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Volume 17
Issue 7
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Genes, Volume 17, Issue 7 (July 2026) – 119 articles

Cover Story (view full-size image): Clinical genomic testing has often yielded results of unclear significance because the abnormalities detected were located in intergenic regions, or the “dark matter” of the genome. Thus, their clinical significance has been a matter of speculation. Functional genomics can explore the clinical implications of such abnormalities more robustly—whether the abnormalities disrupt topologically associating domains (TADs), delete regulatory regions, etc. Some human genetic diseases associated with these intergenic abnormalities and characterized by functional genomics include preaxial polydactyly, Pierre Robin syndrome, and 5q14.3 microdeletion syndrome. While functional genomics is a broad research topic, this review focuses on prior and current efforts to leverage functional genomics within the intergenic regions for human health. View this paper
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15 pages, 1196 KB  
Review
Chromosome 22q11.2 Microduplication Syndrome: A Review of the Literature and 12 New Cases
by Maria Bisba, Eirini Louizou and Spiros Vittas
Genes 2026, 17(7), 844; https://doi.org/10.3390/genes17070844 - 22 Jul 2026
Viewed by 350
Abstract
Background/Objectives: 22q11.2 microduplication syndrome is a rare genetic disorder characterized by the presence of one or two additional copies of a segment within the 22q11.2 region of chromosome 22. While much of the literature has focused on the deletion variant leading to DiGeorge [...] Read more.
Background/Objectives: 22q11.2 microduplication syndrome is a rare genetic disorder characterized by the presence of one or two additional copies of a segment within the 22q11.2 region of chromosome 22. While much of the literature has focused on the deletion variant leading to DiGeorge syndrome, the duplication counterpart has gained increasing attention due to its clinical variability and under-recognition. This review aims to deliver new possibilities to genetic counseling that can be provided in prenatal and postnatal cases as the phenotype of 22q11.2 microduplication carriers cannot be fully predicted. Methods: In the present study, a total of 12 (5 prenatal and 7 postnatal) cases were diagnosed through array-CGH and combined with 679 (95 prenatal and 584 postnatal) cases reported in the literature. This review summarizes the published evidence available up to April 2025. Data on clinical presentations, genetic findings, diagnostic methodologies, and outcomes were extracted and analyzed. Results: The combination of our cases and the reported cases with 22q11.2 microduplication syndrome revealed a broad phenotypic spectrum. Common clinical features include neurodevelopmental disorders, and cardiac anomalies. Importantly, the syndrome exhibits variable expressivity and reduced penetrance, with more than 70% of the findings to be inherited by one of the parents. Conclusions: 22q11.2 microduplication syndrome presents a heterogeneous clinical picture with variable expressivity and incomplete penetrance, posing challenges in diagnosis and genetic counseling, particularly when predicting prenatal outcomes. Awareness of its diverse manifestations is crucial for clinicians to consider this syndrome in the differential diagnosis and to provide informed counseling. Full article
(This article belongs to the Special Issue Advances in Prenatal and Postnatal Genetic Testing: Precision Diagnosis for Genetic Disorders)
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26 pages, 3212 KB  
Article
Toward More Accurate Diagnosis in Neurofibromatosis Type 1: A Dual-Level Analysis of Clinical and Molecular Data with Exploratory Genotype–Phenotype Correlations in a Romanian Cohort
by Lăcrămioara Ionela Butnariu, Ecaterina Grigore, Thomas Gabriel Schreiner, Ludmila Darie, Setalia Popa and Ioana Grigore
Genes 2026, 17(7), 843; https://doi.org/10.3390/genes17070843 - 22 Jul 2026
Viewed by 407
Abstract
Background/Objectives: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in the NF1 gene, characterized by high phenotypic variability. Methods: We present clinical and molecular data from a Romanian cohort of 54 patients initially diagnosed clinically. Results: Phenotypic evaluation [...] Read more.
Background/Objectives: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in the NF1 gene, characterized by high phenotypic variability. Methods: We present clinical and molecular data from a Romanian cohort of 54 patients initially diagnosed clinically. Results: Phenotypic evaluation (n = 54) revealed a high prevalence of café-au-lait macules (100%), Lisch nodules (64.8%), axillary/inguinal freckling (61.1%), and cutaneous neurofibromas (42.6%). Due to financial constraints (genetic testing not covered by the national health system), molecular confirmation by next-generation sequencing (NGS) was possible in only 12 patients (mostly sporadic cases and young children). Genetic testing identified a diverse spectrum of variants, including frameshift (41.7%, n = 5), nonsense (33.3%, n = 4), missense (16.7%, n = 2), and one splicing deletion (8.3%, n = 1). A novel complex NF1 frameshift variant, c.7504_7508delinsC (p.Ser2502Argfs*24) in exon 54, was identified in a patient exhibiting an aggressive phenotype characterized by plexiform neurofibromas, a malignant peripheral nerve sheath tumor (MPNST), and severe skeletal abnormalities. Additionally, a recurrent nonsense variant, NF1 c.910C>T (p.Arg304*), was detected in two unrelated individuals. Conclusions: The high proportion of sporadic cases (58.3%) in the molecularly tested subgroup underscores the critical role of early genetic screening. By integrating clinical data from 54 patients with the first molecular characterization of NF1 in Romania, this study expands the mutational spectrum and provides preliminary, descriptive insights into genotype–phenotype correlations. It also proposes a cost-effective diagnostic algorithm adapted for resource limited settings and lays the groundwork for future multicenter initiatives. Given the exploratory nature of the molecular subgroup (n = 12), all genotype–phenotype observations require validation in larger independent cohorts. Full article
(This article belongs to the Section Genetic Diagnosis)
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15 pages, 3972 KB  
Article
Comparative Assessment of Automated and Manual DNA Extraction Methods for the Genetic Analysis of Degraded Bone Samples
by Christina Amory and Walther Parson
Genes 2026, 17(7), 842; https://doi.org/10.3390/genes17070842 - 22 Jul 2026
Viewed by 1072
Abstract
Background: Efficient DNA extraction from degraded skeletal remains is essential for forensic and ancient DNA analysis. The main aim of this study was to compare the performance of an automated DNA extraction system with a manual DNA extraction protocol when applied to challenging [...] Read more.
Background: Efficient DNA extraction from degraded skeletal remains is essential for forensic and ancient DNA analysis. The main aim of this study was to compare the performance of an automated DNA extraction system with a manual DNA extraction protocol when applied to challenging skeletal samples. Specifically, the automated Maxwell Forensic Sample Concentrator system was evaluated against a modified manual Dabney extraction protocol. Methods: DNA was extracted from skeletal material originating from twelve human individuals. Maxwell extractions using 50 mg and/or 100 mg of starting material were compared with Dabney extractions using 50 mg. DNA extracts were quantified using SD quants targeting nuclear DNA and two mitochondrial DNA fragments. Selected extracts were further analysed by mitochondrial DNA sequencing. Results: Both extraction approaches generated comparable DNA yields and sequencing results for moderately degraded samples. In the highly degraded samples analysed in this study, the Dabney protocol generally yielded higher nuclear and mitochondrial DNA quantities and was often associated with a higher sequencing performance. The Maxwell system nevertheless performed well for less degraded material and, in some cases, produced sequencing results comparable to Dabney. Maxwell extraction with 100 mg input was effective for better-preserved samples but was less consistent for highly degraded material. Conclusions: The efficiency of the extraction methods depended largely on the degree of DNA degradation. The findings of this study suggest that the Dabney protocol may be more suitable for heavily degraded skeletal remains, whereas the automated Maxwell system represents a practical and efficient option for less degraded samples. The choice of method therefore depends on the sample condition and the analytical objectives. Full article
(This article belongs to the Special Issue Molecular Mechanisms and Applications of Forensic Genetics)
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23 pages, 31801 KB  
Article
Macrophage-Centered Integration of Single-Cell and Bulk Transcriptomic Data Identifies CCL3, CCL4, and JUNB as Inflammatory Regulatory Signatures in Ulcerative Colitis
by Haoyang Meng, Yongliang Chen, Yongchun Chai, Sike Yu, Peiyao Ma, Ruibin Lei, Shuhan Zhou and Wenliang Lv
Genes 2026, 17(7), 841; https://doi.org/10.3390/genes17070841 - 22 Jul 2026
Viewed by 382
Abstract
Objectives: This study aimed to identify and characterize macrophage-associated inflammatory regulatory signatures in ulcerative colitis (UC) by integrating bulk and single-cell transcriptomic data, and to explore their potential regulatory and pharmacological relevance. Methods: Two colonic bulk microarray datasets (GSE179285 and GSE87466) and one [...] Read more.
