Hum. Mutat. [JOURNAL]
Sun
200 papers
RETRACTION: "Differential Effects of AKT1(p.E17K) Expression on Human Mammary Luminal Epithelial and Myoepithelial Cells".
Mutation H
Hum Mutat · 2026 · PMID 42395890 · Full text
[This retracts the article DOI: 10.1002/humu.22100.].
[This retracts the article DOI: 10.1002/humu.22100.].
Diagnostic Yield of Genome Sequencing in an Iranian Exome-Negative Autosomal-Recessive Intellectual Disability Cohort.
Shokouhian E, Moslemi M, Moghadam MG … +11 more , Molaei N, Alagha P, Reshadmanesh A, Arzhangi S, Ghodratpour F, Celik M, Kadioglu IS, Edizadeh M, Akbari MR, Kahrizi K, Najmabadi H
Hum Mutat · 2026 · PMID 42388363 · Full text
Intellectual disability (ID) affects approximately 1%-3% of the population and spans diverse clinical presentations with marked genetic heterogeneity, especially in consanguineous populations where autosomal-recessive ID...
Intellectual disability (ID) affects approximately 1%-3% of the population and spans diverse clinical presentations with marked genetic heterogeneity, especially in consanguineous populations where autosomal-recessive ID is common. Despite advances in diagnostic methods, ~50% of individuals with ID remain without a molecular diagnosis. Genome sequencing (GS) can detect variant classes poorly captured by other methodologies, including deep intronic splice changes and structural variants. We performed short-read GS on 38 Iranian autosomal recessive intellectual disability (ARID) families that remained unsolved after exome sequencing (ES) and two phases of reanalysis. Sequencing and variant calling were performed on DRAGEN Bio-IT Platform with GRCh38 and variants were annotated in Golden helix Varseq software and the AnnotSV tool. GS yielded diagnoses in 2 of 38 families (5.3%), identifying a homozygous deep-intronic variant (c.1473 + 519C > T) that creates a cryptic donor site and a 57-bp pseudoexon, and a homozygous ~103-kb deletion removing the in-frame Exon 2. Additionally, GS uncovered a homozygous missense variant that represents a novel candidate gene for ARID, but further studies are required to confirm the gene-disease association. The and variants were uniquely detectable by GS. In conclusion, in a challenging, ES-negative ARID cohort, GS provided an additional ~5.3% diagnostic yield by uncovering a noncoding splice alteration and a large intragenic deletion. These results underscore GS as a valuable, though still modest, tool over ES and highlight significant interpretation challenges in noncoding regions. Continued advances in functional assays and complementary long-read technologies will be essential to further reduce the diagnostic gap in unresolved ID.
Exploring the Functional Impact of Individual Variants With a Fast and Robust Cell-Based Method.
Nitschke NJ, Almosailleakh M, Issa II … +13 more , Skov CA, Lund CC, Hansen JW, Jespersen JS, Raaschou-Jensen K, Schöllkopf C, Severinsen MT, Porse B, Weischenfeld J, Roug AS, Andersen MK, Frödin M, Grønbæk K
Hum Mutat · 2026 · PMID 42369211 · Full text
Germline variants are found in up to 4% of patients with acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDSs), with a higher prevalence among males and a late onset. In this study, we analyzed 647 Danish pa...
Germline variants are found in up to 4% of patients with acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDSs), with a higher prevalence among males and a late onset. In this study, we analyzed 647 Danish patients with suspected myeloid neoplasms to assess the frequency of germline variants and the functional impact of variants of uncertain significance (VUSs) using a cell-based assay, CRISPR-Select. We identified 16 variants in 30 patients, 14 of whom were confirmed or predicted as germline variants. Eight germline variants were classified as likely pathogenic/pathogenic (LP/P), and three as VUSs. We generated a monoallelic K562 cell line and used it for CRISPR-Select assessment of variant effects on proliferation and survival. Pathogenic variants impaired proliferation, while benign variants did not. Missense variants had a more subtle effect than truncating ones, suggesting hypomorphic phenotypes. One VUS had a significant negative effect on proliferation, suggesting it to be pathogenic, while the other two had no effect, suggesting them to be benign. These findings confirm a 2.4% frequency of LP/P DDX41 germline variants in Danish patients and demonstrate the value of CRISPR-Select in distinguishing pathogenic from benign variants.
Modeling the Effects of Single Nucleotide Polymorphisms (SNPs) on the Structure and Function of the Human Gene: An In Silico Study.
Anzoom N, Hossain MA, Hossain MT … +5 more , Uddin MM, Khan M, Islam MS, Ansari SA, Rahman MH
Hum Mutat · 2026 · PMID 42369210 · Full text
The proto-oncogene plays a critical role in multiple cancers and developmental disorders, where nonsynonymous single nucleotide polymorphisms (nsSNPs) may alter protein stability, function, and therapeutic response. In...
