Genes

16 pages, 3380 KB

Open AccessArticle

4-Phenylbutyrate Plus Wildtype GAT-1 Augmentation: A Dual Therapy to Rescue SLC6A1 Variant-Associated Developmental and Epileptic Encephalopathy

by Aiden James Delahanty, Kaitlin James, Emma Grace Carter, Ziang Debbie Song, Juexin Wang, Melissa Bassette and Jing-Qiong Kang

Genes 2026, 17(8), 983; https://doi.org/10.3390/genes17080983 - 21 Aug 2026

Viewed by 372

Abstract

Background: Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that [...] Read more.

Background: Pathogenic variants in SLC6A1, which encodes the γ-aminobutyric acid (GABA) transporter GAT-1, cause developmental and epileptic encephalopathies (DEEs) through reduced GABA uptake, impaired transporter trafficking, and functional haploinsufficiency. 4-phenylbutyrate (PBA) is a clinically available small molecule with chemical-chaperone and histone-deacetylase-inhibitor activities that can rescue misfolded GABAergic proteins, but variant-level rescue data are needed to guide precision treatment. Methods: We report a novel de novo missense mutation p.Ala305Val in GAT-1 encoding SLC6A1, in a patient with myoclonic-atonic epilepsy and a developmental and epileptic encephalopathy phenotype. Ala305Val was compared with the residue-matched comparator p.Ala305Thr (Ala305Thr). Variant effects were evaluated by (i) protein-structure prediction across nine stability-prediction algorithms using the cryo-EM-derived human GAT-1 template (PDB 7Y7W); (ii) 3H-GABA uptake assays in HEK293T cells and in human iPSC-derived astrocytes and cortical neurons; (iii) live-cell confocal microscopy of ER colocalization; (iv) pharmacologic rescue with PBA, TUDCA and salubrinal (v) and GAT-1 cDNA gene-augmentation, alone and in combination with PBA. Results: AI-based stability predictors uniformly indicated destabilization of GAT-1 p.Ala305Val and GAT-1 p.Ala305Thr. GAT-1 p.Ala305Val reduced 3H GABA uptake across HEK293Ts, astrocytes, and neurons. The mutant transporter accumulated within the endoplasmic reticulum (ER), with ER colocalization rising from approximately 30% in wildtype to ~80% in GAT-1 p.Ala305Val; PBA reduced ER retention to approximately ~40% and restored total GAT-1 fluorescence toward wildtype levels. Pharmacochaperones (PBA, TUDCA) restored GABA uptake for the mutant transporters. Wildtype GAT-1 gene augmentation improved GABA uptake in the heterozygous condition but combined PBA plus wildtype allele augmentation produced rescue greater than either intervention alone in the available dose-response ranges. Conclusions: GAT-1 p.Ala305Val is a trafficking-impaired, loss-of-function variant whose dysfunction is amenable to two convergent therapeutic axes: pharmacologic correction of folding and trafficking, and augmentation of functional transporter expression. These findings support a two-pronged precision-medicine framework for SLC6A1-related DEEs in which PBA increased the transporter function augmented by genetic approaches. Full article

(This article belongs to the Special Issue Feature Papers in "Neurogenetics and Neurogenomics": 2026)

► Show Figures

Figure 1

17 pages, 10115 KB

Open AccessArticle

Single-Cell and Bulk Transcriptomics Reveal an Epithelial LTF-LRP11 Signaling Axis Associated with Severe COVID-19 Susceptibility

by Ana Luiza Labbate Bonaldo, Jeferson dos Santos Souza, Jakeline Santos Oliveira, Amanda Piveta Schnepper, Caio Fernando Ferreira Mussatto, Victória Larissa Schimidt Camargo, Paula Paccielli Freire, Otavio Cabral-Marques, Sarah Santiloni Cury and Robson Francisco Carvalho

Genes 2026, 17(8), 982; https://doi.org/10.3390/genes17080982 - 21 Aug 2026

Viewed by 413

Abstract

Background/Objectives: The molecular mechanisms underlying susceptibility to severe COVID-19 remain incompletely understood. We aimed to identify the signaling pathways associated with disease severity by integrating transcriptomic data and characterizing ligand–receptor interactions involved in the host response to SARS-CoV-2 infection. Methods: We integrated publicly [...] Read more.