Objectives: This study aimed to identify and characterize macrophage-associated inflammatory regulatory signatures in ulcerative colitis (UC) by integrating bulk and single-cell transcriptomic data, and to explore their potential regulatory and pharmacological relevance. Methods: Two colonic bulk microarray datasets (GSE179285 and GSE87466) and one single-cell RNA-sequencing dataset (GSE231993) were analyzed. Differential expression analysis, area under the recovery curve-based single-cell gene-set scoring (AUCell) scoring, macrophage high-dimensional Weighted Gene Co-Expression Network Analysis (hdWGCNA), and three machine learning algorithms were combined to prioritize candidate genes. Their expression and diagnostic performance were externally validated. Macrophage trajectory analysis, cell–cell communication analysis, virtual perturbation, transcription factor activity inference, compound prediction, and molecular docking were further performed. Results: Single-cell preprocessing retained 30,737 high-quality cells, and macrophages exhibited relatively high innate immune cell barrier-related gene activity. Integrated screening identified CCL3, CCL4, JUNB, and FOS, whereas machine learning consensus retained CCL3, CCL4, and JUNB as the final signatures. These genes were consistently upregulated in UC, with validation area-under-the-curve values of 0.917, 0.958, and 0.888, respectively. Their expression varied along an inferred macrophage inflammatory state continuum, and UC showed remodeled macrophage-centered communication, including CXCL8–ACKR1 signaling. Virtual perturbation linked CCL3 and CCL4 to chemotaxis and lysosomal programs and JUNB to antigen processing and major histocompatibility complex (MHC) class II pathways; RFX5 was prioritized as a potential upstream regulator. CID11879209 was predicted as a shared candidate compound, with docking energies of −6.55, −6.31, and −4.50 kcal/mol for CCL3, CCL4, and JUNB, respectively. Conclusions: CCL3, CCL4, and JUNB constitute a macrophage-associated inflammatory signature connecting tissue-level UC dysregulation with macrophage state remodeling. These findings provide testable molecular and pharmacological hypotheses requiring further experimental and clinical validation. Full article
(This article belongs to the Section Bioinformatics)
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15 pages, 1848 KB  
Article
Multi-Omics Integration Improves Polygenic Risk Prediction for Lipid Traits: A Multi-Ancestry Study in UK Biobank
by Nayang Shan, Yafang Qiu, Lin Hou and Zuoheng Wang
Genes 2026, 17(7), 840; https://doi.org/10.3390/genes17070840 - 22 Jul 2026
Viewed by 339
Abstract
Background: Polygenic risk scores (PRS) have proven valuable for disease risk prediction, but their predictive utility often remains limited because human traits result from complex interactions between environmental and genetic factors. Blood lipid levels are heritable and clinically important risk factors for [...] Read more.
Background: Polygenic risk scores (PRS) have proven valuable for disease risk prediction, but their predictive utility often remains limited because human traits result from complex interactions between environmental and genetic factors. Blood lipid levels are heritable and clinically important risk factors for cardiovascular disease, yet it remains unclear whether multi-omics integration can enhance lipid trait prediction beyond PRS alone. Methods: We first constructed single-omics scores, where gene expression, plasma protein, and plasma/serum metabolite levels were genetically predicted and weighted by effect sizes estimated via LASSO regression. Subsequently, we implemented two integration strategies to develop composite multi-omics risk scores (MoRS): step-MoRS, which integrates single-omics scores using stepwise regression, and Lasso-MoRS, which directly models all predicted features across omics layers using LASSO regression. Both approaches were evaluated across European, South Asian, and African ancestries within the UK Biobank. Results: MoRS-based methods consistently demonstrated superior predictive accuracy compared to PRS alone for four lipid traits across diverse populations. Notably, Lasso-MoRS prioritized key biomarkers with predictive utility complementary to genomic data. Conclusions: These findings confirm that integrating multi-omics biomarkers with genomic data significantly enhances lipid trait prediction across diverse ancestries, offering biological insights into the molecular regulation of lipid metabolism. Full article
(This article belongs to the Special Issue Application of Bioinformatics in Complex Traits)
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13 pages, 251 KB  
Article
Report of Multilocus Inherited Neoplasia Alleles Syndrome in a Chilean Oncology Institute: New Combinations and Genetic Landscape
by Francisca Sepúlveda Bustos, Fernanda Martin Merlez, Danitza Campos Jadrijevic, María Paz Saavedra and Carolina Selman Bravo
Genes 2026, 17(7), 839; https://doi.org/10.3390/genes17070839 - 22 Jul 2026
Viewed by 314
Abstract
Background/Objectives: Multilocus Inherited Neoplasia Alleles Syndrome (MINAS) is defined by the presence of germline pathogenic or likely pathogenic variants in two or more distinct cancer susceptibility genes (CSGs) in the same individual. Although carriers may present more complex phenotypes, the clinical and [...] Read more.
Background/Objectives: Multilocus Inherited Neoplasia Alleles Syndrome (MINAS) is defined by the presence of germline pathogenic or likely pathogenic variants in two or more distinct cancer susceptibility genes (CSGs) in the same individual. Although carriers may present more complex phenotypes, the clinical and molecular spectrum of MINAS remains poorly characterized, particularly in underrepresented populations. We aim to describe this phenomenon in a cohort of individuals from a Chilean institution. Methods: We retrospectively reviewed individuals evaluated at the Oncogenetic Counseling Unit of Fundación Arturo López Pérez (FALP) between 2020 and 2026 who underwent hereditary cancer multi-gene panel testing. Cases fulfilling MINAS criteria were described. We analyzed the association between MINAS and age at cancer diagnosis or multiple primary cancers, and reviewed reported cases with the same gene combinations. Results: From 1962 individuals tested, 398 harbored a pathogenic or likely pathogenic variant, and 14 fulfilled MINAS criteria, yielding a prevalence of 3.51% among positive cases. Breast cancer was the most common tumor type (76.9%), and ATM and CDKN2A were the most frequently involved genes. MINAS was significantly associated with a younger age at cancer diagnosis, but not with multiple primary cancers. Conclusions: MINAS prevalence in our cohort and the association with a younger diagnosis of cancer was consistent with published series. We identified seven previously unreported gene combinations, and common founder variants shifted the pattern away from predominantly BRCA-associated combinations. Despite the small sample size, this study adds relevant data from an underrepresented Latin American population. Full article
(This article belongs to the Section Genetic Diagnosis)
18 pages, 4169 KB  
Article
Prime Editing-Based Functional Characterization Supports a Likely Pathogenic Interpretation of NF1 c.6394T>C (p.Ser2132Pro)
by Jiayu Wu, Guangyu Li, Song Liu, Chenyu Ma and Xiaoyue Wang
Genes 2026, 17(7), 838; https://doi.org/10.3390/genes17070838 - 21 Jul 2026
Viewed by 378
Abstract
Background/Objectives: NF1 encodes neurofibromin, a RAS-GTPase-activating protein (GAP), and heterozygous loss-of-function variants cause neurofibromatosis type 1. Missense variants outside the GAP-related domain (GRD) are difficult to classify because supporting functional evidence is limited. NF1 c.6394T>C (p.Ser2132Pro) is currently listed in ClinVar as [...] Read more.
Background/Objectives: NF1 encodes neurofibromin, a RAS-GTPase-activating protein (GAP), and heterozygous loss-of-function variants cause neurofibromatosis type 1. Missense variants outside the GAP-related domain (GRD) are difficult to classify because supporting functional evidence is limited. NF1 c.6394T>C (p.Ser2132Pro) is currently listed in ClinVar as a variant of uncertain significance. We examined its functional consequences and evaluated whether the resulting evidence supports a likely pathogenic interpretation under the ACMG/AMP framework. Methods: We evaluated p.Ser2132Pro using population databases, evolutionary conservation, calibrated in silico predictors, and structural mapping onto the full-length cryo-EM model of neurofibromin. The variant was then introduced at the endogenous NF1 locus in HEK293T and A375 cells by prime editing, and we measured neurofibromin abundance, transcript levels, RAS-GTP dynamics, and MAPK pathway reactivation after PLX4032 treatment. Evidence was integrated under the ACMG/AMP framework. Results: p.Ser2132Pro was absent from population databases, affected a highly conserved residue buried within the C-terminal HEAT domain, and received concordant deleterious predictions from calibrated in silico tools. At the endogenous locus, p.Ser2132Pro reduced neurofibromin abundance by 88–95% in both cell models while NF1 transcript levels were only modestly reduced, impaired RAS-GTP signal termination, doubled steady-state RAS-GTP in A375 cells, and produced 5-fold higher ERK phosphorylation than the non-targeting control under PLX4032 treatment. Conclusions: These findings support a cellular loss-of-function effect of p.Ser2132Pro characterized primarily by reduced neurofibromin abundance with impaired neurofibromin-dependent RAS regulation. Under a conservative ACMG/AMP interpretation, the combined evidence supports a Likely Pathogenic interpretation of NF1 c.6394T>C (p.Ser2132Pro). Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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20 pages, 24585 KB  
Article
Transcriptome Dynamics of Terminal Buds During Flower Bud Morphogenesis in Blueberry
by Xingyu Lu, Dongyu Sun, Yinyan Yang, Yalan Liu, Qin Yang and Biyan Zhou
Genes 2026, 17(7), 837; https://doi.org/10.3390/genes17070837 - 21 Jul 2026
Viewed by 273
Abstract
Background/Objectives: Flower bud morphogenesis is a critical developmental phase during which blueberry transitions from vegetative to reproductive growth, yet the transcriptome dynamics and regulatory networks within buds during this process have not been systematically characterized. Methods: Terminal buds of the rabbiteye [...] Read more.
