Genes

20 pages, 4037 KB

Open AccessArticle

TYK2 Deficiency Presenting as Refractory Disseminated BCG/Tuberculosis Infection in a Kazakh Child: A Case Report with Genetic Confirmation

by Nurgul Sikhayeva, Svetlana Volodchenko, Elena Kovzel, Aiganym Toleuzhanova, Aliya Romanova, Gulnar Tortayeva, Yelena Sagandykova, Marina Morenko, Aidos Bolatov and Ilyas Akhmetollayev

Genes 2025, 16(12), 1445; https://doi.org/10.3390/genes16121445 - 2 Dec 2025

Abstract

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where [...] Read more.

Background/Objectives: Hereditary anomalies in the TYK2 gene are the basis of a rare primary immunodeficiency, immunodeficiency-35, typified by an augmented vulnerability to mycobacterial and viral infections. Clinical overlap with chronic granulomatous disease (CGD) and other granulomatous disorders complicates diagnosis, particularly in nations where universal BCG vaccination is instituted. We present a pediatric case from Kazakhstan to broaden the clinical and molecular spectrum of TYK2-related immunodeficiency and accentuate diagnostic challenges. Methods: The proband underwent clinical assessment, immunophenotyping, and biochemical analysis during episodes of active pathology and subsequent follow-up. Whole-exome sequencing (WES) was executed, followed by confirmatory Sanger sequencing and segregation analysis in first-degree kin. Functional assays for phagocyte oxidative burst and phagocytosis were conducted to exclude CGD. Results: WES identified two rare TYK2 variants (c.209_212del, pathogenic; c.2395G>A, previously reported as pathogenic in a Chinese patient with TYK2 deficiency) and a heterozygous MEFV duplication (c.761_764dup). Paternal DNA was unavailable; therefore, allelic phase could not be formally established, but the combined genotype and phenotype are consistent with autosomal recessive TYK2 deficiency. Sanger sequencing confirmed segregation of the frameshift TYK2 variant in the mother, while the clinically healthy brother carried only the wild-type allele. The missense alteration was exclusive to the proband. Conclusions: This case exemplifies the significance of contemplating TYK2 deficiency in pediatric patients with refractory mycobacterial infections, particularly in BCG-endemic locales. Genetic validation provided a definitive diagnosis, differentiating the condition from CGD and informing patient management. To our knowledge, this constitutes one of the inaugural genetically confirmed instances of TYK2 deficiency in Central Asia, enhancing regional epidemiological comprehension and emphasizing the role of molecular diagnostics in directing treatment and vaccination policies. Full article

(This article belongs to the Special Issue Genetics and Genomics of Heritable Pediatric Disorders)

31 pages, 2851 KB

Open AccessReview

Genetic, Clinical and Neuroradiological Spectrum of MED-Related Disorders: An Updated Review

by Alessandro Fazio, Roberta Leonardi, Lorenzo Aliotta, Manuela Lo Bianco, Gennaro Anastasio, Giuseppe Messina, Corrado Spatola, Pietro Valerio Foti, Stefano Palmucci, Antonio Basile, Martino Ruggieri and Emanuele David

Genes 2025, 16(12), 1444; https://doi.org/10.3390/genes16121444 - 2 Dec 2025

Abstract

Background/Objectives: The Mediator (MED) complex is an essential regulator of RNA polymerase II transcription. There is increasing evidence that pathogenic variants in several MED subunits are the cause of neurodegenerative and neurodevelopmental phenotypes, collectively referred to as “MEDopathies”. This review aims to summarize [...] Read more.

Background/Objectives: The Mediator (MED) complex is an essential regulator of RNA polymerase II transcription. There is increasing evidence that pathogenic variants in several MED subunits are the cause of neurodegenerative and neurodevelopmental phenotypes, collectively referred to as “MEDopathies”. This review aims to summarize current knowledge on the genetic basis, clinical manifestations, and neuroradiological features of MED-related disorders. Methods: We undertook a narrative synthesis of the literature focusing on the MED subunits most commonly associated with neurological disorders, including MED1, MED8, MED11, MED12/MED12L, MED13/MED13L, MED14, MED17, MED20, MED23, MED25, MED27, and CDK8. Sources included peer-reviewed genetic, clinical, and imaging studies, supplemented by relevant case reports and cohort analyses. In addition, representative facial phenotypes associated with selected MED variants (MED11, MED12, MED13, MED13L, MED25) were visualized for educational purposes using artificial intelligence-based image generation derived from standardized clinical descriptors. Results: All MEDopathies show converging clinical patterns: global developmental delay/intellectual disability, hypotonia, epilepsy, speech disorders, and behavioral comorbidity. Non-neurological involvement, such as craniofacial or cardiac anomalies, is subunit-specific. Neuroradiological features include callosal abnormalities (agenesis, thinning, dysmorphia), delayed or hypomyelination, progressive cerebral and cerebellar atrophy, basal ganglia signaling changes, pontine hypoplasia, and, in MED27 deficiency, a “hot cross bun” sign. Gene-specific constellations emphasize catastrophic infantile progression (MED11), X-linked syndromes with callosal defects (MED12/MED12L), language-dominant phenotypes (MED13), and syndromic intellectual disability with systemic features (MED13L). Conclusions: The growing spectrum of MEDopathies argues for their recognition as a unified nosological group with overlapping clinical and radiological signatures. Characteristic MRI constellations may serve as diagnostic clues and guide targeted molecular testing. Future directions include longitudinal imaging to describe disease progression and the integration of genomic data with curated clinical radiological datasets to refine genotype-phenotype correlations. Full article

(This article belongs to the Collection Study on Genotypes and Phenotypes of Pediatric Clinical Rare Diseases)

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20 pages, 888 KB

Open AccessReview

Role of Genetic and Epigenetic Biomarkers in Treatment-Resistant Depression: A Literature Review

by Petra Sulić, Andrea Ražić Pavičić, Biljana Đapić Ivančić, Tamara Božina, Nada Božina and Maja Živković

Genes 2025, 16(12), 1443; https://doi.org/10.3390/genes16121443 - 2 Dec 2025

Abstract

Background: Treatment-resistant depression (TRD) affects up to 30–40% of patients with major depressive disorder and remains a major therapeutic challenge. Genetic and epigenetic factors are increasingly recognized as key contributors to both vulnerability and treatment response. Methods: We conducted a narrative review of [...] Read more.