The proto-oncogene plays a critical role in multiple cancers and developmental disorders, where nonsynonymous single nucleotide polymorphisms (nsSNPs) may alter protein stability, function, and therapeutic response. In this study, a total of 28,335 SNPs from the NCBI dbSNP database, including 2377 nsSNPs, were systematically analyzed using 10 in silico prediction tools. Among these 33 high-risk variants were identified with 28 predicted to destabilize protein. Further structural and functional analyses highlighted 11 potentially pathogenic nsSNPs (R721G, A756D, Y791C, E734K, E805K, F893L, R897Q, R897G, R912Q, R912G, and M918T), predominantly clustered within the tyrosine kinase domain, suggesting functional hotspots may contribute disease susceptibility. Molecular docking of eight inhibitors revealed mutation-specific differences in drug binding affinity. Among the tested compounds, entrectinib exhibited consistently strong binding affinities across all variants (-9.7 to -10.7 kcal/mol), whereas reduced binding affinities were observed for several inhibitors against E734K, A756D, and R897G variants. Molecular dynamics simulations further supported these findings, showing that A756D, E734K, and R897Q variants maintained comparatively stable conformations, whereas R897G and Y791C exhibited increased structural flexibility and destabilization. Survival analyses revealed that RET dysregulation correlates with poor prognosis in thyroid cancer, lung carcinoma, breast cancer, and sarcoma. Clinical databases reported that p.Met918Thr (pathogenic) and p.Arg897Gln (risk factor) emerged as significant variants linked to MEN2-related cancers and Hirschsprung disease. As a conclusion, this integrative in silico study identifies deleterious nsSNPs with potential structural, functional, and therapeutic significance providing mechanisms for precision oncology and future clinical investigation.
Driver Mutation Subtypes Differentially Shape Immune Evasion Landscapes in Melanoma: An AI-Driven Inflammatory Pathway Model Implicating CCNE1.
Mao C, Chen G, Tang J … +3 more , Leng R, Zhou X, Yang J
Hum Mutat · 2026 · PMID 42369209 · Full text
BACKGROUND: Melanoma harbors highly heterogeneous tumor immune microenvironments shaped by driver mutations in BRAF, NRAS, and NF1. How mutational context modulates inflammatory signaling and immune evasion mechanisms of...
BACKGROUND: Melanoma harbors highly heterogeneous tumor immune microenvironments shaped by driver mutations in BRAF, NRAS, and NF1. How mutational context modulates inflammatory signaling and immune evasion mechanisms of prognosis-related genes remains poorly understood. METHODS: ssGSEA scored 15 inflammatory pathways across four cohorts (TCGA, GSE19234, GSE22153, and GSE65904). Cross-cohort univariate Cox regression and a 10-algorithm machine learning framework identified and optimized a prognostic model. Immune microenvironment differences across BRAF, NRAS, NF1, and Triple-WT subtypes were characterized using ESTIMATE, CIBERSORT, and GSVA. CCNE1 was validated by shRNA knockdown in melanoma cell lines, and a mutation subtype-specific virtual knockdown model was constructed from scRNA-seq data. RESULTS: The prognostic model achieved a 5-year AUC of 0.95 in TCGA and outperformed published signatures in three of four cohorts. High-risk patients showed markedly reduced immune infiltration (ImmuneScore = -0.51) and an immunosuppressive phenotype. Mutation subtype analysis revealed distinct immune landscapes: NF1-mutant tumors showed the highest antigen presentation and IFN- pathway enrichment; BRAF-mutant tumors displayed the highest stromal score and M0 macrophage proportions; and NRAS-mutant tumors exhibited the lowest NK cell activity and most pronounced immunosuppression. CCNE1 was the gene most strongly correlated with the risk score and was validated as an independent poor prognostic marker across all cohorts. shRNA-mediated knockdown inhibited migration and enhanced adhesion in melanoma cell lines. Virtual knockdown modeling showed that CCNE1 suppression upregulated antigen presentation genes (HLA-A/B/C, B2M, and TAP1/2) and downregulated immune checkpoint molecules in a mutation subtype-dependent manner, with the strongest proimmunogenic effects in NF1-mutant cells and LAG3 downregulation predominantly in BRAF-mutant cells. CONCLUSION: This study establishes a high-performance inflammatory pathway-based prognostic model for melanoma and demonstrates that driver mutation subtypes differentially shape the immune microenvironment landscape. CCNE1 functions as a key oncogenic immune regulator whose modulation of antigen presentation and immune checkpoint expression is contingent on mutational context, most prominently in NF1-mutant tumors, underscoring the value of mutation-informed personalized immunotherapy strategies in melanoma.
Comment on "When the Outcome Contains the Exposure: Methodological Limits of a Genome-Wide Cross-Trait Analysis of Type 2 Diabetes and MASLD".
Wu Q, Zhang C
Hum Mutat · 2026 · PMID 42369208 · Full text
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AI-Augmented Hematological Signatures for Equitable Detection of Hereditary Hemolytic Anemia Carriers: A Global Systematic Review and Meta-Analysis.