Background/Objectives: Flower bud morphogenesis is a critical developmental phase during which blueberry transitions from vegetative to reproductive growth, yet the transcriptome dynamics and regulatory networks within buds during this process have not been systematically characterized. Methods: Terminal buds of the rabbiteye blueberry ‘Brightwell’ were sampled at six time points spanning from summer shoot cessation to bud swelling and dormancy entry. RNA sequencing, trend clustering, and Pearson correlation network analyses were performed to identify potentially important genes and regulatory relationships. Results: A total of 26,302 differentially expressed genes were identified, with a major transcriptomic shift at week 15. From four major expression trends, 1050 candidate genes were selected, including 176 flowering-related genes, 770 transcription factors, and 277 hormone-related genes. Photoperiod and vernalization pathway genes (COLs, VRN1, etc.) were predominantly down-regulated, whereas age pathway genes (SPLs) and MADS-box flower development genes (FULs, AP3, PI, and SEP2, etc.) were up-regulated. The floral integrators FT and SOC1 exhibited opposite expression dynamics: SOC1 was highly expressed during the early-to-mid stage, whereas FT peaked at the late stage, with the two showing opposing co-expression and correlation patterns. This suggests stage-specific divergence between the two integrators in coordinating flower bud differentiation and dormancy entry. Multiple hormone pathways (IAA, BR, JA, and SA, etc.) converged independently onto floral regulatory hubs through their biosynthesis/metabolism and signal transduction genes, with numerous transcription factors also involved. Conclusions: These findings provide a comprehensive view of bud transcriptome dynamics and propose a molecular regulatory framework integrating flowering signals, hormones, and transcriptional cascades, offering a theoretical foundation and gene resources for blueberry breeding. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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14 pages, 13995 KB  
Article
Diabetic Hyperglycemia Induces Region-Specific Transcriptomic Remodeling in the Cochlea
by Ting-Yu Chang, Cheng-Tien Wu, Fong-Ling Chung, Shing-Hwa Liu and Ting-Hua Yang
Genes 2026, 17(7), 836; https://doi.org/10.3390/genes17070836 - 21 Jul 2026
Viewed by 268
Abstract
Background/Objectives: Diabetes mellitus is associated with sensorineural hearing loss, but the cochlear molecular alterations related to this complication remain unclear. This pilot study aimed to characterize auditory function and region-specific transcriptomic changes in the diabetic cochlea. Methods: A streptozotocin-induced type 1 diabetic mouse [...] Read more.
Background/Objectives: Diabetes mellitus is associated with sensorineural hearing loss, but the cochlear molecular alterations related to this complication remain unclear. This pilot study aimed to characterize auditory function and region-specific transcriptomic changes in the diabetic cochlea. Methods: A streptozotocin-induced type 1 diabetic mouse model was established. Auditory function was assessed by auditory brainstem response (ABR) testing. Next-generation RNA sequencing was performed on micro-dissected cochlear regions, including the modiolus, lateral wall, and organ of Corti, followed by differential expression and gene ontology analyses. Results: STZ-induced diabetic mice showed elevated ABR thresholds compared with control mice. RNA sequencing revealed region-specific transcriptomic alterations across cochlear regions, with the lateral wall showing the greatest changes. Cross-region analysis identified a shared transcriptional signature consisting of 32 upregulated and 2 downregulated genes across the modiolus, lateral wall, and organ of Corti. Gene Ontology analysis showed enrichment of immune-related, inflammatory, metabolic stress-associated, and membrane-associated signaling. Conclusions: STZ-induced diabetes was associated with ABR threshold elevation and shared as well as region-specific cochlear transcriptomic alterations in this mouse model. These findings provide a region-specific cochlear transcriptomic resource for diabetes-associated auditory dysfunction and support future studies using larger cohorts, independent molecular validation, histological assessment, and cell-type-resolved approaches. Full article
(This article belongs to the Section RNA)
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20 pages, 3470 KB  
Article
Phenotypic Changes and Physiological Genetic Responses of Oryza sativa L. Roots Under Stress of Nanoplastics (NPs) and Cadmium (Cd) in Single and Combination Forms
by Haitao Liu, Hui Wang, Ling Liu, Ying Li, Chaoyu Lv, Yanhao Liu, Jingwen Gong and Lingling Liu
Genes 2026, 17(7), 835; https://doi.org/10.3390/genes17070835 - 21 Jul 2026
Viewed by 305
Abstract
Background/Objectives: Both NPs and Cd alone exert adverse effects on plant growth by disrupting physiological processes and gene expression. However, the mechanisms underlying their combined effects on plant genetic responses remain incompletely understood. Methods: The rice seedlings were used as the [...] Read more.
Background/Objectives: Both NPs and Cd alone exert adverse effects on plant growth by disrupting physiological processes and gene expression. However, the mechanisms underlying their combined effects on plant genetic responses remain incompletely understood. Methods: The rice seedlings were used as the experimental material, with the following six treatments established: CK (Control, no NPs and Cd), 10 and 100 mg·L−1 NPs, and 0.5 mg·L−1 Cd alone and combination. Seedlings at the three-leaf stage were treated in hydroponic culture for 7 days, after which root-development parameters, root viability, MDA and soluble sugar contents, and SOD and POD activities were measured, along with transcriptomic analysis. Results: The results show that root length, number of root tips, and root surface area were highest in CK compared with all NPs and Cd treatments, particularly. Significant differences were observed between the CK and both the high-concentration NPs and all Cd treatments groups (p < 0.05). Root growth progressively declined with increasing NP concentrations; the combination of 100 mg·L−1 NPs and 0.5 mg·L−1 Cd exhibited synergistic toxicity, which decreased root length, number of root tips, and root surface area by 14%, 22%, and 4% compared with 0.5 Cd, whereas 10 mg·L−1 NPs significantly alleviated Cd-induced root damage for the three root parameters above in the following order: 0.5 Cd < 0.5 Cd-10 NPs < 10 NPs. In terms of physiological changes, 10 mg·L−1 NPs reduced MDA levels and enhanced SOD and POD activities in roots exposed to Cd; in contrast, 100 mg·L−1 NPs exacerbated Cd-induced membrane peroxidation and decreased SOD and POD activities. In the high-concentration NPs and all Cd-treated groups, all aforementioned indicators exhibited significant differences compared with the CK (p < 0.05). Transcriptomic and WGCNA analyses revealed that the expression levels of OsGRP162 (regulating resistance) and OsCYP2 (inhibiting lateral root formation under overexpression) were significantly higher in 0.5 Cd-100 NPs compared with the other five treatments, while OsTubA2 (positively regulating root length) exhibited a different pattern. Differentially expressed genes (DEGs) in experimental groups of 10 NPS_vs_0.5 Cd-10 NPS and 100 NPS_vs_0.5 Cd-100 NPS were predominantly enriched in glutathione metabolism and the MAPK signaling pathway, respectively. The key genes OsMT4C, OsMT4B and OsYSL2 (associated with transmembrane signal transduction), and OsABCB5 and OsCUL1-3 (involved in negative regulation of root elongation) exhibited reduced expression levels in 0.5 Cd-10 NPs, whereas OsYDA2 and OsAGO1c (related to antioxidant defense) showed upregulated expression. Conversely, the opposite gene expression patterns were observed in 0.5 Cd-100 NPs. Conclusions: These findings demonstrate that both NPs and Cd adversely affect rice seedlings; however, low concentrations of NPs mitigate Cd toxicity, while high concentrations exacerbate it. Therefore, to prevent elevated NP concentrations in plant growth environments, plastic usage and processing should be standardized. Full article
(This article belongs to the Section Genes & Environments)
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15 pages, 1129 KB  
Review
Genetic Determinants of Autoimmune Myocarditis: From Candidate Genes to GWAS Insights
by Humza Pirzadah, Zainab Ibrahim, Yaseen Pirzadah and Nabiha Yusuf
Genes 2026, 17(7), 834; https://doi.org/10.3390/genes17070834 - 21 Jul 2026
Viewed by 422
Abstract
Autoimmune myocarditis is an inflammatory disease of the myocardium driven by immune dysregulation and genetic predisposition. Recent advances in genomics, including genome-wide association studies (GWAS), have revealed key loci and pathways involved in disease susceptibility. This review synthesizes current knowledge on genetic determinants, [...] Read more.
Autoimmune myocarditis is an inflammatory disease of the myocardium driven by immune dysregulation and genetic predisposition. Recent advances in genomics, including genome-wide association studies (GWAS), have revealed key loci and pathways involved in disease susceptibility. This review synthesizes current knowledge on genetic determinants, from classical candidate genes to emerging GWAS findings, and explores their clinical implications for risk stratification and precision medicine. Full article
(This article belongs to the Special Issue Genetic Aspects of Autoimmune Diseases)
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14 pages, 2697 KB  
Article
An Interpretable Four-Gene Cell-Cycle Signature Links Malignant Progression to Adverse Survival in Adult Primary Diffuse Glioma: A CGGA Transcriptome Study
by Hongkai Jia, Nan Pu and Chunyan Tian
Genes 2026, 17(7), 833; https://doi.org/10.3390/genes17070833 - 21 Jul 2026
Viewed by 281
Abstract
Background: Adult diffuse gliomas are biologically heterogeneous and clinically lethal. We evaluated whether a compact transcriptomic program could summarize malignant progression and adverse survival. Methods: We analyzed adult primary WHO grades II–IV gliomas from the CGGA mRNAseq_693 cohort and used CGGA mRNAseq_325 as [...] Read more.