Background: Treatment-resistant depression (TRD) affects up to 30–40% of patients with major depressive disorder and remains a major therapeutic challenge. Genetic and epigenetic factors are increasingly recognized as key contributors to both vulnerability and treatment response. Methods: We conducted a narrative review of studies published between 2021 and 2025, focusing exclusively on DNA- and RNA-based biomarkers of TRD. Twelve studies met the inclusion criteria, covering candidate gene analyses, genome-wide association studies (GWAS), neuroimaging–genetic approaches, and microRNA profiling. Results: Genetic investigations consistently implicate neuroplasticity-related genes (BDNF, NTRK2, PTEN, SYN1, MAPK1, and GSK3B) in the risk of TRD and its relapse. Variants in glutamatergic receptor genes (GRIN2A, GRIN2B, GRIA2, GRIA3) were predicted to result in a rapid and sustained response to ketamine. Genomic approaches further demonstrated that composite genetic panels outperform single-variant predictors. In parallel, microRNAs such as miR-1202, miR-16, miR-135, miR-124, miR-223, and miR-146a emerged as dynamic biomarkers of treatment response, particularly in cohorts treated with ketamine or electroconvulsive therapy. Conclusions: DNA- and RNA-based biomarkers provide promising avenues for improving the understanding and management of TRD. Their integration into clinical frameworks could support patient stratification, individualized treatment selection, and real-time monitoring of therapeutic efficacy. Future research should prioritize replication, methodological harmonization, and longitudinal validation to facilitate the translation of findings into precision psychiatry. Full article

(This article belongs to the Special Issue Psychiatric Pharmacogenomics)

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28 pages, 1621 KB

Open AccessReview

From Metabolic to Epigenetic Memory: The Impact of Hyperglycemia-Induced Epigenetic Signature on Kidney Disease Progression and Complications

by Sara Cannito, Ida Giardino, Maria D’Apolito, Alessandra Ranaldi, Francesca Scaltrito, Massimo Pettoello-Mantovani and Annamaria Piscazzi

Genes 2025, 16(12), 1442; https://doi.org/10.3390/genes16121442 - 2 Dec 2025

Abstract

Chronic kidney disease is a significant global health burden and a leading cause of cardiovascular morbidity and mortality. Diabetes mellitus is the primary cause of kidney disease, driving the progression of both micro- and macrovascular complications. Sustained hyperglycemia initiates a cascade of deleterious [...] Read more.

Chronic kidney disease is a significant global health burden and a leading cause of cardiovascular morbidity and mortality. Diabetes mellitus is the primary cause of kidney disease, driving the progression of both micro- and macrovascular complications. Sustained hyperglycemia initiates a cascade of deleterious molecular and cellular events, including mitochondrial dysfunction, inflammation, oxidative stress, and dysregulated apoptosis and autophagy, which collectively contribute to the progression of renal injury. Beyond these well-established mechanisms, a compelling body of evidence highlights the pivotal role of epigenetic alterations (such as DNA methylation, histone post-translational modifications, and non-coding RNAs) in mediated long-term kidney damage. The interplay between transcriptional and epigenetic regulation underlies the phenomenon of the “metabolic memory”, wherein cellular dysfunction persists even after glycemic control is achieved. This review synthesizes the current knowledge on mechanisms sustaining metabolic and epigenetic memory, with a particular focus on the epigenetic machinery that establishes and maintains these signals, a concept increasingly termed “epigenetic memory.” Given their reversible nature, epigenetic determinants are emerging as promising biomarkers and a compelling therapeutic avenue. Targeting these “epifactors” offers a novel strategy to halt progression to end-stage renal disease, thereby paving the way for precision medicine approaches in diabetes-related renal disease. Full article

(This article belongs to the Section Epigenomics)

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13 pages, 1306 KB

Open AccessReview

Plant-Derived miRNAs as Potential Cross-Kingdom Cancer Regulators

by Aizhan Rakhmetullina, Zuzanna Lubas and Piotr Zielenkiewicz

Genes 2025, 16(12), 1441; https://doi.org/10.3390/genes16121441 - 2 Dec 2025

Abstract

MicroRNAs (miRNAs) are key posttranscriptional regulators of gene expression that influence cancer initiation, progression, and therapeutic response. While most studies have focused on endogenous miRNAs, emerging evidence has highlighted the role of plant-derived miRNAs as exogenous dietary regulators capable of cross-kingdom gene modulation. [...] Read more.