Background/Objectives: The molecular mechanisms underlying susceptibility to severe COVID-19 remain incompletely understood. We aimed to identify the signaling pathways associated with disease severity by integrating transcriptomic data and characterizing ligand–receptor interactions involved in the host response to SARS-CoV-2 infection. Methods: We integrated publicly available bulk RNA-sequencing data from nasopharyngeal (NP) swabs (GSE152075) and single-cell RNA-sequencing data from bronchoalveolar lavage fluid samples (GSE145926). Analyses focused on secreted ligands and their cognate receptors and were performed in relation to demographic and clinical characteristics associated with susceptibility to severe COVID-19, including sex, age, and viral load. Results: Patients with characteristics associated with increased susceptibility to severe disease, including male sex, advanced age, and high viral load, exhibited transcriptional programs enriched for inflammatory and immune-response pathways. In contrast, individuals with lower susceptibility displayed reduced expression of 43 ligand genes compared with matched negative controls, suggesting distinct secretory programs associated with the host response to infection. We identified an association between the expression of lactoferrin (LTF) and its receptor, LDL receptor-related protein 11 (LRP11), and susceptibility to severe COVID-19. LRP11 was predominantly expressed in human pulmonary epithelial cells, and its expression increased during SARS-CoV-2 infection in monkeys. Conclusions: Our findings provide insight into the molecular mechanisms associated with susceptibility to severe COVID-19 through the analysis of ligand and receptor expression in nasopharyngeal swabs and bronchoalveolar lavage fluid samples. The association between LTF and LRP11 highlights a potentially relevant signaling axis in disease pathogenesis and provides a rationale for future functional studies aimed at clarifying its role in COVID-19 severity. Full article

(This article belongs to the Special Issue Systems Biology of Single Cells: Bridging Genomics and Functional Insights)

► Show Figures

Graphical abstract

29 pages, 2001 KB

Open AccessReview

BMAL1-Mediated Circadian Regulation of Oocyte Quality and IVF Outcomes

by Charalampos Voros, Nektaria Zagorianakou, Stylianos Makrydimas, Fotios Chatzinikolaou, Georgios Papadimas, Aristotelis Marios Koulakmanidis, Nikolaos Thomakos, Panagiotis Antsaklis, Georgios Daskalakis and George Makrydimas

Genes 2026, 17(8), 981; https://doi.org/10.3390/genes17080981 - 21 Aug 2026

Viewed by 452

Abstract

Successful embryo development transpires far before fertilization inside the meticulously regulated microenvironment of the ovarian follicle. Increasing data indicates that circadian regulatory systems influence several processes that define oocyte competence, including mitochondrial activity, oxidative balance, meiotic development, and cellular metabolism. Brain and muscle [...] Read more.

Successful embryo development transpires far before fertilization inside the meticulously regulated microenvironment of the ovarian follicle. Increasing data indicates that circadian regulatory systems influence several processes that define oocyte competence, including mitochondrial activity, oxidative balance, meiotic development, and cellular metabolism. Brain and muscle ARNT-like protein 1 (BMAL1), an essential transcription factor in circadian regulation, has garnered significant interest due to its crucial involvement in ovarian physiology and reproductive function. Dysregulated BMAL1 signaling has been linked to compromised folliculogenesis, diminished steroidogenesis, mitochondrial dysfunction, elevated oxidative stress, and irregularities in meiotic spindle organization, all of which may negatively impact oocyte quality and early embryo development. Recent experimental and clinical findings indicate that results of assisted reproduction may be influenced by circadian disruption, sleep problems, obesity, ageing, and metabolic dysfunction. Full article

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

► Show Figures

Figure 1

16 pages, 3574 KB

Open AccessArticle

Functional Characterization of Patient-Derived Myotubes Carrying ANO5 and ORAI3 Variants in RYR1-Negative Malignant Hyperthermia Susceptibility

by Hirotsugu Miyoshi, Sachiko Otsuki, Kenshiro Kido, Ayako Sumii, Tsuyoshi Ikeda, Guoqiang Xia, Yuko Noda, Tomomi Ishii, Satoshi Kamiya, Soshi Narasaki, Huei-Ming Yeh, Pei-Lung Chen, Yasuko Ichihara, Keiko Mukaida and Yasuo M. Tsutsumi

Genes 2026, 17(8), 980; https://doi.org/10.3390/genes17080980 - 20 Aug 2026

Viewed by 346

Abstract

Background/Objectives: Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder of skeletal muscle primarily associated with pathogenic variants in RYR1; however, a substantial proportion of MH-susceptible individuals lack identifiable variants in known genes. This study aimed to identify novel genetic contributors in Ca [...] Read more.