Background: Adult diffuse gliomas are biologically heterogeneous and clinically lethal. We evaluated whether a compact transcriptomic program could summarize malignant progression and adverse survival. Methods: We analyzed adult primary WHO grades II–IV gliomas from the CGGA mRNAseq_693 cohort and used CGGA mRNAseq_325 as an independent validation cohort. CDK1, CCNB2, CDCA3, and PTTG1 were prioritized through a transparent, literature-informed mitotic-gene framework. Four classifiers were evaluated by five-fold cross-validation repeated 20 times, with all preprocessing restricted to each training fold. A training-defined four-gene score was assessed by Kaplan–Meier and Cox models. Results: The primary cohort contained 415 tumors, including 396 with evaluable survival. We identified 773 differentially expressed genes between WHO grade IV and WHO grades II/III tumors, and all four candidate genes increased monotonically with grade. In repeated cross-validation, the SVM achieved the highest mean AUROC of 0.793 ± 0.048 (95% CI 0.784–0.802), with average precision of 0.701 ± 0.063. In the independent CGGA mRNAseq_325 cohort (n = 226), logistic regression achieved an AUROC of 0.792. The four-gene score and a broader four-marker proliferation index showed similar discrimination, supporting the interpretation of the signature as a compact proliferation-axis proxy. The training-set median cut-off was −0.153. The score remained associated with shorter survival after adjustment for age, grade, and IDH status in the primary cohort (n = 359; HR = 1.28, 95% CI 1.10–1.49; p = 0.002) and in the independent cohort (n = 217; HR = 1.58, 95% CI 1.25–2.00; p < 0.001). Conclusions: The four-gene score captures grade-associated proliferative biology and reproducible survival risk across two CGGA cohorts. It is a research biomarker rather than a standalone diagnostic or clinical decision tool. Full article
(This article belongs to the Section Bioinformatics)
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25 pages, 1046 KB  
Systematic Review
Genetic and Epigenetic Mechanisms Underlying Phenotypic Discordance in Monochorionic Monozygotic Twins: A Systematic Review
by Dario Colacurci, Giuseppe Maria Maruotti, Gabriele Saccone, Anna Maria D’Agostino, Maria Virginia De Santis, Mariagrazia Riccardi, Mirko Martirani, Maurizio Guida and Laura Sarno
Genes 2026, 17(7), 832; https://doi.org/10.3390/genes17070832 - 21 Jul 2026
Viewed by 433
Abstract
Background: Monochorionic twin pregnancies provide a unique model to investigate fetal phenotypic discordance, because both fetuses share a single placenta and interconnected vascular circulation. Although most monochorionic twins are monozygotic, clinically relevant differences may arise through genetic, epigenetic, placental, and stochastic developmental mechanisms. [...] Read more.
Background: Monochorionic twin pregnancies provide a unique model to investigate fetal phenotypic discordance, because both fetuses share a single placenta and interconnected vascular circulation. Although most monochorionic twins are monozygotic, clinically relevant differences may arise through genetic, epigenetic, placental, and stochastic developmental mechanisms. Methods: This systematic review was conducted according to PRISMA 2020 and registered in PROSPERO (CRD420261432361). PubMed/MEDLINE, Embase, and Scopus were searched from inception to June 2026. Eligible studies included monochorionic monozygotic twin pairs with discordant congenital, developmental, or syndromic phenotypes, confirmed or clearly inferable monochorionicity, and at least one genomic, cytogenetic, or epigenetic investigation; studies describing confirmed monochorionic dizygotic twinning were excluded. Findings were synthesized qualitatively. Results: The search identified 1357 records. After duplicate removal and screening, 48 studies fulfilled the eligibility criteria, comprising 441 monozygotic twin pairs; 37 were single-pair case reports, whereas one large retrospective cohort study alone contributed 193 pairs (44% of the entire pooled sample). Reported phenotypes included congenital heart disease, chromosomal abnormalities, disorders of sex development, imprinting disorders, neurodevelopmental disease, endocrine disorders, renal anomalies, skeletal disorders, and multisystem malformations. Molecular methods included karyotyping, FISH, chromosomal microarray, array-CGH, CNV analysis, WES, WGS, targeted sequencing, and methylation profiling. Proposed mechanisms included postzygotic chromosomal errors, somatic mutations, tissue-specific mosaicism, discordant or shared CNVs, differential methylation, imprinting defects, variable expressivity, blood chimerism, unequal placental sharing, TTTS, TAPS, sFGR, and uteroplacental insufficiency. Conclusions: Phenotypic discordance in monochorionic twins is rarely explained by a single mechanism. Available evidence supports a multifactorial model in which postzygotic genetic events, epigenetic regulation, placental vascular factors, and stochastic developmental processes interact. Full article
(This article belongs to the Special Issue Fetal Genetic Disorders: Diagnosis and Therapy)
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19 pages, 22264 KB  
Article
Single-Cell Profiling Identifies a CCR2+ Neutrophil-like Population Associated with Colorectal Cancer Liver Metastasis in a Murine Model
by Zi-Jun Yan, Yuan-Jie Yin, Yu-Ting Wang, Xian-Qi Zhang, Xiong-Hui Wang, Xi Chen, Cai-Ning Zhao and Rong Liu
Genes 2026, 17(7), 831; https://doi.org/10.3390/genes17070831 - 21 Jul 2026
Viewed by 434
Abstract
Background/Objectives: Colorectal liver metastases (CRLMs) are a major contributor to recurrence and mortality in colorectal cancer (CRC), with approximately a quarter of patients developing liver metastases over the course of the disease. Bone-marrow-derived myeloid lineages are sent into the circulatory system and colonize [...] Read more.
Background/Objectives: Colorectal liver metastases (CRLMs) are a major contributor to recurrence and mortality in colorectal cancer (CRC), with approximately a quarter of patients developing liver metastases over the course of the disease. Bone-marrow-derived myeloid lineages are sent into the circulatory system and colonize pre-metastatic niches, yet the transcriptional programs by which they establish a pro-metastatic microenvironment remain incompletely defined. Methods: Using an MC38 splenic-injection CRLM mouse model, we generated single-cell RNA sequencing (scRNA-seq) profiles of FACS-sorted CD11b+Gr1+ bone marrow myeloid cells, together with bulk RNA sequencing profiles of bone marrow and peripheral blood. Downstream analyses were performed in silico, including clustering and annotation, trajectory inference, cell–cell communication analysis, weighted gene co-expression network analysis (WGCNA), and pathway enrichment, with subset specificity examined against a public dataset of E. coli (Escherichia coli)-infected mice. Results: Within the CD11b+Gr1+ compartment, a CCR2+ neutrophil-like population (Ly6g+S100a8/9+) emerging during terminal differentiation was identified, which was enriched in CRLM mice but nearly absent in controls. Communication inference revealed an FN1-CD44 interaction involving mature neutrophils, which was associated with an epithelial–mesenchymal transition signature and upregulation of Tgfb1 and Il1b. This subpopulation was not recovered in the infection dataset, suggesting relative specificity to CRLMs. Conclusions: Within the constraints of a splenectomized hepatic colonization model, integrated transcriptomic analysis highlighted a CCR2+ bone marrow neutrophil-like population as a candidate contributor to CRLM, challenging the view that CCR2+ pro-metastatic myeloid cells are exclusively monocytic and suggesting candidate biomarkers and therapeutic targets for further study. Full article
(This article belongs to the Section Bioinformatics)
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26 pages, 14429 KB  
Article
Integrated Bioinformatics and Machine Learning Analysis Identifies Inflammation-Related Biomarkers and Immune Infiltration Patterns in Atherosclerosis
by Le Zhang and Yu Liu
Genes 2026, 17(7), 830; https://doi.org/10.3390/genes17070830 - 21 Jul 2026
Viewed by 304
Abstract
Background: Atherosclerosis (AS) is a chronic inflammatory vascular disease lacking reliable biomarkers for early diagnosis and risk stratification. This study aimed to identify hub genes with diagnostic potential and characterize immune microenvironment remodeling in AS. Methods: GSE43292 and GSE100927 were integrated as the [...] Read more.
Background: Atherosclerosis (AS) is a chronic inflammatory vascular disease lacking reliable biomarkers for early diagnosis and risk stratification. This study aimed to identify hub genes with diagnostic potential and characterize immune microenvironment remodeling in AS. Methods: GSE43292 and GSE100927 were integrated as the training cohort (n = 168), while GSE41571, GSE120521, and GSE28829 served as independent validation cohorts (n = 48). Batch effects were corrected using the ComBat algorithm. Differentially expressed genes (DEGs) were identified using limma, followed by GO/KEGG enrichment analysis. LASSO regression and Random Forest analysis were performed to identify hub genes. A logistic regression diagnostic model was constructed and evaluated using ROC analysis, 5-fold cross-validation, and external validation. Immune infiltration was assessed using ssGSEA, and correlations between hub genes and immune cells were analyzed using Spearman correlation. Results: A total of 1349 DEGs (870 upregulated and 479 downregulated) were identified. GO and KEGG analyses demonstrated significant enrichment of immune- and inflammation-related biological processes and pathways. Seven hub genes (IBSP, XAF1, SCAMP5, SAMD9L, MYBL1, PCDH12, and CDH19) were identified through the combined application of LASSO regression and Random Forest analysis. The 7-gene logistic model achieved excellent performance in the training cohort (AUC = 0.992, 95% CI: 0.981–1.000), with a mean 5-fold cross-validation AUC of 0.984 ± 0.014, and maintained robust performance in three independent validation cohorts (AUC range: 0.952–1.000). Immune infiltration analysis revealed extensive immune microenvironment remodeling, with significantly increased infiltration of 22 of the 24 immune cell types, particularly monocytes, macrophages, and myeloid cells. Spearman correlation analysis demonstrated strong associations between hub genes, particularly SAMD9L and IBSP, and immune cell infiltration. Conclusions: This study identified a robust 7-gene diagnostic signature for AS and revealed its close association with the inflammatory immune microenvironment, providing potential biomarkers for early diagnosis and risk stratification. Full article
(This article belongs to the Section Bioinformatics)
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14 pages, 4645 KB  
Article
Novel and Known DHX37 Variants in 46,XY DSD: Expanding the Genotypic and Phenotypic Spectrum
by Xiaocha Xu, Xiaocheng Wu, Shuai Chen, Haixia Miao, Kexin Fang, Dingwen Wu, Yi Zhang and Xin Yang
Genes 2026, 17(7), 829; https://doi.org/10.3390/genes17070829 - 21 Jul 2026
Viewed by 298
Abstract
Objective: To investigate the clinical characteristics, inheritance patterns, and genotype–phenotype correlations of DHX37 variants in 46,XY disorders of sex development (DSD). Methods: We retrospectively reviewed 108 patients with 46,XY karyotype who underwent DSD evaluation and trio-based whole-exome sequencing (trio-WES) at our center between [...] Read more.