MicroRNAs (miRNAs) are key posttranscriptional regulators of gene expression that influence cancer initiation, progression, and therapeutic response. While most studies have focused on endogenous miRNAs, emerging evidence has highlighted the role of plant-derived miRNAs as exogenous dietary regulators capable of cross-kingdom gene modulation. This review summarises current knowledge regarding plant-derived miRNAs and their ability to regulate human cancer-related genes. Experimental findings indicate that plant miRNAs can withstand gastrointestinal digestion, enter the circulation, and regulate the expression of oncogenes, tumour suppressors, long noncoding RNAs, and immune checkpoint molecules via canonical RNA-induced silencing mechanisms. Specific examples include miR-156a, miR-159a-3p, miR-166a, miR-167e-5p, miR-171, miR-395e, miR-2911, miR-4995 and miR-5754, which exhibit anticancer activities across various cancer types and modulate key signalling pathways in mammalian cells, highlighting their potential as cross-kingdom regulators with therapeutic relevance. In addition to these characterised miRNAs, certain plant groups, which are rich in bioactive compounds, remain unexplored as sources of functional miRNAs, representing a promising avenue for future research. Collectively, these studies underscore the ability of plant-derived miRNAs to modulate mammalian gene expression and suggest their potential as diet-based or synthetic therapeutic agents. Further investigations into their bioavailability, target specificity, and functional relevance could inform innovative strategies for cancer prevention, integrating nutritional, molecular biological, and therapeutic approaches. Full article

(This article belongs to the Special Issue Function and Regulatory Mechanism of MicroRNAs in Cancers)

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Graphical abstract

12 pages, 378 KB

Open AccessArticle

Host Immunogenetics and Chronic HCV Infection Shape Atopic Risk in Pediatric Beta-Thalassemia: A Genotype–Phenotype Study

by Caterina Cuppari, Alessio Mancuso, Laura Colavita, Clelia Cusmano, Valeria Tallarico, Valerio Caruso, Roberto Chimenz, Mimma Caloiero, Mariarosa Calafiore, Antonina La Mazza and Luciana Rigoli

Genes 2025, 16(12), 1440; https://doi.org/10.3390/genes16121440 - 2 Dec 2025

Abstract

Background: Pediatric patients with beta-thalassemia (BT) face unique immunologic challenges due to chronic transfusions and viral exposure. Hepatitis C virus (HCV), a common infection in polytransfused individuals, may influence immune polarization. However, the combined effect of chronic HCV and host immunogenetics on allergic [...] Read more.

Background: Pediatric patients with beta-thalassemia (BT) face unique immunologic challenges due to chronic transfusions and viral exposure. Hepatitis C virus (HCV), a common infection in polytransfused individuals, may influence immune polarization. However, the combined effect of chronic HCV and host immunogenetics on allergic sensitization remains incompletely understood. Objective: To assess total serum IgE levels and allergic manifestations in HCV-positive vs. HCV-negative BT patients, and explore associations with common polymorphisms in IL10, TLR7, IL4, and IFNG genes Methods: This cross-sectional observational study enrolled 46 BT patients (37 HCV-positive, 9 HCV-negative) and 50 healthy controls. Clinical allergy history, total IgE levels (ELISA), and skin prick tests (SPT) for aeroallergens were collected. Genotyping for IL10 −1082, TLR7 rs179008, IL4 −589, and IFNG +874 polymorphisms was performed. Associations between genotypes, HCV status, and IgE levels were analyzed descriptively due to small sample size Results: HCV-positive BT patients had lower mean IgE levels (18.73 ± 4.2 IU/mL) and fewer reported allergic symptoms (21.6%) compared to HCV-negative counterparts (118.76 ± 7.9 IU/mL; 55.5%). The IL10 −1082 AA and TLR7 rs179008 TT genotypes were more common in the HCV-positive group and were associated with lower IgE levels. No associations were noted for IL4 or IFNG variants. Splenectomy appeared to further modify IgE levels in HCV-negative patients. Due to limited power and absence of multivariate analysis, findings are exploratory. These preliminary observations may inform future studies of immune deviation in chronically infected pediatric cohorts. Conclusions: Chronic HCV infection may contribute to immune tolerance and reduced allergic expression in BT patients, potentially modulated by IL10 and TLR7 genotypes. Further studies with functional immune profiling and larger cohorts are required. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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18 pages, 11393 KB

Open AccessArticle

What Do Single-Cell Models Already Know About Perturbations?

by Andreas Bjerregaard, Iñigo Prada-Luengo, Vivek Das and Anders Krogh

Genes 2025, 16(12), 1439; https://doi.org/10.3390/genes16121439 - 2 Dec 2025

Abstract

Background: Virtual cells are embedded in widely used single-cell generative models. Nonetheless, the models’ implicit knowledge of perturbations remains unclear. Methods: We train variational autoencoders on three gene expression datasets spanning genetic, chemical, and temporal perturbations, and infer perturbations by differentiating [...] Read more.

Background: Virtual cells are embedded in widely used single-cell generative models. Nonetheless, the models’ implicit knowledge of perturbations remains unclear. Methods: We train variational autoencoders on three gene expression datasets spanning genetic, chemical, and temporal perturbations, and infer perturbations by differentiating decoder outputs with respect to latent variables. This yields vector fields of infinitesimal change in gene expression. Furthermore, we probe a publicly released scVI decoder trained on the

CELL \times GENE

Discover Census (

\sim 5.7

M mouse cells) and score genes by the alignment between local gradients and an empirical healthy-to-disease axis, followed by a novel large language model-based evaluation of pathways. Results: Gradient flows recover known transitions in Irf8 knockout microglia, cardiotoxin-treated muscle, and worm embryogenesis. In the pretrained Census model, gradients help identify pathways with stronger statistical support and higher type 2 diabetes relevance than an average expression baseline. Conclusions: Trained single-cell decoders already contain rich perturbation-relevant information that can be accessed by automatic differentiation, enabling in-silico perturbation simulations and principled ranking of genes along observed disease or treatment axes without bespoke architectures or perturbation labels. Full article

(This article belongs to the Special Issue Machine Learning in Cancer and Disease Genomics)

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19 pages, 3312 KB

Open AccessArticle

Global Transcriptome Analysis Reveals the Molecular Mechanism Underlying Seed Physical Dormancy Formation in Medicago sativa

by He Li, Xiaoying Kang, Xu Li, Feng Yuan, Zeng-Yu Wang and Maofeng Chai

Genes 2025, 16(12), 1438; https://doi.org/10.3390/genes16121438 - 1 Dec 2025

Abstract

Seed physical dormancy, also known as hard-seededness, is a characteristic commonly found in higher plants, which functions to prevent water and oxygen from passing through the impermeable seed coat. Background: Notably, seed dormancy has emerged as a critical factor in the domestication [...] Read more.