Ali NT, Abdullah RS, Mehdi MAH … +4 more , Ali GS, Ali HM, Gubran ANM, Al-Abd NM
Hum Mutat · 2026 · PMID 42369207 · Full text
Artificial intelligence (AI) augmentation of routine hematological tests offers a promising strategy to improve hereditary hemolytic anemia (HHA) carrier detection in premarital screening, especially in resource-limited...
Artificial intelligence (AI) augmentation of routine hematological tests offers a promising strategy to improve hereditary hemolytic anemia (HHA) carrier detection in premarital screening, especially in resource-limited settings. HHA in this review specifically encompasses -thalassemia, -thalassemia, sickle cell disease (including HbS and HbC variants), and other hemoglobinopathies with autosomal recessive inheritance patterns requiring carrier detection for prevention. These conditions share hemolytic phenotypes but differ in hematological signatures, necessitating separate subgroup analyses. This global systematic review and meta-analysis evaluated the diagnostic accuracy, equity implications, and implementation challenges of AI-augmented complete blood count (CBC), blood smear, and erythrocyte sedimentation rate (ESR) for HHA carrier identification. We systematically searched seven databases and included 85 studies ( = 133,498 participants, 23 countries). AI-augmented screening achieved a pooled sensitivity of 92.8% (95% CI: 91.3%-94.1%) and specificity of 91.5% (89.7%-93.0%), representing a 12.3% sensitivity improvement over conventional interpretation ( < 0.001). However, significant geographic disparities were observed: sensitivity in Sub-Saharan Africa was 86.5% compared with 94.8% in the Middle East ( < 0.001), partly due to algorithmic bias against African HbS/HbC variants and infrastructural barriers. Deep learning models achieved the highest sensitivity (95.1%), whereas explainable artificial intelligence (XAI) provided optimal specificity (94.3%). Integrating CBC with blood smear increased specificity by 5.5% at minimal additional cost. AI triage reduced confirmatory testing by 23.7%, saving $8.50 per individual. For equitable implementation, we recommend the following: (1) federated learning to include underrepresented genotypes, (2) WHO/CDC certification of affordable, offline-capable edge AI devices, and (3) mandatory XAI compliance with bias audits. AI can transform HHA screening, but deliberate efforts are needed to avoid exacerbating global health inequities. Importantly, 68% of validation studies used research-grade rather than routine clinical samples, and prospective clinic-to-algorithm validation remains a critical gap requiring urgent attention before real-world deployment.
Pharmacovigilance Signal Detection and Mutually Exclusive Driver Mutations of the PI3K/AKT Pathway in Breast Cancer Treated With Capivasertib.
Luo Z, Shi Y, Zhu B … +4 more , Huang Q, Zhang W, Shi Y, Yang X
Hum Mutat · 2026 · PMID 42369206 · Full text
BACKGROUND AND OBJECTIVE: This study is aimed at comprehensively evaluating the real-world safety profile and underlying molecular mechanisms of the AKT inhibitor capivasertib by integrating pharmacovigilance data, compu...
BACKGROUND AND OBJECTIVE: This study is aimed at comprehensively evaluating the real-world safety profile and underlying molecular mechanisms of the AKT inhibitor capivasertib by integrating pharmacovigilance data, computational biology, and multiomics analyses. METHODS: Adverse event (AE) reports from the FAERS database were analyzed using disproportionality algorithms (ROR, PRR, BCPNN, EBGM) to detect significant safety signals. To elucidate potential toxicological mechanisms, we employed network toxicology and molecular docking, further validated by 100 ns molecular dynamics (MD) simulations. Additionally, bulk genomic cohorts (e.g., TCGA, METABRIC) and single-cell RNA sequencing (scRNA-seq) datasets were utilized to assess mutation patterns and delineate key targets within the tumor microenvironment (TME). RESULTS: Analysis of 22,143 AE reports yielded 133 significant safety signals, predominantly involving metabolism (e.g., hyperglycemia), the gastrointestinal system (e.g., nausea, stomatitis), and dermatological conditions (e.g., rash). Pathway enrichment highlighted the PI3K-AKT, HIF-1, and EGFR signaling networks. Integrative analyses identified critical toxicity-related modulators, notably AKT1, IGF1, PTEN, TP53, and GSK3B. Crucially, MD simulations robustly confirmed the thermodynamic stability of the capivasertib-GSK3B complex. Genomic profiling revealed pronounced mutual exclusivity among PIK3CA, AKT1, and PTEN alterations. Furthermore, scRNA-seq analysis demonstrated that GSK3B overexpression defines a highly aggressive, proliferative malignant subpopulation that profoundly reshapes intercellular communication with stromal fibroblasts. CONCLUSION: By seamlessly bridging real-world pharmacovigilance with advanced structural biology and single-cell transcriptomics, this study delineates the comprehensive safety landscape of capivasertib. Our findings provide crucial clinical alerts for AE monitoring and offer deep mechanistic insights to optimize personalized therapeutic management in breast cancer.
Lactylation-Related Genes in Ulcerative Colitis: A Multiomics Mendelian Randomization Study for Therapeutic Target Discovery.