Objective: To investigate the clinical characteristics, inheritance patterns, and genotype–phenotype correlations of DHX37 variants in 46,XY disorders of sex development (DSD). Methods: We retrospectively reviewed 108 patients with 46,XY karyotype who underwent DSD evaluation and trio-based whole-exome sequencing (trio-WES) at our center between January 2021 and December 2025. Six probands with DHX37 variants and no concurrent pathogenic or likely pathogenic variants in other known DSD-associated genes were analyzed in detail. Clinical presentations, endocrine profiles, imaging findings, and pedigree data were collected. Variant segregation was confirmed by Sanger sequencing; variants were assessed using in silico prediction, conservation analysis, and structural modeling, and were classified according to ACMG/AMP guidelines. Results: The six probands exhibited marked phenotypic heterogeneity, with manifestations ranging from complete gonadal dysgenesis to mild testicular underdevelopment with gynecomastia. Six heterozygous DHX37 missense variants were identified across distinct functional domains: one in RecA1 [c.1000C>T (p.Arg334Trp)], four in RecA2 [c.1379T>C (p.Val460Ala), c.1432G>A (p.Gly478Arg), c.1730A>G (p.Asp577Gly), and c.1954G>A (p.Val652Ile)], and one in the linker region proximal to the HA2 domain [c.2180C>T (p.Thr727Met)]. Of these, p.Arg334Trp is an established pathogenic variant; p.Gly478Arg has been reported previously, albeit in the same patient included in the present study; and the remaining four were novel. According to ACMG/AMP guidelines, p.Arg334Trp was classified as pathogenic, and the remaining five as variants of uncertain significance. Conclusions: This study provides additional case evidence supporting the pathogenicity of p.Arg334Trp and expands the DHX37 variant spectrum. Computational and structural analyses suggest that p.Gly478Arg may underlie the testicular regression syndrome phenotype of the corresponding proband and that the four novel variants may be involved in testicular development. However, these genotype–phenotype correlations remain speculative; larger cohorts and in vitro functional assays are warranted to confirm these associations. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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20 pages, 7231 KB  
Article
Identification of Potential Biomarkers for Rheumatoid Arthritis Based on Integrated Bioinformatics and Single-Cell RNA-Seq
by Jinling Zhang and Ke Han
Genes 2026, 17(7), 828; https://doi.org/10.3390/genes17070828 - 21 Jul 2026
Viewed by 394
Abstract
Background/objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint damage and systemic complications. Despite multiple treatment options, many patients fail to achieve sustained remission. Our study aimed to integrate bioinformatics and single-cell RNA-seq analyses to identify potential biomarkers and [...] Read more.
Background/objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes progressive joint damage and systemic complications. Despite multiple treatment options, many patients fail to achieve sustained remission. Our study aimed to integrate bioinformatics and single-cell RNA-seq analyses to identify potential biomarkers and therapeutic targets and explore bioactive compounds from traditional Chinese medicine (TCM). Methods: We integrated gene expression quantitative trait loci (eQTL), protein quantitative trait loci (pQTL), and genome-wide association study (GWAS) data for RA using two-sample Mendelian randomization to identify causal druggable genes. Bulk transcriptomics and machine learning were used for candidate gene screening and validation, while single-cell RNA-seq analysis characterized cell type-specific expression and functional relevance. TCM compound screening, molecular docking, and molecular dynamics (MD) simulations were subsequently performed. Results: CXCL6, IFNG, and SLAMF1 were identified as RA-associated candidate targets with distinct cell type-specific expression patterns, strong immune associations, and favorable diagnostic performance. Functional analyses linked these genes to immune activation and intercellular communication. In silico analyses prioritized sesamin, (+)-Ganoderic acid Mf, and (24R)-saringosterol as candidate compounds, with the IFNG–(+)-Ganoderic acid Mf complex showing stable behavior during MD simulation. Conclusions: This integrative framework identified CXCL6, IFNG, and SLAMF1 as candidate biomarkers and druggable targets for RA. Sesamin, (+)-Ganoderic acid Mf, and (24R)-saringosterol warrant further experimental evaluation. These findings provide a basis for future mechanistic and translational studies. Full article
(This article belongs to the Section Bioinformatics)
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14 pages, 2102 KB  
Article
Coordinated Transcriptional Repression of CAV1 and CAV2 in Thoracic Aortic Aneurysm: A microRNA Regulatory Network Analysis
by Dimitrios E. Magouliotis, Serge Sicouri, Vasiliki Androutsopoulou, Massimo Baudo, Thanos Athanasiou, Dimitrios V. Avgerinos, John Skoularigis, Grigorios Giamouzis, Basel Ramlawi and Andrew Xanthopoulos
Genes 2026, 17(7), 827; https://doi.org/10.3390/genes17070827 - 20 Jul 2026
Viewed by 303
Abstract
Background: Thoracic aortic aneurysm (TAA) is a potentially life-threatening degenerative disease whose principal danger arises from progressive aortic dilation with the attendant risk of rupture and dissection and which is characterized by extracellular matrix breakdown, smooth muscle loss, and endothelial dysfunction. Caveolae, plasma [...] Read more.
Background: Thoracic aortic aneurysm (TAA) is a potentially life-threatening degenerative disease whose principal danger arises from progressive aortic dilation with the attendant risk of rupture and dissection and which is characterized by extracellular matrix breakdown, smooth muscle loss, and endothelial dysfunction. Caveolae, plasma membrane microdomains built from caveolins (CAV1-3) and cavins (CAVIN1-4), govern nitric oxide (NO) signaling, endocytosis, and mechanotransduction. We hypothesized that downregulation of caveolae-associated genes, driven in part by microRNAs, contributes to endothelial failure and vascular remodeling in TAA. Methods: Normalized transcriptomic expression values for five caveolae-associated genes were retrieved from the GSE26155 dataset (43 TAA and 43 control aortas) using GEO2R. Differential expression was assessed for CAV1, CAV2, CAV3, CAVIN1, and CAVIN2, and Spearman correlation with Deming regression explored inter-gene relationships. Functional enrichment (Enrichr) and experimentally validated microRNA-target interactions (miRTarBase) were used to infer regulatory and mechanistic networks. CpG island mapping and gene-gene interactome construction (GeneMANIA) complemented the analyses. Results: CAV1 and CAV2 were downregulated in TAA at nominal significance (CAV1, p = 0.0225; CAV2, p = 0.0361); after Benjamini–Hochberg correction across the five candidate genes both differences attenuated to a consistent trend (q approximately 0.09), while the two caveolins were strongly co-expressed (Spearman r = 0.527, p < 0.001; Deming CAV2 = 1.881 × CAV1-0.892), indicating coordinated transcriptional regulation. Network analysis linked both genes to NOS3, NOSTRIN, EGFR, HRAS, and RAC1, consistent with impaired endothelial nitric oxide and GTPase signaling. Gene Ontology enrichment highlighted endothelial proliferation, nitric oxide metabolism, calcium homeostasis, vesicle organization, and MAPK regulation. Database-supported analysis (miRTarBase) identified miR-93-5p, miR-199a-3p, miR-203a-3p, and the miR-29 family as experimentally validated candidate repressors of CAV1/CAV2. Conclusions: This integrative transcriptomic and microRNA analysis identifies coordinated CAV1 and CAV2 downregulation as a candidate molecular event in thoracic aortic aneurysm, associated with caveolar loss, endothelial dysfunction, and disrupted nitric oxide homeostasis. The CAV1/CAV2-microRNA axis represents a candidate mechanistic signature warranting further investigation as a potential therapeutic target in aortic disease. Full article
(This article belongs to the Special Issue Genetic Epidemiology of Multifactorial Diseases)
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15 pages, 4825 KB  
Article
Recalibrating Therapeutic Priorities for Duchenne Muscular Dystrophy: A Critical Synthesis of Approved and Emerging Strategies Through the Lens of an Underrepresented Population
by Saken Khaidarov, Aizhan Moldakaryzova, Dias Dautov, Nurgul Sagatbayeva, Banu Yeszhan, Bayan Nurgaliyeva, Saltanat Kenbayeva, Gulban Abdullayeva, Marat Rabandiyarov, Karlygash N. Tazhibayeva, Assel Sadykova, Aibek Yermekbay, Askar Aidarov, Daulet Aidarov, Aray Aidarova, Saniyam Kurbaniyazova, Nazym Abiyrova and Mukhit Kulmaganbetov
Genes 2026, 17(7), 826; https://doi.org/10.3390/genes17070826 - 20 Jul 2026
Viewed by 1647
Abstract
Background: Duchenne muscular dystrophy (DMD) has, for the first time, several mutation-specific drugs in clinical use. Four exon-skipping antisense oligonucleotides and one adeno-associated virus (AAV) micro-dystrophin gene therapy carry US FDA approval, and one nonsense-readthrough agent (ataluren) holds a conditional European authorisation that [...] Read more.