Seed physical dormancy, also known as hard-seededness, is a characteristic commonly found in higher plants, which functions to prevent water and oxygen from passing through the impermeable seed coat. Background: Notably, seed dormancy has emerged as a critical factor in the domestication of leguminous plants. Alfalfa (Medicago sativa L.) is a globally cultivated high-quality legume forage crop, while the seeds from different varieties maintain varying degrees of hard-seededness. However, the molecular mechanisms underlying physical dormancy in alfalfa seeds remain poorly understood. In particular, the regulatory mechanisms at the transcriptomic level remain unclear, which has hindered the breeding process of varieties with low hard-seededness. Methods: In this study, we performed global transcriptome analysis to discover the genes specifically expressed in the alfalfa seed coat and provide insights into alfalfa seeds’ physical dormancy domestication traits. RNA sequencing was performed on various alfalfa tissues, including roots, stems, leaves, flowers, and seed coats. Results: This analysis led to the identification of 4740 seed coat-specific expressed genes, including key genes such as KNOX4 (a class II KNOTTED-like homeobox gene), qHs1 (encoding endo-1,4-β-glucanase), GmHs1-1 (encoding a calcineurin-like metallophosphoesterase), and KCS12 (β-ketoacyl-CoA synthase). In addition, several seed coat-specific transcription factor families were identified, including ERF, B3, and NAC, among others. Furthermore, a comparison of gene expression profiles between seeds with and without physical dormancy revealed 60 upregulated and 197 downregulated genes associated with physical dormancy. Crucially, functional enrichment analysis demonstrated that these genes are predominantly associated with lipid metabolism pathways, particularly those involved in the formation of “monolayer-surrounding lipid storage bodies.” Conclusions: This key finding suggests that the establishment of physical dormancy is closely linked to the biosynthesis and deposition of specialized lipid-based layers in the seed coat, which likely constitute the primary barrier to water penetration. Our study thus provides fundamental insights and a valuable genetic resource for future functional studies aimed at deciphering and manipulating physical dormancy in alfalfa. Full article

(This article belongs to the Special Issue Genetics and Breeding of Forage)

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17 pages, 1677 KB

Open AccessReview

Molecular Cargo of Exosomes in Prostate Cancer: A Multi-Omics Perspective on Liquid Biopsies

by Roxana Andra Coman, Andreea Nutu, Stefan Strilciuc, Liviuta Budisan and Ioana Berindan-Neagoe

Genes 2025, 16(12), 1437; https://doi.org/10.3390/genes16121437 - 1 Dec 2025

Abstract

Prostate cancer is one of the most common cancers affecting men, and finding better ways to detect and monitor it remains a top priority in oncology. In recent years, scientists have focused their attention on different classes of extracellular bodies, among them the [...] Read more.

Prostate cancer is one of the most common cancers affecting men, and finding better ways to detect and monitor it remains a top priority in oncology. In recent years, scientists have focused their attention on different classes of extracellular bodies, among them the small ones called exosomes. Exosomes are nanoscale extracellular vesicles (30–200 nm) released into body fluids, where they transport molecular cargo reflective of their cell of origin. Instead of serving as liquid biopsies themselves, exosomes present in accessible fluids such as plasma and urine can be analyzed as part of minimally invasive liquid biopsy strategies without the need for surgery or tissue sampling. In prostate cancer, exosomes are not just passive carriers: they actively influence how cancer grows, spreads, and responds to treatment. Exosomes can be extracted from simple fluid samples, opening the door to faster, safer, and more personalised approaches to diagnosis and care. Exosome content is analysed for the molecular profiling of tumours, including genomics, transcriptomics, proteomics, and metabolomics. This has led to the discovery of new biomarkers that may help detect prostate cancer earlier, predict its aggressiveness, and monitor the effectiveness of treatment. This review synthesizes current multi-omics data on exosomal cargo in prostate cancer, highlighting diagnostic, prognostic, and therapeutic implications as well as existing challenges to clinical translation. Full article

(This article belongs to the Section Human Genomics and Genetic Diseases)

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19 pages, 1128 KB

Open AccessArticle

Barriers, Limitations, and Experiences with Clinical Trials—Treatment in Rare Diseases with Prader–Willi Syndrome as an Example

by Merlin G. Butler, Spencer Silvey and Harold J. P. van Bosse

Genes 2025, 16(12), 1436; https://doi.org/10.3390/genes16121436 - 1 Dec 2025

Abstract

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study [...] Read more.