Background/Objectives: Malignant hyperthermia (MH) is a life-threatening pharmacogenetic disorder of skeletal muscle primarily associated with pathogenic variants in RYR1; however, a substantial proportion of MH-susceptible individuals lack identifiable variants in known genes. This study aimed to identify novel genetic contributors in Ca²⁺-induced Ca²⁺ release (CICR)-positive patients without RYR1 variants and to evaluate their functional relevance. Methods: Among 29 CICR-positive individuals without pathogenic variants identified by gene panel testing, five patients underwent whole-exome sequencing (WES). In one family, heterozygous variants in ANO5 (p.Arg547Gln) and ORAI3 (p.Arg287Cys) were identified. To evaluate their functional significance, intracellular Ca²⁺ dynamics were analyzed in primary myotubes derived from Case 165, an affected individual carrying both variants, and compared with those from CICR-negative controls and CICR-positive patients harboring RYR1 variants. Results: Myotubes derived from Case 165 demonstrated enhanced sensitivity to caffeine and 4-chloro-m-cresol, elevated resting intracellular Ca²⁺ levels, and greater Ca²⁺ reduction under Ca²⁺-free conditions compared with CICR-negative controls, resembling the phenotype observed in the RYR1 variant group. In contrast, dantrolene-induced Ca²⁺ reduction was significantly greater only in the RYR1 variant group. Conclusions: These findings suggest that ANO5 and ORAI3 variants may contribute to abnormal Ca²⁺ regulation in MH-susceptible individuals without RYR1 mutations and highlight the importance of combining genomic analysis with functional validation to identify novel genetic contributors to MH susceptibility. Full article

(This article belongs to the Section Bioinformatics)

► Show Figures

Figure 1

12 pages, 1777 KB

Open AccessArticle

Dissecting Missing Heritability in Rare Inherited Macular Dystrophies

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

Genes 2026, 17(8), 979; https://doi.org/10.3390/genes17080979 - 20 Aug 2026

Viewed by 490

Abstract

Background/Objectives: To describe the genetic resolution rate, molecular findings, and genotype–phenotype correlations of non-ABCA4 and non-BEST1 inherited macular dystrophies (IMDs) within an Irish inherited retinal disease (IRD) registry. Methods: Retrospective review of individuals with a clinical diagnosis of macular or cone [...] Read more.

Background/Objectives: To describe the genetic resolution rate, molecular findings, and genotype–phenotype correlations of non-ABCA4 and non-BEST1 inherited macular dystrophies (IMDs) within an Irish inherited retinal disease (IRD) registry. Methods: Retrospective review of individuals with a clinical diagnosis of macular or cone dystrophy. Comprehensive phenotyping (dilated ocular biomicroscopy, multimodal retinal imaging, visual electrophysiology) and genetic testing (panel-based next-generation sequencing, single-gene testing, whole exome/genome sequencing, WES/WGS). Variants were interpreted using ACMG AMP criteria, and genotype-phenotype match was confirmed through multidisciplinary review. Results: 232 patients with macular/cone dystrophies were identified. ABCA4 and BEST1 accounted for most molecular diagnoses (47.4%). Removing ABCA4 and BEST1, 59.0% of IMDs were genetically unresolved, higher than the rate in general IRD cohorts. Deep phenotyping enabled diagnostic reclassification in 13/72 (18.1%), namely achromatopsia, congenital stationary night blindness, and oculocutaneous albinism. Further genetic testing resolved 35/72 (48.6%) of those unresolved on first-line testing, with PRPH2 being most prevalent (n = 12), followed by GUCY2D, CRB1, PROM1, and CRX. Characteristic phenotypic signatures—such as CRB1-associated retinal thickening and retinoschisis or PROM1-associated Stargardt-like changes—supported known genotype–phenotype correlations. Conclusions: Genetic resolution rates for rare IMDs remain lower than pan-retinal IRD phenotypes. Beyond ABCA4 and BEST1, IMDs exhibit substantial genetic and phenotypic heterogeneity (24 genotypes in this cohort), with low molecular diagnostic rates despite comprehensive sequencing approaches. Detailed multimodal phenotyping (i.e., structural, functional and extra-ocular) is essential to refine diagnosis, guide genetic testing and interpret candidate variants. Genetic testing is challenging when the retinal phenotype is advanced (i.e., atrophy) or lacks pathognomonic features. Meticulous phenotyping (functional, structural and systemic) and broader genomic strategies (e.g., WES/WGS) may further increase diagnostic yield, though gene panel content is constantly improving. Consistently improving molecular diagnostic rates will ensure equitable access to emerging gene-specific therapies. Full article