Background: Duchenne muscular dystrophy (DMD) has, for the first time, several mutation-specific drugs in clinical use. Four exon-skipping antisense oligonucleotides and one adeno-associated virus (AAV) micro-dystrophin gene therapy carry US FDA approval, and one nonsense-readthrough agent (ataluren) holds a conditional European authorisation that has since been placed under review; ataluren has never been approved by the FDA. Regulatory approval, however, has not translated cleanly into demonstrable clinical benefit, and in resource-limited settings it has not translated into access at all. Methods: We compiled published efficacy estimates for each approved therapy: the EMBARK randomised trial for delandistrogene moxeparvovec (Elevidys), the STRIDE registry for ataluren, and the long-term extension studies of eteplirsen, golodirsen, viltolarsen and casimersen. We read these alongside mutation-spectrum and clinical data from a Kazakh DMD cohort (n = 34), one of the first Central Asian populations to be characterised systematically. Because these sources differ in design, population, endpoint and follow-up, the comparison is indirect and descriptive rather than pooled or statistical. On that basis we assembled three descriptive maps: biological versus clinical efficacy, eligibility versus access, and an order-of-magnitude estimate of cost per year of preserved ambulation. Results: Across the approved therapies, larger biological dystrophin restoration did not correspond to longer preservation of walking. We describe this as the absence of the expected positive association rather than as evidence of a negative one: the comparison rests on a small number of drugs whose values come from heterogeneous studies. We did not—and with these data could not—test it as a formal correlation. Ataluren, with roughly 2% dystrophin restoration, was associated with a longer reported delay in loss of ambulation than Elevidys, which restores 34–51% micro-dystrophin. In the Kazakh cohort, 26.5% of patients were biologically eligible for exon-skipping and 11.8% for ataluren, yet realistic access to any mutation-specific therapy was effectively zero as of April 2026. Our order-of-magnitude cost estimates ran from about $12,000 per additional year of ambulation for standard of care to about $1.3 million for AAV gene therapy, a hundredfold range that did not track clinical effect. Conclusions: We argue that the conventional priority ordering (gene therapy first, exon-skipping second, standard care as background) does not hold up when weighed against patient-relevant outcomes and cost, and may reasonably be inverted for resource-limited systems. This is our interpretation of an indirect comparison, not an evidence-based clinical recommendation. On that reading, the highest-value investments for Central Asia are early molecular diagnosis, universal access to glucocorticoids and specialised physiotherapy, and individual-import pathways for ataluren, while AAV gene therapy is, in our view, a lower near-term priority until its durability and safety data improve. Full article
(This article belongs to the Collection Study on Genotypes and Phenotypes of Pediatric Clinical Rare Diseases)
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15 pages, 885 KB  
Article
Association of SCAP Gene Polymorphisms with Ambulatory Blood Pressure Parameters in College Students
by Yuan Zeng, Bin Mao, Jian Zhang, Sha Xia, Zhe Wu, Shang Li, Xiuqin Hong and Yide Yang
Genes 2026, 17(7), 825; https://doi.org/10.3390/genes17070825 - 19 Jul 2026
Viewed by 212
Abstract
Background/Objectives: Abnormal blood pressure (BP) in youth is strongly linked to genetic predisposition, particularly involving lipid metabolism genes. However, little is known about whether such polymorphisms affect ambulatory BP (ABP) parameters and whether other factors modify the associations in youth populations. Methods [...] Read more.
Background/Objectives: Abnormal blood pressure (BP) in youth is strongly linked to genetic predisposition, particularly involving lipid metabolism genes. However, little is known about whether such polymorphisms affect ambulatory BP (ABP) parameters and whether other factors modify the associations in youth populations. Methods: A total of 510 medical students from a university in Changsha were included. Multivariable linear regression and logistic regression models were used to analyze the association between sterol regulatory element-binding protein cleavage-activating protein (SCAP) gene polymorphisms and ABP parameters among youth. Results: After adjusting for age, sex, BMI, ethnicity, monthly household income per capita, salt intake habits, fruit and vegetable intake frequency, smoking, drinking, history of hypertension and waist circumference, carriers of the A allele of rs76558868 had higher daytime systolic blood pressure (SBP) than G allele carriers (β = 1.55, SE = 0.77, p = 0.046, corrected p = 0.092). A significant interaction between rs12487736 and sex on 24 h SBP (pinteraction = 0.023) and daytime SBP (pinteraction = 0.048) levels was found. In males, the CC genotype carriers had elevated 24 h SBP (β = 3.53, SE = 1.36, p = 0.010, corrected p = 0.020) and daytime SBP (β = 3.18, SE = 1.53, p = 0.040, corrected p = 0.080) levels compared to TC/TT genotype carriers, whereas no significant association was found in females. In addition, we also noted an interaction between rs76558868 and sex on 24 h SBP (pinteraction = 0.016), nighttime SBP (pinteraction = 0.027) and nighttime diastolic blood pressure (DBP) (pinteraction = 0.025) levels; the A allele carriers had significantly higher 24 h SBP (β = 2.02, SE = 0.84, p = 0.018, corrected p = 0.036), nighttime SBP (β = 2.64, SE = 0.98, p = 0.008, corrected p = 0.016) and DBP levels (β = 1.65, SE = 0.63, p = 0.009, corrected p = 0.018) compared to G allele carriers among males, but not in females. Conclusions: An interaction between SCAP gene polymorphisms and sex was observed for ABP parameters among college students. These findings provide insights for future targeted early hypertension prevention and personalized health management strategies. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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24 pages, 6242 KB  
Article
A Novel Magnetic Bead-Based Differential DNA Extraction Method with Potential for High-Throughput Automation in Forensic Casework: A Proof-of-Concept Study
by Amy-Leigh Whittaker, William P. Allan, Mark W. Perlin and Laura J. Heathfield
Genes 2026, 17(7), 824; https://doi.org/10.3390/genes17070824 - 19 Jul 2026
Viewed by 339
Abstract
Background/Objectives: Sexual offences remain a global challenge, disproportionality affecting developing and conflict-stricken countries. Differential DNA extraction (DDE) is standardly applied to intimate swabs collected in these cases to separate and purify sperm and epithelial fractions ahead of DNA profiling. Whilst DNA purification [...] Read more.
Background/Objectives: Sexual offences remain a global challenge, disproportionality affecting developing and conflict-stricken countries. Differential DNA extraction (DDE) is standardly applied to intimate swabs collected in these cases to separate and purify sperm and epithelial fractions ahead of DNA profiling. Whilst DNA purification steps using magnetic bead technology are routinely automated in general forensic workflows, the separation step within DDE workflows usually relies on centrifugation, which is challenging to automate in a high-throughput manner. This proof-of-concept study aimed to develop a novel method to separate sperm and epithelial fractions using magnetic bead technology to enable a fully automated and high-throughput DDE workflow. Methods: First, the Macherey-Nagel NucleoMag® Forensic DNA kit’s protocol for forensic samples was modified to be DDE-based, and different magnetic beads for the separation and purification steps were assessed on mock sexual offence samples. Once a working protocol was established, variables within the protocol were systematically adjusted to improve quality metrics and DNA profiling outcomes. The top-performing method was then assessed with decreased input biological material and on a post-coital swab. Results: The DDE protocol developed in this study identified Cytiva SeraSil-MagTM magnetic beads to successfully separate epithelial and sperm fractions, which will enable a fully automated and high-throughput DDE workflow for the first time. DNA extracted from the sperm fraction of mock sexual offence samples prepared with 1 μL of semen input yielded a mean Y-target DNA yield of 25.04 ng (SD = 15.11 ng), a median M:F ratio of 1:3.53 (range = 1:1.08–1:22.46) and a mean log(LR) of 12.01 (SD = 5.41) when the female contributor’s DNA profile was unknown. Conclusions: The proof-of-concept of a magnetic bead-based DDE method was successfully demonstrated across a range of different semen input volumes, and the benefit of information-preserving genotyping using the TrueAllele® system was demonstrated. Full article
(This article belongs to the Special Issue Novel Strategies in Forensic Genetics)
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36 pages, 1243 KB  
Review
Hexokinase 2 and Carbohydrate Metabolism: A Multifaceted Metabolic Hub
by Roman Maslanka, Justyna Folta, Magdalena Lubińska, Łukasz Słota and Renata Zadrag-Tecza
Genes 2026, 17(7), 823; https://doi.org/10.3390/genes17070823 - 19 Jul 2026
Viewed by 387
Abstract
Hexokinase 2 (Hxk2p) is a key enzyme in glucose metabolism but also acts as a central regulator linking glucose-dependent signaling with cellular physiology in Saccharomyces cerevisiae. Beyond its catalytic function in glycolysis, Hxk2p acts as a regulator of carbon catabolite repression, influencing [...] Read more.
