. RESULTS: Compared with the NC group, rats exposed to CIH or LPS showed elevated blood pressure and an increased heart rate, along with impaired cardiac function, as evidenced by reduced LVEF ( < 0.05) and LVFS ( < 0.05), along with increased LVDd ( < 0.05) and LVDs ( < 0.05). BYHW treatment significantly ameliorated the CIH-induced cardiac dysfunction and ventricular dilation ( < 0.05), and these improvements were further enhanced by cotreatment with BYHW and the NF-B inhibitor PDTC ( < 0.05). Conversely, cotreatment with BYHW and the NF-B agonist LPS attenuated the cardioprotective effects of BYHW ( < 0.05). Histologically, BYHW significantly reduced CIH-induced myocardial structural disruption, inflammatory cell infiltration, and fibrosis (CVF) ( < 0.05), effects that were potentiated by cotreatment with BYHW and PDTC, and counteracted by cotreatment with BYHW and LPS. At the molecular level, Western blot and qPCR analyses revealed that BYHW significantly reduced both the protein and mRNA levels of NF-B, LOX, Collagen I, and Collagen III ( < 0.05) compared with the NC group. This suppression was further enhanced by cotreatment with BYHW and PDTC and attenuated by cotreatment with BYHW and LPS. CONCLUSION: BYHW improves cardiac function and reduces myocardial inflammation and fibrosis in SD rats with CIH. This effect may be related to the inhibition of the NF-B/LOX signaling pathway. Cotreatment with BYHW and PDTC enhances this therapeutic effect, while cotreatment with BYHW and LPS attenuates this effect. This study provides preliminary experimental evidence for the cardioprotective effects of BYHW.
Causal Relationships Between Plasma Metabolites, Inflammatory Factors, and Oral Cancer Risk: A Comprehensive Mendelian Randomization Study With Mediation Analysis.
Hu S, Liu C, Ren M
Hum Mutat · 2026 · PMID 41660552 · Full text
This study conducted a large-scale Mendelian randomization analysis using genome-wide single nucleotide polymorphisms (SNPs) as instrumental variables to investigate the causal relationships between 1400 circulating meta...
This study conducted a large-scale Mendelian randomization analysis using genome-wide single nucleotide polymorphisms (SNPs) as instrumental variables to investigate the causal relationships between 1400 circulating metabolites and oral cancer risk. The genetic data were derived from the Canadian Longitudinal Study on Aging (CLSA) cohort and the IEU OpenGWAS database. The study employed germline genetic variants captured in genome-wide association studies for causal inference, combined with mediation analysis and CAL-27 cell experimental validation. The results identified 61 metabolites with significant causal relationships with oral cancer through SNP instrumental variables (29 with protective effects and 32 increasing risk) and revealed 14 inflammatory factors as key mediating variables, with mediation effects accounting for 1.4%-17.4% of the total effects. Cell experiments further confirmed that aspartate significantly downregulates CCL11 expression and secretion and exerts anti-inflammatory effects by suppressing inflammatory factors, including IL-1, IL-6, and TNF-. Conversely, CCL11 overexpression promotes malignant cellular behavior, but these effects can be reversed by aspartate through inhibition of NF-B and MAPK signaling pathways. This study elucidates a genetic variant-driven "metabolism-inflammation" carcinogenic pathway, providing novel insights into the mechanisms of oral cancer development and demonstrating significant translational potential for precision prevention and precision therapy.
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