Background/Objectives: Developing and implementing clinical trials for rare diseases is complicated by the incomplete understanding of the varied genotype and subsequent phenotypic differences of a condition, particularly when low numbers of subjects are enrolled in a study. Moreover, a small-scale clinical study may indicate a positive outcome but have too small of a sampling population to adequately evaluate unwanted outcomes. Prader–Willi syndrome (PWS) is one such genetic disorder with varied subtypes and heterogeneity, where little progress has been made in treatment discoveries. Recently, the FDA approved diazoxide choline for treating key features of hyperphagia and obesity associated with PWS based on clinical trial experience. Diazoxide choline activates the ATP-sensitive potassium channel (KATP) of pancreatic beta cells, inhibiting the release of insulin. One of the subunits of KATP is the protein Kir6.2, the gene product of KCNJ11. Methods: Web-based programs and datasets were used to study the gene and protein functional enrichments of Kir6.2 and KCNJ11, including shared gene and/or protein–protein interactions, and biological processes and functions. Results: Four essential domains of related functions were identified: (1) apoptosis, protein degradation, and inflammation; (2) the coupling of G proteins needed for KATP channel activation; (3) glucose metabolism and control; and (4) the maintenance of intracellular ionic homeostasis. Conclusions: Cellular metabolism in the pancreas is linked to membrane excitability by KATP, which regulates insulin production, energy production and storage, appetite regulation, and fatty acid synthesis. As such, diazoxide choline may influence several biological systems beyond pancreatic and metabolic functions. Full article

(This article belongs to the Special Issue Molecular Basis in Rare Genetic Disorders)

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12 pages, 2887 KB

Open AccessArticle

Gene Regulation in Comorbid Migraine and Myogenic Temporomandibular Disorder Pain

by Ran Tao, Sufang Liu, Hui Maltezos and Feng Tao

Genes 2025, 16(12), 1435; https://doi.org/10.3390/genes16121435 - 1 Dec 2025

Abstract

Background/Objectives: Previous studies have demonstrated an association between migraine headache and temporomandibular joint disorders (TMDs), with a higher prevalence of TMD symptoms in patients with migraine. Methods: In this study, we conducted RNA sequencing to identify differentially expressed genes (DEGs) in the spinal [...] Read more.

Background/Objectives: Previous studies have demonstrated an association between migraine headache and temporomandibular joint disorders (TMDs), with a higher prevalence of TMD symptoms in patients with migraine. Methods: In this study, we conducted RNA sequencing to identify differentially expressed genes (DEGs) in the spinal trigeminal nucleus caudalis of mice with migraine-like pain and/or myogenic TMD. Results: We observed 204 upregulated and 274 downregulated genes in the comorbid migraine and TMD group compared to the control group. We identified 15 ferroptosis-related DEGs enriched in the pathways of neurodegeneration, cellular homeostasis, interleukin signaling, and pain response. Gene Ontology analysis highlighted the involvement of neuroinflammatory response and monoamine transmembrane transporter activity, while Gene Set Enrichment analysis showed enrichment in chemokine signaling, cell cycle, and calcium signaling pathways. Immune infiltration analysis identified M0 macrophages, immature dendritic cells, neutrophils, and eosinophils as key responders. Hub genes in the protein–protein interaction network included Gm7536, Rpl17, Rpl22l1, Rpl14, Rps8, Rps29, Rpl35, Gm4889, Gm11808, Rps27rt, Rps12-ps3, Rpl10-ps3, Gm9843, Oas1c, Il1b, and Serpine1, indicating their synergistic roles in such orofacial pain comorbidity. Conclusions: Our results suggest that the comorbid migraine and TMD can regulate gene expressions involving ferroptosis and immune cell responses and the identified DEGs could be targeted to develop novel therapies for this painful comorbidity. Full article

(This article belongs to the Section Neurogenomics)

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17 pages, 8806 KB

Open AccessArticle

Identification and Characterization of the Efbzip Gene Family in Erianthus fulvus and Exploration of Functional Genes Involved in Sucrose Metabolism

by Changzu Zhao, Weiyou Nong, Zhenfeng Qian, Qian Ding, Yujie Wang, Lilian He and Fusheng Li

Genes 2025, 16(12), 1434; https://doi.org/10.3390/genes16121434 - 1 Dec 2025

Abstract

Background/Objectives: Sugarcane (Saccharum spp.) is a major global sugar crop, and improving sucrose accumulation is critical for industry and bioenergy. Due to its high Brix content, Erianthus fulvus (E. fulvus) is valuable for genetic improvement of sugarcane. The bZIP [...] Read more.

Background/Objectives: Sugarcane (Saccharum spp.) is a major global sugar crop, and improving sucrose accumulation is critical for industry and bioenergy. Due to its high Brix content, Erianthus fulvus (E. fulvus) is valuable for genetic improvement of sugarcane. The bZIP transcription factor family critically regulates plant sucrose metabolism, but its roles in sugarcane remain largely unexplored. Methods: Through bioinformatics methods, Efbzip gene family members were systematically identified within the genome of E. fulvus. Gene expression patterns in distinct plant tissues were examined by RNA-seq and quantitative real-time PCR (qRT-PCR). Furthermore, genes potentially involved in sucrose metabolism were screened using transient expression assays and subcellular localization studies conducted in tobacco. Results: Seventy-nine Efbzip genes were identified and classified into nine subgroups, showing uneven distribution across ten chromosomes. Among ten conserved motifs, Motif1 was most conserved. Subcellular localization and physicochemical analyses showed most Efbzip proteins were hydrophilic and nuclear-localized. Cis-regulatory element analysis suggested Efbzip proteins regulate sucrose metabolism through hormone and light-responsive pathways. Segmental duplication primarily drove Efbzip gene family expansion. qRT-PCR showed predominant expression in stems and leaves, with subgroup-specific patterns. Nuclear localization of Efbzip52 was confirmed. Transient overexpression of Efbzip52, Efbzip61, and Efbzip64 significantly increased sucrose content in tobacco leaves, with highly statistically significant (p < 0.0001). Conclusions: In this study, the Efbzip gene family of E. fulvus was systematically characterized for the first time. Key candidate genes potentially involved in sucrose metabolism were identified, providing potential targets for the genetic improvement of sugarcane. Full article