An N, Wang R, Jiao H … +4 more , Lu Z, Dou Y, Zheng L, Ding Z
Hum Mutat · 2026 · PMID 42369205 · Full text
BACKGROUND: Ulcerative colitis (UC), a chronic and nonspecific intestinal inflammatory disease, has seen a rising incidence rate worldwide year by year. Its pathogenesis remains incompletely understood. Lactylation modif...
BACKGROUND: Ulcerative colitis (UC), a chronic and nonspecific intestinal inflammatory disease, has seen a rising incidence rate worldwide year by year. Its pathogenesis remains incompletely understood. Lactylation modification is closely related to the generation of inflammation. Exploring the pathogenesis of UC from the perspective of lactylation is of great significance for the understanding and treatment of UC. METHOD: Forty-six lactylation genes were retrieved from the literature and intersected with the eQTLGen whole blood cis-eQTL to screen 29 candidate genes. Taking UC (finngen_R12_ULCERNAS, 482,657 participants) in the Finnish database as the outcome, significant eQTLs were selected as instrumental variables. The core genes were identified through multimodel Mendelian randomization with inverse variance weighting and heterogeneity and pleiotropy tests. Subsequently, the causal association was reverified by SMR, and differential expression analysis was performed after batch correction in combination with the GEO dataset. The expression profiles of cell subpopulations were analyzed based on single-cell data (GSE214695). Finally, the UC inflammation model was constructed by LPS-induced colonic epithelial cells, and the expression changes of the target genes were verified and determined by qPCR experiments. Then, the expression of the genes in the UC was re-examined in the spatial transcriptome samples. RESULT: Mendelian randomization identified EP300, LDHC, and STMN1 as causal genes involved in the lactylation mechanism of UC. The GEO dataset shows that EP300 and STMN1 are significantly upregulated in the UC group. Single-cell maps revealed that STMN1 was enriched in B cells, LDHC, and EP300 in endothelial cells. The qPCR experiment and spatial transcriptome sample confirmed that STMN1 was upregulated most significantly. CONCLUSION: STMN1 and EP300 have been identified as causal genes for UC. The expression of STMN1 in UC significantly increased, and it was specifically enriched in B cells and monocytes. Lactic acid modification may participate in the pathogenesis of UC by driving immune imbalance, providing a genetic basis for the development of new diagnostic markers and targeted lactate intervention strategies.
Hypoxia-Associated Molecular Subtypes Reveal Immune Checkpoint, Ferroptosis, and m6A Regulatory Heterogeneity in Pediatric Vasculitis.
Liu B
Hum Mutat · 2026 · PMID 42369204 · Full text
BACKGROUND: Vasculitis is a heterogeneous inflammatory vascular disorder with substantial clinical and molecular diversity. However, hypoxia-associated molecular subtypes in pediatric vasculitis and their differences fro...
BACKGROUND: Vasculitis is a heterogeneous inflammatory vascular disorder with substantial clinical and molecular diversity. However, hypoxia-associated molecular subtypes in pediatric vasculitis and their differences from adult vasculitis remain poorly defined. METHODS: Transcriptomic data of pediatric and adult vasculitis were obtained from the GEO database. RNA-seq data from GSE129752 were normalized by log (TPM+1) transformation. Hypoxia-related genes were used for consensus clustering of pediatric vasculitis samples. Immune checkpoint, ferroptosis-related, and m6A methylation regulator genes were compared between subtypes. Differentially expressed genes between pediatric and adult vasculitis were identified using limma, followed by Gene Ontology enrichment analysis using clusterProfiler. RESULTS: Consensus clustering separated pediatric vasculitis into two hypoxia-associated subtypes, high hypoxia pediatric vasculitis population (high_hypoxia group) and low hypoxia pediatric vasculitis population (low_hypoxia group), with distinct transcriptomic profiles. High_hypoxia group showed higher expression of multiple immune checkpoint genes, including HAVCR2, IGSF8, ITPRIPL1, LAG3, PDCD1, SIGLEC15, and TIGIT. Ferroptosis-related genes EMC2 and ATP5MC3 were also elevated in the high_hypoxia group. In addition, most m6A regulators, including FTO, METTL14, WTAP, and RBM15, were significantly upregulated in the high_hypoxia group. Comparison between pediatric and adult vasculitis identified 85 differentially expressed genes, including 21 upregulated and 64 downregulated genes in pediatric vasculitis. Functional enrichment suggested that pediatric vasculitis was associated with fibroblast proliferation and vascular remodeling, whereas adult vasculitis was enriched in immature T-cell regulation and fatty acid transport. Germline mutation-related genes, including VHL, BRCA1, RET, and MUTYH, showed coordinated correlations with age-related vasculitis. CONCLUSION: Hypoxia-associated molecular heterogeneity exists in pediatric vasculitis and we observed age-related transcriptomic differences between pediatric and adult disease. These findings provide a foundation for precision classification and future mechanism-based therapeutic strategies.