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

► Show Figures

Figure 1

28 pages, 13734 KB

Open AccessArticle

Genetic Structure of the Perennial Flax Trifecta: Linum austriacum, L. lewisii, L. perenne

by Hannah J. Hall, Neil O. Anderson, Donald L. Wyse and Kevin J. Betts

Genes 2026, 17(8), 978; https://doi.org/10.3390/genes17080978 - 20 Aug 2026

Viewed by 315

Abstract

Background/Objectives. Annual flaxseed (Linum usitatissimum) is the most cultivated Linum species. Perennial species (Linum austriacum, Linum lewisii, Linum perenne) show potential as alternative oilseed and fiber sources. It is critical to determine genetic variation in any [...] Read more.

Background/Objectives. Annual flaxseed (Linum usitatissimum) is the most cultivated Linum species. Perennial species (Linum austriacum, Linum lewisii, Linum perenne) show potential as alternative oilseed and fiber sources. It is critical to determine genetic variation in any collection to understand relationships and utilization within a breeding program. The research objectives were to analyze the genetic structure of the trifecta perennial flax using single-nucleotide polymorphic (SNP) markers for species differentiation and to discover potential Centers of Origin and/or diversity. Methods. We tested 70 USDA-GRIN-global wild populations (19 L. austriacum, 32 L. lewisii, 19 L. perenne; N = 850 seedling genotypes) to generate 9804 DArTseqLD SNPs (Group 1). Results. After filtering, within L. austriacum, 1199 SNPs (261 genotypes; Group 2) remained; in L. lewisii, there were 90 unique SNPs (273 genotypes; Group 3); in L. perenne, there were 2716 SNPs (309 genotypes; Group 4). Four genetic clusters were detected using STRUCTURE, consistent with principal coordinate analysis and SplitsTrees. Clear distinctions within and among each perennial species’ populations were found, separating into two distinct pure taxon groupings, along with peripheral populations or outliers. Both L. austriacum and L. lewisii potentially had two putative Centers of Origin, although L. perenne had one. Conclusions. The occurrence of sympatric Linum species in the wild could explain the occurrence of peripheral population groups within each taxon, although other explanations are also possible. This may be consistent with the potential for genetic exchange between the perennial species and the greater genetic variability available. Future research will evaluate additional Linum to further delineate the genetic structure and variation within the genus Linum. Full article

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

► Show Figures

Graphical abstract

17 pages, 11487 KB

Open AccessArticle

Integrated Analysis of Multiple Databases Identifies Tissue Inhibitor of Metalloproteinase 1 Expression and Its Association with the Immune Microenvironment in Colorectal Cancer

by Yun Xie, Jun Li, Zuwei Yan and Wenguang Zhang

Genes 2026, 17(8), 977; https://doi.org/10.3390/genes17080977 - 20 Aug 2026

Viewed by 399

Abstract

Background: In recent decades, the incidence of colorectal cancer (CRC) has been rising worldwide. CRC ranks second in cancer-related mortality. The identification of reliable biomarkers for early diagnosis and prognosis prediction, along with a deeper understanding of the underlying molecular events, holds substantial [...] Read more.