Hexokinase 2 (Hxk2p) is a key enzyme in glucose metabolism but also acts as a central regulator linking glucose-dependent signaling with cellular physiology in Saccharomyces cerevisiae. Beyond its catalytic function in glycolysis, Hxk2p acts as a regulator of carbon catabolite repression, influencing the expression of genes required for the utilization of alternative carbon sources and mitochondrial activity. Accumulating evidence indicates that deletion of HXK2 triggers a systemic, multidirectional reprogramming of cellular metabolism and physiology that mimics calorie restriction conditions even in nutrient-rich environments. This widespread metabolic reconfiguration involves a fundamental shift from a rapid fermentative mode to an energy-efficient respiratory state, including the redistribution of carbon flux between glycolysis, the pentose phosphate pathway, and respiration. These changes are associated with alterations in ATP homeostasis, biosynthetic capacity, redox balance, and proteostasis. Crucially, because of its implications in genomic regulation, the absence of Hxk2p induces global transcriptional remodelling, whereby the expression of genes involved in respiratory and alternative carbon source metabolism is derepressed, while the expression of glycolytic and biosynthetic genes is downregulated. Ultimately, these pleiotropic adaptations work synergistically, affecting cellular fitness and increasing cell reproductive potential. Therefore, Hxk2p integrates metabolic and signaling pathways that link carbon source utilization with cellular growth, cell cycle, energy homeostasis, and stress responses. This review summarizes current knowledge on Hxk2p function in carbohydrate metabolism, with particular emphasis on its regulatory roles and their implications for gene expression, cellular physiology, and proliferation capacity. Full article
(This article belongs to the Special Issue New Insight into the Genetic and Molecular Aspects of Yeast Nutrient Metabolism)
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19 pages, 289 KB  
Review
Spatial Omics Technologies in Glioblastoma Research: Principles, Applications, and Best Practices
by Maxime Vanmechelen, Chiara Caprioli, Paul M. Clement, Ann Hoeben and Frederik De Smet
Genes 2026, 17(7), 822; https://doi.org/10.3390/genes17070822 - 18 Jul 2026
Viewed by 381
Abstract
Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, characterized by inevitable recurrence, extensive inter-and intratumoral heterogeneity, and resistance to current therapies. A defining feature of GBM is the dynamic interplay between malignant cells and a diverse tumor microenvironment (TME), [...] Read more.
Background/Objectives: Glioblastoma (GBM) remains the most aggressive primary brain tumor in adults, characterized by inevitable recurrence, extensive inter-and intratumoral heterogeneity, and resistance to current therapies. A defining feature of GBM is the dynamic interplay between malignant cells and a diverse tumor microenvironment (TME), which together drive disease progression, therapeutic adaptation, and relapse. Understanding these complex cellular ecosystems has therefore become a major focus of glioblastoma research. Recent advances in spatial omics technologies have transformed our ability to investigate GBM biology directly within intact tissue architectures. Over the past five years, an expanding array of spatial transcriptomic, proteomic, and multi-omic platforms has enabled high-dimensional characterization of cellular states, cell–cell interactions, and tissue niches while preserving spatial context. These approaches have generated unprecedented insights into tumor organization, cellular plasticity, immune landscapes, vascular niches, and treatment-induced ecosystem remodeling. Methods: In this review, we provide an overview of spatial omics applications in glioblastoma research so far. Results: We summarize the technologies employed, the types and numbers of patient samples analyzed, and the major biological and clinical insights generated. We compare the strengths and limitations of different spatial platforms, discuss key considerations for study design and data interpretation, and highlight emerging trends in multimodal and longitudinal analyses. Conclusions: By integrating both technological and biological perspectives, this review serves as a practical resource for researchers seeking to implement spatial omics approaches in glioblastoma studies and to advance precision neuro-oncology. Full article
(This article belongs to the Special Issue Emerging Insights in Single-Cell and Spatial Omics for Disease Mechanisms)
14 pages, 5136 KB  
Article
Genetic Variations in TNFAIP3 and CTLA4 and Their Association with Circulating TNF-α and sCTLA4 Levels in Kurdish Patients with Rheumatoid Arthritis
by Sonia Elia Ishaq, Taban Kamal Rasheed, Niaz Albarzinji and Shukur Wasman Smail
Genes 2026, 17(7), 821; https://doi.org/10.3390/genes17070821 - 18 Jul 2026
Viewed by 343
Abstract
Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by sustained synovial inflammation and systemic immune activation. Genetic polymorphisms in key immune-regulatory pathways are thought to influence both disease susceptibility and progression. This study aimed to characterize sequence variation within selected [...] Read more.
Background/Objectives: Rheumatoid arthritis (RA) is a chronic autoimmune disease marked by sustained synovial inflammation and systemic immune activation. Genetic polymorphisms in key immune-regulatory pathways are thought to influence both disease susceptibility and progression. This study aimed to characterize sequence variation within selected coding regions of TNFAIP3 and CTLA4 in Kurdish patients with RA and to evaluate circulating TNF-α and soluble CTLA-4 (sCTLA-4) levels in the same cohort. Methods: Eighty-seven participants (67 RA patients, 20 controls) were enrolled. Serum TNF-α and sCTLA-4 concentrations were quantified by ELISA. Genomic DNA was extracted and targeted Sanger sequencing of selected coding regions of TNFAIP3 and CTLA4 was performed in RA patients. Variant identification was conducted relative to GRCh38 and annotated using dbSNP and Genome Aggregation Database (gnomAD). GeneMANIA was used for network-based contextualization. Results: In the 218-bp targeted region of TNFAIP3, 103 sequence-level variant occurrences were identified in RA patients, including substitutions and insertion/deletion events. In the 136-bp targeted region of CTLA4, 33 sequence-level variant occurrences were identified, also including substitutions and insertion/deletion events. RA patients exhibited significantly elevated serum TNF-α levels compared with controls (p = 0.025), whereas sCTLA-4 levels did not differ significantly. Conclusions: This study provides the first targeted characterization of TNFAIP3 and CTLA4 genetic variation in Kurdish RA patients and integrates these findings with circulating inflammatory biomarkers. Although not designed to assess disease susceptibility, the study provides a valuable descriptive genetic resource for this population and complements existing evidence implicating NF-κB regulation and immune checkpoint signaling in RA. These findings establish a strong foundation for future case–control, genotype–phenotype, and functional investigations. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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12 pages, 2388 KB  
Article
LAMB2 p.E991K Mutation-Mediated Atherosclerosis in Rabbit
by Ronghan Zhang, Chao Mu, Shujun Yang and Liqiang Jiang
Genes 2026, 17(7), 820; https://doi.org/10.3390/genes17070820 - 18 Jul 2026
Viewed by 249
Abstract
Background: Atherosclerosis is a major pathological basis of cardiovascular disease and is influenced by both genetic and environmental factors. Although genome-wide association studies have identified the LAMB2 p.E987K variant as a susceptibility locus for atherosclerosis, its functional role remains unclear. Methods: [...] Read more.
Background: Atherosclerosis is a major pathological basis of cardiovascular disease and is influenced by both genetic and environmental factors. Although genome-wide association studies have identified the LAMB2 p.E987K variant as a susceptibility locus for atherosclerosis, its functional role remains unclear. Methods: In this study, a rabbit model carrying the homologous LAMB2 p.E991K mutation was generated using the CRISPR/Cas9-SpG system and subjected to a high-fat diet to induce atherosclerosis. Results: LAMB2 mutant rabbits exhibited increased body weight and significant lipid metabolic abnormalities. Oil Red O staining demonstrated enhanced lipid accumulation and larger atherosclerotic plaques in the aorta. In addition, α-SMA expression was reduced, whereas CD4 and MCP-1 expression was elevated, suggesting vascular smooth muscle cell loss and altered immune responses. Laminin β2 (LAMB2) expression was markedly decreased and accompanied by basement membrane disruption. Furthermore, activation of the NLRP3 inflammasome was observed in mutant rabbits. Conclusions: These findings demonstrate that the LAMB2 p.E991K mutation promotes HFD-induced atherosclerosis by impairing basement membrane integrity, enhancing inflammation, and disrupting lipid metabolism, highlighting LAMB2 as a genetic modifier of atherosclerosis susceptibility. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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19 pages, 288 KB  
Review
From Old to Bold: Advancing microRNA Studies in Sudden Cardiac Death Through Molecular Analysis of FFPE Heart Tissue
by Alessia Bernini Di Michele, Chiara Turchi and Mauro Pesaresi
Genes 2026, 17(7), 819; https://doi.org/10.3390/genes17070819 - 17 Jul 2026
Viewed by 323
Abstract
Background/Objectives: Sudden cardiac death (SCD) is a natural death of cardiac origin, accounting for an estimated 6–9 million deaths worldwide each year and representing a major public health challenge. Despite its clinical and forensic relevance, the molecular investigation of SCD remains limited. Peripheral [...] Read more.
Background/Objectives: Sudden cardiac death (SCD) is a natural death of cardiac origin, accounting for an estimated 6–9 million deaths worldwide each year and representing a major public health challenge. Despite its clinical and forensic relevance, the molecular investigation of SCD remains limited. Peripheral blood or fresh tissue, the preferred specimens for post-mortem genetic testing, are not always available, and DNA extracted from formalin-fixed paraffin-embedded (FFPE) tissues is often suboptimal for conventional genetic analyses. This review evaluates the potential of archived FFPE cardiac tissue as a source for microRNA (miRNA) analysis in molecular autopsy. Methods: A narrative review was conducted by collecting studies investigating miRNA expression in FFPE cardiac tissue relevant to SCD. Ten studies met the inclusion criteria and were critically analyzed. Results: Although the available evidence remains limited, recent studies have identified several differentially expressed miRNAs associated with cardiac diseases relevant to SCD. Owing to their small size and remarkable stability, miRNAs remain detectable in FFPE tissues despite fixation and long-term storage, making them attractive molecular biomarkers. While most available studies were conducted in clinical rather than forensic settings, they demonstrate the feasibility and analytical robustness of miRNA profiling in archived FFPE cardiac specimens. Conclusions: This review underlines the importance of reconsidering archived FFPE tissues not merely as historical or morphological resources, but as promising matrices for molecular autopsy of SCD supporting the identification and validation of novel molecular biomarkers. Full article
(This article belongs to the Special Issue Advanced Research in Forensic Genetics—2nd Edition)
20 pages, 255 KB  
Article
Integrating Genetic Data and Electronic Medical Records to Reassess Variant Pathogenicity in the Taiwanese Han Population
by Wei-De Lin, Ting-Yuan Liu, Yu-Chia Chen, Chi-Chou Liao and Fuu-Jen Tsai
Genes 2026, 17(7), 818; https://doi.org/10.3390/genes17070818 - 17 Jul 2026
Viewed by 270
Abstract
Background: Variant interpretation in clinical genomics requires integration of population-specific allele frequencies, curated database annotations, and phenotype evidence. However, variants annotated as pathogenic or likely pathogenic in reference databases may have different allele frequencies across populations, and electronic medical record (EMR) data may [...] Read more.