Compound Heterozygous Variants in the Phospholipase Gene PNPLA6 Cause Hypopituitarism and Vision Loss.
Vishnopolska S, Liu J, Camilletti MA … +12 more , Mayer JM, Garcia LI, Brinkmeier M, Vaiani E, Vidal SH, Ciaccio M, Di Palma MI, Belgorosky A, Marti M, Hufnagel RB, Camper SA, Perez-Millan MI
Hum Mutat · 2026 · PMID 42327344 · Full text
PNPLA6 is a conserved lysophospholipase essential for maintaining nervous system integrity. Biallelic mutations in have been identified in individuals with a broad spectrum of disorders that can include ataxia, vision l...
PNPLA6 is a conserved lysophospholipase essential for maintaining nervous system integrity. Biallelic mutations in have been identified in individuals with a broad spectrum of disorders that can include ataxia, vision loss, and pituitary hormone deficiency. Here, we report the identification of novel compound heterozygous variants in (p.T1115P and p.Pro1142_Ala1143ins14) in a 10-year-old girl with combined pituitary hormone deficiency, including growth hormone, thyroid-stimulating hormone, and gonadotropins. She also has vision loss and neurodevelopmental delay. Functional validation demonstrates that both variants, a missense substitution affecting a highly conserved residue within the catalytic domain and an intronic variant generating a novel splice acceptor site, completely abolish NTE activity, establishing their pathogenicity. Little is known about the cause of hypopituitarism in individuals with deficiency. Here, we report the cell-type-specific expression of PNPLA6 in mouse pituitary development and in adult animals. PNPLA6 is expressed broadly in SOX2+ stem cells within the pituitary primordium as early as e10.5, prior to lineage specification, suggesting a role in progenitor maintenance and early differentiation. In neonates and adults, expression predominates in the cells that produce growth hormone and pro-opiomelanocortin. These findings suggest that PNPLA6 could influence pituitary development at early stages, as well as contribute to the altered function of hormone-secreting cells.
c.2233C > T Is Involved in Human Familial Ovarian Immature Teratoma With c.262C > T.
Hao Y, Kang X, Liu Y … +3 more , Fan H, Li Y, Kang S
Hum Mutat · 2026 · PMID 42327343 · Full text
We previously identified the germline mutation c.262C > T in as a genetic susceptibility factor of hereditary ovarian immature teratoma (OIT). However, not all female carriers in that family had OIT. In this study, we a...
We previously identified the germline mutation c.262C > T in as a genetic susceptibility factor of hereditary ovarian immature teratoma (OIT). However, not all female carriers in that family had OIT. In this study, we analyzed the genetic differences among these individuals, aiming to explore whether any genes may be copathogenic with . The subjects were recruited from two three-generation pedigrees of hereditary OIT. Whole-exome sequencing (WES) was performed, and the candidate variants were subsequently tested by Sanger sequencing. Moreover, bioinformatics was used to assess the mutation with MutationTaster and Combined Annotation Dependent Depletion (CADD), and pathogenicity was predicted according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The effect of the mutation on CDHR2 expression was evaluated by RT-qPCR, Western blotting, and immunofluorescence with confocal microscopy. WES revealed that, unlike the two unaffected sisters, both affected second-generation individuals harbored a germline mutation in (c.2233C > T, p.R745X) in addition to the mutation in (c.262C > T, p.R86C). c.2233C > T is a truncating mutation that was predicted to be deleterious by MutationTaster and CADD and classified as pathogenic according to the ACMG criteria. Our in vitro experiments revealed that mRNA and protein expression levels were significantly lower in cells with the 2233T allele than in those with the 2233C allele. Moreover, the localization of the mutant product in cells was significantly different from that of the wild-type protein. The mutant group exhibited abnormal accumulation of small-molecule metabolites, along with aberrant activation of the signaling cascade. Our findings suggest that the c.2233C > T variant may have a synergistic effect with in hereditary OIT or act as a modifier gene in OIT development.
The Performance of Prediction Tools for Variant Curation in a Panel of Cancer Genes.
Nelson N, Niaz A, Fairfax K … +3 more , Bryan TM, Lucas S, Dickinson J
Hum Mutat · 2026 · PMID 42327342 · Full text
Rare single base pair changes in genes are an important cause of disease, as they can reside in key regions of the gene influencing biological function by impacting the protein conformation and protein interactions. Gene...
Rare single base pair changes in genes are an important cause of disease, as they can reside in key regions of the gene influencing biological function by impacting the protein conformation and protein interactions. Generation of the necessary experimental evidence to define the outcome of the presence of these gene variants is time-consuming and costly. These challenges have led to the development of a plethora of prediction tools. These tools frequently use similar sources of information and are trained on overlapping multigene 'truth' datasets. However, frequently there has been no quantitative validation of the performance of these tools for individual genes. Here, we have applied the ClinGen Sequence Variant Interpretation Working Group's recommended score thresholds and AlphaMissense predictions to a set of predisposition gene variants with established pathogenicity/benignity. Of the genes assessed (, , , and ), when recommended thresholds were used, tool predictions showed inferior sensitivity (< 65%) for pathogenic variants and inferior sensitivity (≤ 81%) for benign variants. AlphaMissense outperformed the other tools for but did not improve predictive accuracy for variants. This validation study highlights that tool performance can be gene-specific and is dependent on the 'training set' on which the algorithm is built. Where there are sufficient numbers of established benign and pathogenic missense variants based on clinical and functional evidence, the use of tool scores should be validated for individual genes. For genes where this is not possible and gene-agnostic score cut-offs are used, consideration of missense variant-protein structural impact relationships is suggested.