(This article belongs to the Section Plant Genetics and Genomics)

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20 pages, 4060 KB

Open AccessArticle

Secondary Ophthalmic Features Represent Diagnostic Clues and Potential Points of Intervention for Inherited Retinal Diseases (Target 5000 Report 3)

by Kirk A. J. Stephenson, Julia Zhu, Marcus Conway, Bridget Moran, Adrian Dockery, Laura Whelan, Jacqueline Turner, James J. O’Byrne, D. Ian Flitcroft, G. Jane Farrar and David J. Keegan

Genes 2025, 16(12), 1433; https://doi.org/10.3390/genes16121433 - 1 Dec 2025

Abstract

Background/Objective: Inherited retinal degenerations (IRDs) are the leading cause of blind registration in children and adults, yet 30–40% of cases remain genetically unresolved. Deep ophthalmic phenotyping may help to address this shortfall by identifying characteristic phenotypes. We describe the ophthalmic features of patients [...] Read more.

Background/Objective: Inherited retinal degenerations (IRDs) are the leading cause of blind registration in children and adults, yet 30–40% of cases remain genetically unresolved. Deep ophthalmic phenotyping may help to address this shortfall by identifying characteristic phenotypes. We describe the ophthalmic features of patients with stationary or progressive inherited retinal diseases other than outer retinal degeneration (i.e., secondary ophthalmic features, SOFs). Methods: This is a retrospective review of all patients attending an ophthalmic genetics clinic with a genetically confirmed IRD focusing on SOFs including refractive error, cataract, retinal detachment (RRD), cystoid macular lesions (CML) and epiretinal membrane (ERM). These features were assessed in the context of phenotype and genotype. Results: In a cohort of 429 genotyped patients, ≥1 SOFs were seen in 70.2% of patients, with 36.6% being affected by multiple SOFs. Refractive error (63.3%) and cataract (43.4%) were the most common secondary features, with a subset affected by CML (14.7%), ERM (10%) and RRD (4.7%). Conclusions: SOFs are common in patients with IRDs and most are amenable to therapeutic intervention even when no primary treatment (e.g., gene therapy) is available. We highlight patterns associated with genotypes and disease groups which may aid harmonisation of clinical and genetic diagnoses. Full article

(This article belongs to the Special Issue Genetic Diagnosis and Therapeutics of Eye Diseases)

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13 pages, 789 KB

Open AccessArticle

Endometrial Microbial Profile in Infertile Women with Chronic Endometritis: Intensified Culturomics and 16S rDNA Gene Sequencing

by Bárbara Lara-del-Río, Rocío Sánchez-Ruiz, Mónica Bernal-Sánchez, Francisco Ruiz-Cabello-Osuna, José María Navarro-Marí and José Gutiérrez-Fernández

Genes 2025, 16(12), 1432; https://doi.org/10.3390/genes16121432 - 1 Dec 2025

Abstract

Background/Objectives: Chronic endometritis (CE) has been linked to implantation failure, recurrent pregnancy loss, and endometrial dysbiosis with low Lactobacillus abundance. We assessed the endometrial microbiota in infertile women with CE and the added value of combining intensified culturomics with 16S rDNA NGS. Methods: [...] Read more.

Background/Objectives: Chronic endometritis (CE) has been linked to implantation failure, recurrent pregnancy loss, and endometrial dysbiosis with low Lactobacillus abundance. We assessed the endometrial microbiota in infertile women with CE and the added value of combining intensified culturomics with 16S rDNA NGS. Methods: Cross-sectional study with descriptive results of 15 endometrial biopsies analyzed in parallel by intensified culture and 16S rDNA (V3–V6) sequencing (RA threshold ≥ 5%). Results: Culture yielded growth in 13/15 samples (86.7%), whereas NGS reported findings in 15/15 (100%). NGS provided additional taxa beyond culture in 14/15 (93.3%), while culture identified taxa missed by NGS in 10/15 (66.7%). In both culture-negative cases, NGS detected ≥1 taxon. Lactobacillus spp. appeared exclusively by NGS in 26.7% of samples; Fannyhessea vaginae showed the highest mean RA by NGS and did not grow in culture, underscoring complementarity. Conclusions: 16S NGS complements intensified culturomics for characterizing the endometrial microbiota in CE, enhancing detection—especially when culture is negative—and supports a combined, clinically contextualized interpretation. Larger, controlled cohorts are warranted to validate diagnostic and prognostic utility. Full article

(This article belongs to the Section Molecular Genetics and Genomics)

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19 pages, 5799 KB

Open AccessArticle

Unveiling Novel Traits Associated with Ulcerative Colitis via Phenome-Wide Associations Enhanced by Polygenic Risk Statistics

by Yiming Wu, Ling Liu, Meltem Ece Kars, Rui Li, Menglong Li and Yuval Itan

Genes 2025, 16(12), 1431; https://doi.org/10.3390/genes16121431 - 30 Nov 2025

Abstract

Background: Ulcerative colitis (UC) is a major form of inflammatory bowel disease affecting the gastrointestinal tract. Increasing evidence suggests UC is predisposed to co-occurring with other autoimmune diseases, yet its pathogenesis remains insufficiently understood. Large-scale biobank-based cross-trait genetic analyses may provide insights [...] Read more.