Background: Variant interpretation in clinical genomics requires integration of population-specific allele frequencies, curated database annotations, and phenotype evidence. However, variants annotated as pathogenic or likely pathogenic in reference databases may have different allele frequencies across populations, and electronic medical record (EMR) data may provide useful but incomplete clinical context. Methods: In this study, we used the China Medical University Hospital Genetic Biobank (CMUH-GB) and linked EMRs to evaluate ClinVar-annotated candidate variants in a Taiwanese Han population. Genotyped array variants were filtered by quality control, mapped to ClinVar, and prioritized if annotated as pathogenic or likely pathogenic and observed with an alternative allele frequency greater than 0.0001 in CMUH-GB. Results: After an updated annotation review, EMR linkage, exclusion of known rare-disease cases or ineligible loci, and retention of variants with clinically relevant EMR phenotypes, 11 candidate variants were analyzed. These variants were located in SCN5A, KCNH2, FBP1, PAH, ACADS, TBX6, BRCA1, LDLR, GP6, and SLC4A11. Several candidate variants showed substantially higher allele frequencies in CMUH-GB and the Taiwan Biobank than reported in some external population datasets. Genotype–phenotype association analyses were performed using additive genetic models with covariate adjustment and Benjamini–Hochberg false discovery rate correction. No interpretable association remained statistically significant after correction. SCN5A rs794728912 models for long QT syndrome and cardiac conduction defects were not estimable because no cases were observed among alternative-allele carriers, resulting in sparse-event separation. A nominal GP6 association with coagulation defects did not remain significant after correction. These findings support population-specific reassessment prioritization of selected ClinVar-annotated variants but do not constitute formal ACMG/AMP reclassification. Conclusions: Our study highlights the value and limitations of integrating hospital-based genotyping data with EMR-derived phenotypes for ancestry-aware variant interpretation in underrepresented populations. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
31 pages, 20196 KB  
Article
Integrated Single-Cell and Spatial Transcriptomic Analysis Reveals the Immunoregulatory Role of MIF Signaling in Colorectal Cancer
by Yuxian Liu, Junyuan Zhang, Xiaohui Li, Xingjie Chen, Kangcheng Xu and Yanni Cao
Genes 2026, 17(7), 817; https://doi.org/10.3390/genes17070817 - 17 Jul 2026
Viewed by 423
Abstract
Background: The cellular heterogeneity and spatial organization patterns of the tumor microenvironment (TME) play a crucial role in colorectal cancer (CRC) progression, but their spatial distribution and cellular communication mechanisms require further elucidation. This study aims to systematically dissect the cellular heterogeneity [...] Read more.
Background: The cellular heterogeneity and spatial organization patterns of the tumor microenvironment (TME) play a crucial role in colorectal cancer (CRC) progression, but their spatial distribution and cellular communication mechanisms require further elucidation. This study aims to systematically dissect the cellular heterogeneity and spatial organization characteristics of the CRC microenvironment by integrating single-cell and spatial transcriptomic data. Methods: Single-cell RNA sequencing and spatial transcriptomics data of primary CRC were integrated to characterize the TME. Intercellular signaling patterns were elucidated through communication analysis, spatial niche clustering, ligand–receptor pair analysis, and spatial expression mapping. The ESTIMATE algorithm was applied to assess the correlation between TME scores and pathway-associated genes. Drug sensitivity prediction was performed using the oncoPredict. Results: Single-cell analysis identifies nine major cell types, revealing significant cellular heterogeneity. Intercellular communication analysis demonstrates that the MIF signaling pathway plays a prominent role within the TME communication network, with MIF-(CD74+CD44) and MIF-(CD74+CXCR4) identified as dominant receptor complexes. Spatial transcriptomic analysis reveals distinct spatial functional partitioning of these signaling axes. Signaling flow analysis indicates an immunosuppressive “tumor–immune” axis mediated by MIF signaling from tumor epithelial cells to immune cells. MIF expression is negatively correlated with ImmuneScore, while its receptors CD74, CD44, and CXCR4 are positively correlated. Drug sensitivity analysis reveals potential associations between key genes (MIF, CD74, CD44, and CXCR4) in the MIF pathway and various anti-tumor drugs. Conclusions: Our study reveals the cellular heterogeneity of the CRC microenvironment from multiple perspectives, elucidates the key mechanisms of the MIF signaling pathway, and provides potential therapeutic targets for CRC treatment. Full article
(This article belongs to the Section Bioinformatics)
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19 pages, 1408 KB  
Article
A Neural-Network-Free Calibration Matches or Beats Deep Single-Cell Perturbation Response Models Across Four Datasets
by Bingchi Sun, Haibin Zheng, Jinyin Chen and Jingjing Jin
Genes 2026, 17(7), 816; https://doi.org/10.3390/genes17070816 - 17 Jul 2026
Viewed by 390
Abstract
Background/Objectives: Deep generative models such as scGen are the standard for predicting how an unseen cell type or species responds to a perturbation under leave-one-group-out (LOCO). We ask whether the deep model’s advantage over a one-line linear baseline is learnable without any [...] Read more.
Background/Objectives: Deep generative models such as scGen are the standard for predicting how an unseen cell type or species responds to a perturbation under leave-one-group-out (LOCO). We ask whether the deep model’s advantage over a one-line linear baseline is learnable without any neural network. Methods: We decompose scGen’s edge into two leakage-free analytic pieces (per-type response magnitude and per-gene response direction) and add a per-gene affine moment-matching step. The resulting calibration, AMM-SimWMag, uses no neural network and is CPU-only. We evaluate it on a nine-metric panel across 4 datasets spanning 3 biologies and 2 LOCO axes (cell type and species), using a dataset-stratified test (a Stouffer combination of per-dataset signed-rank tests, Holm-adjusted). Results: AMM-SimWMag is competitive-or-best (within 0.003 of scGen) on 8–9 of 9 metrics on each of 4 datasets. It significantly improves on scGen on eight of nine metrics, favoured in all four datasets on seven; the lone exception, the per-gene log-fold-change correlation, is a tie-or-better everywhere. Against three modern baselines (scPRAM, biolord and CPA) on the same protocol, it beats biolord and CPA on 9/9 metrics and scPRAM on 7/9 (pooled). The affine moment-matching step improves distribution distances (MMD, energy, sliced-Wasserstein), though C2ST stays near 1.0 for all methods. Conclusions: AMM-SimWMag recovers the deep model’s advantage over a linear baseline without any neural network. No single deep model is robust across all four biologies, whereas AMM-SimWMag matches or beats them across 4 datasets, CPU-only and reproducibly. Full article
(This article belongs to the Section Bioinformatics)
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17 pages, 2331 KB  
Article
GmPP2C113, a Soybean Protein Phosphatase, Positively Regulates Both Salt Tolerance and Symbiotic Nodulation
by Danxia Ke, Zhaoyuan Zhou, Xiaoli Song, Jianuo Lin and Kexin Zhang
Genes 2026, 17(7), 815; https://doi.org/10.3390/genes17070815 - 17 Jul 2026
Viewed by 330
Abstract
Background/Objectives: Protein phosphatase type 2C (PP2C) family members are key signaling hubs in plants, but their roles in mediating the trade-off between stress adaptation and symbiotic interactions remain unclear. This study aimed to investigate the function of soybean GmPP2C113, which was identified as [...] Read more.
Background/Objectives: Protein phosphatase type 2C (PP2C) family members are key signaling hubs in plants, but their roles in mediating the trade-off between stress adaptation and symbiotic interactions remain unclear. This study aimed to investigate the function of soybean GmPP2C113, which was identified as a potential regulator linking salt stress responses and symbiotic nodulation, in coordinating these two biological processes in soybean (Glycine max). Methods/Results: The GmPP2C113 gene was cloned, and its subcellular localization, transcriptional activity, and protein interactions were characterized. Expression patterns under salt stress and rhizobial inoculation were analyzed. The biological role of GmPP2C113 was assessed using transgenic soybean plants overexpressing GmPP2C113. GmPP2C113 was localized in the nucleus and possessed transcriptional activation capability and interacted with GmPP2C47. Its expression was strongly induced by salt stress and by rhizobial infection, with the highest levels detected in mature nodules. Overexpression of GmPP2C113 significantly enhanced salt tolerance, upregulated stress-related genes, increased nodule numbers, and promoted symbiotic nodulation under salt stress by inducing nodulation marker genes. Conclusions: These results identify GmPP2C113 as a positive modulator of salt tolerance and reveal its novel role as a molecular node that sustains symbiotic nodulation under salt stress. This provides insight into the coordinated regulation of stress adaptation and symbiosis in soybean. Full article
(This article belongs to the Special Issue Abiotic Stress in Crop: Molecular Genetics and Genomics)
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