Cross-Strand Chimeric RNA Signature Predicts Prognosis and Identifies Tumor Immune Microenvironment Associations in Gastric Cancer.
Cheng S, Cui M, Li X … +5 more , Huang Y, Wen X, Wei S, Zhang S, Huang H
Hum Mutat · 2026 · PMID 42327341 · Full text
Cross-strand chimeric RNAs (cscRNAs) represent an emerging class of noncanonical fusion transcripts arising from bidirectional transcription, yet their landscape and functional significance in gastric cancer remain unexp...
Cross-strand chimeric RNAs (cscRNAs) represent an emerging class of noncanonical fusion transcripts arising from bidirectional transcription, yet their landscape and functional significance in gastric cancer remain unexplored. Here, we systematically investigated cscRNA expression patterns, prognostic relevance, and tumor immune microenvironment associations in gastric cancer through integrated computational and experimental approaches. Analysis of 372 TCGA-STAD samples revealed tumor-specific cscRNA enrichment that was independent of clinicopathological variables including tumor stage, histological grade, and lymph node metastasis status. Through a three-layer machine learning pipeline integrating univariate screening, multivariate feature selection, and bootstrap stability validation, we identified six cscRNA-enriched genomic regions that collectively formed a reproducible prognostic signature. Patients stratified by the risk score model showed significantly divergent survival outcomes (median survival: 18.9 vs. 69.0 months; univariate HR = 2.54, < 0.001), and the risk score retained independent prognostic value after adjusting for clinical covariates (multivariable HR = 2.86, < 0.001). In an exploratory analysis of an independent validation cohort (GSE122401, = 26), high-risk tumors showed features consistent with an immunosuppressive microenvironment, including reduced CD8+ T-cell infiltration ( = 0.042), elevated regulatory T-cell proportions ( = 0.028), and lower immune scores ( = 0.006). Subgroup analyses by microsatellite instability and Epstein-Barr virus status ( = 4 and = 6, respectively) suggested differential immune patterns warranting confirmation in larger cohorts. Experimental validation confirmed cscR-819 as a bona fide posttranscriptional cscRNA product, whose knockdown significantly inhibited gastric cancer cell proliferation, migration, and colony formation while promoting apoptosis. Mechanistically, cscR-819 was predominantly localized in the cytoplasm and functioned as a translational regulator, selectively enhancing the translation efficiency of genes involved in cell cycle progression, DNA replication, and antiapoptotic pathways, as demonstrated by polyribosome profiling. In conclusion, our study establishes cscRNAs as functionally relevant contributors to gastric cancer pathogenesis and identifies exploratory associations with tumor immune microenvironment features, positioning cscRNA-based signatures as promising candidate biomarkers for risk stratification and motivating further investigation of cscRNA-immune interactions.
Integrated Single-Cell and Bulk Transcriptomic Analysis Reveals an Endothelial Gene Signature Shaping EndMT and Prognosis in Hepatocellular Carcinoma.
Wei F, You X, Chen Z … +2 more , Chen Y, Chen Z
Hum Mutat · 2026 · PMID 42327340 · Full text
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors of the liver, with increasing incidence and mortality rates globally. This study investigates the role of endothelial cells (ECs) i...
BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most prevalent malignant tumors of the liver, with increasing incidence and mortality rates globally. This study investigates the role of endothelial cells (ECs) in the progression of HCC, particularly focusing on the process of endothelial-to-mesenchymal transition (EndMT) and its underlying molecular mechanisms. METHODS: We utilized single-cell RNA sequencing (scRNA-seq) and multiomics analyses to explore the involvement of ECs in HCC and their transformation mechanisms. The study emphasized the potential application of EC-related genes (ECRGs) in prognostic evaluation for HCC patients. Furthermore, HCC organoids were utilized to validate the functional relevance of selected ECRGs. RESULTS: ECs play a critical role in the progression of HCC, particularly through mechanisms related to EndMT and its influence on patient prognosis. We identified 19 key ECRGs that are pivotal to the initiation and development of HCC and constructed a robust prognostic model using LASSO regression analysis. Notably, this gene signature effectively stratifies HCC subtypes and reveals significant differences in immune cell infiltration and immune checkpoint gene expression among EC-related prognostic groups, underscoring its potential relevance in guiding immunotherapy, sorafenib therapy, and transarterial chemoembolization (TACE) outcomes. Furthermore, the coculture system of HCC and vascular organoids successfully mimicked the EndMT process, revealing spatial colocalization of three ECRGs-MPZL2, KITLG, and PCDH1-with established EndMT markers, suggesting their potential as therapeutic targets in tumor-associated endothelial plasticity. CONCLUSIONS: This study emphasizes ECs' role in HCC progression and how EndMT affects prognosis. HCC organoids revealed ECRGs linked to EndMT, like MPZL2, KITLG, and PCDH1, as potential therapeutic targets.