Background: Ulcerative colitis (UC) is a major form of inflammatory bowel disease affecting the gastrointestinal tract. Increasing evidence suggests UC is predisposed to co-occurring with other autoimmune diseases, yet its pathogenesis remains insufficiently understood. Large-scale biobank-based cross-trait genetic analyses may provide insights into the origins of UC and its comorbidities. Methods: Using the UK Biobank and Mount Sinai BioMe Biobank, we conducted genome-wide association studies (GWASs) in individuals of European ancestry. High-impact rare variants were aggregated for collapsing analysis. Genome-wide significant variants were tested in a phenome-wide association study (PheWAS) to explore UC comorbidities. Polygenic risk scores (PRSs) were derived from large-scale GWASs under different thresholds and functionalities, and the best-performing PRS was further applied in a PRS-based PheWAS. Genetic correlation between UC and highly associated traits was evaluated. Results: GWASs identified four genome-wide significant loci, including two novel variants (rs2314757, p = 4.82 × 10⁻¹¹, OR = 0.81; rs6869382, p = 2.48 × 10⁻⁸, OR = 0.83) and two previously reported UC-associated sites (rs4654925, p = 1.85 × 10⁻⁸, OR = 0.84; rs2836882, p = 1.23 × 10⁻¹¹, OR = 0.78) outside the HLA region. The optimal PRS, constructed with SNPs at p < 0.05, conferred an odds ratio of 5.86 (95% CI: 5.05–6.86) for UC in individuals with the highest versus lowest quintile. Both variant- and PRS-based PheWASs consistently highlighted type 1 diabetes (T1D) as the most significant comorbidity, confirmed by genetic correlation analysis. Conclusions: This study reveals novel loci contributing to UC and highlights comorbidities with shared genetic bases. UC PRSs demonstrated strong utility beyond risk prediction, effectively identifying UC-associated traits. A robust genetic correlation was established between UC and T1D. Full article

(This article belongs to the Section Technologies and Resources for Genetics)

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24 pages, 1095 KB

Open AccessArticle

Generation of a Compendium of Transcription Factor Cascades and Identification of Potential Therapeutic Targets Using Graph Machine Learning

by Sonish Sivarajkumar, Romy Roy, Pratyush Tandale, Ankit Bhardwaj, Kipp W. Johnson, Anoop Titus, Benjamin S. Glicksberg, Shameer Khader, Kamlesh K. Yadav and Lakshminarayanan Subramanian

Genes 2025, 16(12), 1430; https://doi.org/10.3390/genes16121430 - 30 Nov 2025

Abstract

Background: Transcription factors (TFs) are critical regulators of gene expression, and their dysregulation is implicated in diseases like cancer. This study aims to create a comprehensive resource of TF cascades to identify potential therapeutic targets. Methods: We extracted TF interactions from the STRING [...] Read more.

Background: Transcription factors (TFs) are critical regulators of gene expression, and their dysregulation is implicated in diseases like cancer. This study aims to create a comprehensive resource of TF cascades to identify potential therapeutic targets. Methods: We extracted TF interactions from the STRING database, constructed a knowledge graph using graph machine learning, and performed pathway enrichment analysis with Enrichr. Network analysis and PageRank identified influential TFs. Results: We generated 81,488 unique TF cascades, with the longest containing 62 TFs. Key TFs (e.g., MYC, TP53, STAT3) were identified, and enriched pathways included cancer-related processes. A knowledge graph and dataset were made publicly available. Conclusions: This compendium of TF cascades provides a valuable resource for understanding TF interactions and identifying novel drug targets for precision therapeutics. Full article

(This article belongs to the Section Bioinformatics)

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21 pages, 1456 KB

Open AccessArticle

Surviving the Heat: Genetic Diversity and Adaptation in Sudanese Butana Cattle

by Guilherme B. Neumann, Paula Korkuć, Siham A. Rahmatalla, Monika Reißmann, Elhady A. M. Omer, Salma Elzaki and Gudrun A. Brockmann

Genes 2025, 16(12), 1429; https://doi.org/10.3390/genes16121429 - 30 Nov 2025

Abstract

Background: Butana are native Sudanese Bos indicus cattle that are well adapted to arid environments and valued for their relatively high milk performance and resilience under harsh conditions. Despite their adaptive advantages, Butana cattle face the risk of genetic erosion due to low [...] Read more.

Background: Butana are native Sudanese Bos indicus cattle that are well adapted to arid environments and valued for their relatively high milk performance and resilience under harsh conditions. Despite their adaptive advantages, Butana cattle face the risk of genetic erosion due to low production performance and the absence of structured breeding programs underscoring the urgent need to conserve their unique genetic potential for climate-resilient livestock development. Methods: In this study, we analyzed whole-genome sequencing data from 40 Butana cattle to assess their genetic diversity, population structure, signatures of selection, and potential pathogen load. Results: Butana cattle exhibited high nucleotide diversity and low levels of inbreeding, indicating a stable gene pool shaped by natural selection rather than by intensive breeding. Signatures of selection and functional variant analysis revealed candidate genes involved in heat stress adaptation (COL6A5, HSPA1L, TUBA8, XPOT), metabolic processes (G6PD, FAM3A, SLC10A3), and immune regulation (IKBKG, IRAK3, IL18RAP). Enrichment analyses and RoH island mapping consistently highlighted immune and thermoregulatory pathways as key selection targets, distinguishing Butana from both the geographically neighbored Kenana cattle and the specialized dairy cattle breed Holstein. Furthermore, metagenomic screening of unmapped reads detected the tick-borne parasite Theileria annulata and the opportunistic pathogen Burkholderia cenocepacia in all animals, underscoring the importance of integrating pathogen surveillance into genomic studies. Conclusions: Taken together, our findings highlight the distinct adaptive genomic profile of Butana cattle and reinforce their value in breeding programs aimed at improving climate resilience and disease resistance in livestock through the utilization of local breeds. Full article