Translating Osteoarthritis Genetic Risk Into Biomarkers: Opportunities, Pitfalls, and Implementation Considerations.
Meng T, Ma L, Zhang X … +5 more , Han J, Li F, Wu W, Liu S, Liu A
Hum Mutat · 2026 · PMID 42317216 · Full text
Osteoarthritis (OA) is a heterogeneous joint disease in which patients differ widely in onset, progression, pain burden, and inflammatory activity, yet clinical tools for early risk stratification and mechanism-informed...
Osteoarthritis (OA) is a heterogeneous joint disease in which patients differ widely in onset, progression, pain burden, and inflammatory activity, yet clinical tools for early risk stratification and mechanism-informed subtyping remain limited. Human genetic studies have identified many OA-associated loci, but translation into deployable biomarkers has been slow because most signals are polygenic, largely noncoding, and dependent on tissue and cell state. Despite rapid progress in OA genomics, a major remaining challenge is how to systematically convert genetic discoveries into clinically actionable biomarkers that can support risk prediction, biological stratification, and therapeutic development. This review discusses how OA genetic risk can be converted into practical biomarker strategies by combining statistical variant interpretation with joint-resolved biology. We summarize approaches that prioritize likely effector genes and regulatory modes using fine-mapping and molecular QTL evidence, and then place these signals into the correct anatomical and cellular contexts using single-cell and spatial atlases of cartilage, synovium, and subchondral bone. We highlight three classes of outputs that are most likely to be clinically useful: polygenic risk-informed stratification for early monitoring and trial enrichment; compact molecular panels reflecting genetically supported programs in accessible biospecimens; and imaging-omics models that connect structural phenotypes to mechanism-linked biology. We also review common reasons biomarker pipelines fail in OA, including uncertain variant-to-gene assignment, limited portability across populations, tissue accessibility and stage bias, and technical variation across omics and imaging platforms. Finally, we outline what is needed for responsible deployment-standardized assays, clinically meaningful evaluation, external replication in diverse cohorts, and clear governance for privacy, consent, and model accountability.
Integrative Multiomics Analysis Identifies DKK3 as a Germline Susceptibility-Related Regulator of Risperidone Response and Metabolic Risk in Schizophrenia.
Zhang X, Li J, Sun Y … +2 more , Hei G, Song X
Hum Mutat · 2026 · PMID 42317215 · Full text
BACKGROUND: Risperidone is a widely used second-generation antipsychotic for schizophrenia, known for its clinical efficacy but also for long-term metabolic side effects, including weight gain and glucose-lipid dysregula...
BACKGROUND: Risperidone is a widely used second-generation antipsychotic for schizophrenia, known for its clinical efficacy but also for long-term metabolic side effects, including weight gain and glucose-lipid dysregulation. Although its therapeutic effects have been well characterized, the molecular basis linking its benefits and adverse metabolic outcomes remains poorly understood. METHODS: To identify genes mediating both therapeutic and metabolic responses to risperidone, we conducted an integrative multiomics study combining large-scale genetic association data with transcriptomic and epigenetic profiling. Differentially expressed genes following risperidone exposure were intersected with schizophrenia- and metabolism-associated loci using summary data-based Mendelian randomization analysis based on GWAS summary statistics and eQTL data to uncover germline variants, germline susceptibility, and potential germline alteration. DNA methylation profiling from patient-derived peripheral blood mononuclear cells (PBMCs) was used for regulatory validation. RESULTS: We identified 120 genes significantly modulated by risperidone, among which DKK3, EEF1A1, and PRKAA1 were causally associated with schizophrenia and metabolic traits through germline mutation-related regulatory evidence. Notably, DKK3 was downregulated after risperidone exposure and exhibited promoter hypermethylation, consistent with epigenetic regulation interacting with germline alteration and germline susceptibility. Functional correlation analysis revealed that lower DKK3 expression was associated with glycolipid dysregulation, supporting its role as a molecular bridge between antipsychotic action and metabolic liability. CONCLUSION: Our findings identify DKK3 as a germline mutation-related and epigenetically regulated candidate that bridges risperidone's neuropsychiatric benefits with its metabolic risks. This work offers novel insight into the shared molecular basis of antipsychotic response and side effects and suggests DKK3 as a promising biomarker for personalized treatment strategies in schizophrenia informed by germline regulatory variation and potential germline alteration.
Causal Effects and Single-Cell Microenvironmental Implications of Germline Variant-Regulated Lactylation-Related Pro-Oncogenic Genes in Colorectal Cancer.
Sheng B, Wang J
Hum Mutat · 2026 · PMID 42317214 · Full text
BACKGROUND: Colorectal cancer (CRC) is shaped by inherited genetic susceptibility, metabolic reprogramming, epigenetic regulation, and tumor microenvironment (TME) heterogeneity. Lactylation has recently emerged as an ep...
BACKGROUND: Colorectal cancer (CRC) is shaped by inherited genetic susceptibility, metabolic reprogramming, epigenetic regulation, and tumor microenvironment (TME) heterogeneity. Lactylation has recently emerged as an epigenetic mechanism that links lactate accumulation to chromatin remodeling and transcriptional regulation. However, the roles of lactylation-related genes in CRC initiation and progression, particularly from the perspective of SNP-based germline genetic variation, remain to be elucidated. METHODS: We integrated GWAS analysis and single-cell RNA sequencing to identify lactylation-related pro-oncogenic genes with potential genetic causal relevance and to further characterize their cellular localization and microenvironmental implications in CRC. GWAS uses inherited germline genetic variants, particularly SNPs associated with gene expression, as instrumental variables, thereby reducing confounding and reverse causation compared with conventional tumor expression-based analyses. RESULTS: GWAS analysis has identified germline variants in AXIN1, FASN, MLH1, and RAD50 that genetically predicted increased CRC risk. Single-cell analysis was subsequently performed to evaluate the cell-type-specific distribution and functional relevance of these GWAS-identified genes within CRC tissues. Among them, AXIN1 exhibited clearer differential expression and cell-type-specific distribution in CRC-associated cell populations. AXIN1-high cell populations were associated with metabolic adaptation, proliferative activity, lactylation-related transcriptional programs, inflammatory responses, immune regulation, extracellular matrix remodeling, and TME adaptation. Besides, FASN was also confirmed as a genetically supported risk gene implicated in CRC metabolic reprogramming. MLH1 and RAD50 were retained as candidate risk genes at the germline causal level. CONCLUSION: This study integrates germline variant-based causal inference with single-cell microenvironmental interpretation, highlighting germline variant-regulated lactylation in promoting colorectal cancer risk.
From Germline Susceptibility to Therapeutic Vulnerability: DNA Damage Response Gene Mutations Driving Multiple Myeloma Evolution and Precision Therapy.
Shen Q, Wang Y, Cai L … +1 more , Qian J
Hum Mutat · 2026 · PMID 42317213 · Full text
Multiple myeloma (MM) is characterized by genomic instability and therapeutic resistance. Emerging evidence indicates that germline DNA damage response (DDR) mutations, including BRCA1/2, ATM, and CHEK2 variants, contrib...
Multiple myeloma (MM) is characterized by genomic instability and therapeutic resistance. Emerging evidence indicates that germline DNA damage response (DDR) mutations, including BRCA1/2, ATM, and CHEK2 variants, contribute to MM susceptibility, clonal evolution, and treatment response. Inherited DDR defects promote chromosomal instability, reshape the immune microenvironment, and facilitate therapy-driven disease progression. Recent advances in multiomics profiling, single-cell sequencing, and liquid biopsy have improved the functional interpretation and clinical monitoring of DDR alterations. Moreover, DDR-associated vulnerabilities provide opportunities for precision therapies, including PARP inhibitor-based synthetic lethality strategies. This review summarizes the mechanistic and clinical significance of germline DDR alterations in MM and highlights their translational potential in precision oncology.
Functional Analyses in Patient-Derived Neurons Establish Pathogenicity for Splice Variant c.429+5G>A.
Korhorn S, Sharma A, Sprengers JJ … +7 more , Anand S, Ramautar JR, Linkenkaer-Hansen K, Bruining H, Toonen RF, Verhage M, Misra-Isrie M
Hum Mutat · 2026 · PMID 42311236 · Full text
Pathogenic variants cause a broad spectrum of neurodevelopmental disorders. We investigated a patient with developmental delay but no seizures, carrying a heterozygous, predicted splice site variant, c.429+5G>A, initial...
Pathogenic variants cause a broad spectrum of neurodevelopmental disorders. We investigated a patient with developmental delay but no seizures, carrying a heterozygous, predicted splice site variant, c.429+5G>A, initially classified as a variant of uncertain significance. Patient-derived neurons had normal morphology in vitro, but > 40% reduced MUNC18-1/ protein and mRNA levels, comparable with two established loss-of-function variants (Asp262Val and Arg235*). Nonsense-mediated decay inhibition increased transcript levels, and RT-PCR/minigene analysis demonstrated Exon 6 skipping, resulting in a frameshift and premature stop codon. Relative to a large cohort of typically developing children, EEG biomarker analysis revealed elevated long-range temporal correlations in beta and gamma bands, increased delta power, and reduced excitation/inhibition ratio in the beta band. This multimodal assessment demonstrates that c.429+5G>A is a disease-causing variant, and the value of combining functional and clinical data for accurate variant interpretation. Based on this, the patient was included in the EU registry ESCO.
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