(This article belongs to the Section Animal Genetics and Genomics)

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27 pages, 3447 KB

Open AccessArticle

Genetic Insight into Expression-Defined Melanoma Subtypes and Network Mechanisms: An in Silico Study

by Desirèe Speranza, Mariapia Marafioti, Martina Musarra, Vincenzo Cianci, Cristina Mondello, Maria Francesca Astorino, Mariacarmela Santarpia, Natasha Irrera, Mario Vaccaro, Nicola Silvestris, Concetta Crisafulli, Marco Calabrò and Silvana Briuglia

Genes 2025, 16(12), 1428; https://doi.org/10.3390/genes16121428 - 30 Nov 2025

Abstract

Background: Melanoma is a highly heterogeneous neoplasia in which transcriptional profile encodes much of the biological diversity that determines tumor progression and therapeutic response. To refine its molecular stratification and profiles characterization, we conducted an in silico transcriptomic analysis. Methods: Public microarray datasets [...] Read more.

Background: Melanoma is a highly heterogeneous neoplasia in which transcriptional profile encodes much of the biological diversity that determines tumor progression and therapeutic response. To refine its molecular stratification and profiles characterization, we conducted an in silico transcriptomic analysis. Methods: Public microarray datasets from the GEO and ArrayExpress were examined, and the E-MTAB-6697 expression dataset was selected. We used a K-Means clustering algorithm to stratify 194 tumor samples into expression-driven subgroups and analyzed each one to define their transcriptional and biological profiles. Differential expression analysis between identified clusters and controls was performed. Additionally, we applied Weighted-Gene correlation analysis to identify coordinated expression hubs in the tumor dataset and tested the resulting modules for correlation with the identified clusters. Results: Unsupervised clustering of melanoma transcriptomic profiles identified three distinct molecular subtypes characterized by divergent biological programs. While all clusters shared the dysregulation of pathways involved in epidermal differentiation, immune response, and lipid metabolism, they diverged in proliferation, phenotypic plasticity, metabolic adaptation, and apoptotic regulation. Cluster A was characterized by enrichment in DNA replication, repair, and mitochondrial metabolism modules, suggesting a proliferative yet genomically stable state. Cluster B showed enrichment in immune and cytokine signaling pathways alongside reduced proliferative activity, consistent with a quiescent or transitional phenotype. Cluster C displayed coordinated enrichment in cell-cycle, DNA-maintenance, and neuroectodermal reprogramming pathways, indicating a highly plastic and proliferative subtype. Despite these molecular distinctions, all clusters retained an “immunologically hot” profile (IPS 7–8), indicating potential responsiveness to immunotherapy. Conclusions: These findings provide an overview of the functional characteristics of melanoma heterogeneity and identify biological processes that could be targeted by drugs for the development of tailored therapies for each subtype. Nevertheless, future studies in independent clinically annotated cohorts would be required. Full article

(This article belongs to the Section Bioinformatics)

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17 pages, 4150 KB

Open AccessArticle

Characterization of the Mitochondrial Genome of Cavariella salicicola: Insight into the Codon Usage Bias and Phylogenetic Implications in Aphidinae

by Tian-Xing Jing, Yan-Jin Zhang, Pei-Xuan Li, Qian Wang, Jin Yang, Hong-Hua Su and Shuai Zhang

Genes 2025, 16(12), 1427; https://doi.org/10.3390/genes16121427 - 29 Nov 2025

Abstract

Background: Cavariella salicicola (Hemiptera: Aphidinae) is a pest on Salix spp. and various Umbelliferae (Apiaceae) vegetables. However, the taxonomic status and phylogenetic relationship of the genus Cavariella within Aphidinae remain controversial due to the small body size and easily confused external morphology. [...] Read more.

Background: Cavariella salicicola (Hemiptera: Aphidinae) is a pest on Salix spp. and various Umbelliferae (Apiaceae) vegetables. However, the taxonomic status and phylogenetic relationship of the genus Cavariella within Aphidinae remain controversial due to the small body size and easily confused external morphology. Methods: The complete mitochondrial genome of C. salicicola collected from Oenanthe javanica was sequenced using the Illumina platform and compared with C. theobaldi. The codon usage bias of two Cavariella aphids was assessed through Enc plot, PR2 plot, and neutrality plot analyses. Furthermore, phylogenetic trees were constructed based on both Maximum Likelihood and Bayesian Inference analysis. Results: The C. salicicola mitochondrial genome comprises 15,720 bp and represents a typical circular DNA molecule with a high AT content of 83.8%. It contains the standard 37 genes, including 2 ribosomal RNAs (rRNAs), 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), and 2 long non-coding regions (control and repeat regions). Varying degrees of codon usage bias were found across different PCGs, and the bias was predominantly influenced by natural selection rather than mutational pressure. The ratio of nonsynonymous to synonymous substitutions (Ka/Ks) indicated that all PCGs in C. salicicola, as well as most other Aphidinae species, are under strong purifying selection. The phylogenetic analysis based on Maximum Likelihood and Bayesian Inference both strongly supported the monophyly of Aphidinae, Macrosiphini, and Aphidini. Crucially, the monophyletic genus Cavariella was resolved as a sister group to all other sampled species within the tribe Macrosiphini. Conclusions: This study provides new molecular data to support the sister relationship of the genus Cavariella to other Macrosiphini aphids. This study will enhance our understanding of phylogenetic relationships within the subfamily Aphidinae. Full article

(This article belongs to the Special Issue Molecular Evolution, Mitochondrial Genomics and Mitochondrial Genome Expression in Animals: 2024–2025)

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