Background: In recent decades, the incidence of colorectal cancer (CRC) has been rising worldwide. CRC ranks second in cancer-related mortality. The identification of reliable biomarkers for early diagnosis and prognosis prediction, along with a deeper understanding of the underlying molecular events, holds substantial promise for improving patient outcomes. The tissue inhibitor of the metalloproteinase 1 (TIMP1) gene is overexpressed in various gastrointestinal malignancies and contributes to tumor progression. However, its role in regulating the CRC tumor immune microenvironment (TIME) and its potential as a clinically actionable prognostic biomarker remain unclear. Methods: To probe how TIMP1 acts as a prognosis-related candidate biomarker in colorectal carcinoma, TCGA-derived datasets were adopted to conduct Kaplan–Meier survival assessment. We also investigated the connection between the expression abundance of TIMP1 and the infiltration of immune populations and intratumoral lymphocytes; furthermore, immune checkpoint-related genes were systematically assessed across multiple tumor types via the TISIDB and TIMER2.0 platforms, with particular emphasis on CRC. We adopted the ESTIMATE scoring system to figure out how TIMP1 gene expression correlates with the phenotypic properties of the colorectal-cancer TIME. We relied on the limma toolkit for the screening of differential transcripts from high-TIMP1 and low-TIMP1 cohorts. Enrichment assessments covering Gene Ontology terms and Kyoto Encyclopedia of Genes and Genomes entries were then carried out to predict the potential biological pathways associated with TIMP1. We constructed the protein–protein interaction map for TIMP1-interacting partners via the STRING repository. To further explore TIMP1-correlated genes, we performed Venn diagram intersection analysis combined with Spearman’s correlation test. Finally, quantitative reverse-transcription PCR was then implemented to detect TIMP1 messenger-RNA abundance inside the RKO colorectal carcinoma cell line as well as normal colonic epithelial CCD-18Co cells, which offered in vitro experimental verification for our bioinformatic outcomes. Results: According to outcome data, TIMP1 transcripts were markedly up-regulated in CRC specimens and cell lines relative to normal samples. Elevated TIMP1 expression served as a poor-prognosis indicator for overall survival (hazard ratio [HR] = 0.43, 95% confidence interval [CI] = 0.29–0.64, p < 0.001) and disease-specific survival (HR = 0.39, 95% CI = 0.22–0.68, p = 0.001) among colorectal-carcinoma patients. TIMP1-high and TIMP1-low groups exhibited notable differences in immune cell infiltration (CD8⁺ T, macrophage, mast, neutrophil, B, monocyte, dendritic, and CD4⁺ T cells). TIMP1 expression was also significantly correlated with tumor-infiltrating lymphocytes, key immune checkpoint genes (e.g., CD274 [PD-L1] and CTLA4), and immunomodulatory chemokines (e.g., CCL3 and CCL5). Twelve TIMP1-interacting DEGs were selected: COL5A1, FN1, PRG4, and a cluster of nine MMPs (MMP1/2/3/7/8/9/11/13/14), all of which showed significant positive correlations with TIMP1 (r = 0.31–0.63, all p < 0.001). Conclusions: TIMP1 expression correlates with features of the tumor immune microenvironment and extracellular matrix remodeling in CRC, suggesting that TIMP1 shows potential as a candidate biomarker. However, its potential as a therapeutic target warrants further experimental investigation. Full article

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

► Show Figures

Figure 1

21 pages, 2967 KB

Open AccessReview

Chronic Urticaria-Associated Syndromes: Is Andersen–Tawil Syndrome One of Them?

by Vedrana Bulat, Lucija Zanze, Mirta Peček, Dajana Smoljan-Filipović, Katarina Dragun and Liborija Lugović-Mihić

Genes 2026, 17(8), 976; https://doi.org/10.3390/genes17080976 - 19 Aug 2026

Viewed by 620

Abstract

The spectrum of syndromes associated with chronic urticaria (CU) is broad, ranging from monogenic autoinflammatory diseases (a single gene defect drives disease through dysregulated innate immunity) to multifactorial and acquired conditions (urticaria arises as part of a broader, polygenic or immune-mediated systemic process). [...] Read more.

The spectrum of syndromes associated with chronic urticaria (CU) is broad, ranging from monogenic autoinflammatory diseases (a single gene defect drives disease through dysregulated innate immunity) to multifactorial and acquired conditions (urticaria arises as part of a broader, polygenic or immune-mediated systemic process). Monogenic autoinflammatory conditions presenting with urticaria include cryopyrin-associated periodic syndromes (CAPS)—encompassing familial cold autoinflammatory syndrome (FCAS), Muckle–Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID/CINCA) and the broader group of familial cold urticarias. Monogenic conditions with well-characterized gain-of-function NLR family pyrin domain containing 3 (NLRP3) variants present with recurrent hives, a cardinal feature associated with recurrent fevers. Multifactorial and acquired autoinflammatory or immune-mediated conditions include Schnitzler syndrome, adult-onset Still’s disease, hypereosinophilic syndrome, Gleich syndrome, Wells syndrome, and Sjögren syndrome. Multifactorial conditions, including Schnitzler syndrome and Still’s disease, manifest similarly, with CU as an initial sign and a shared pathogenic mechanism of innate immune dysregulation, with interleukin-1β playing a central, pro-inflammatory role as a major pyrogen. Here, we also present a female patient with clinically established Andersen–Tawil syndrome (ATS) who developed recurrent hives on her extremities within minutes after vigorous exercise. To our knowledge, this is the first report of a co-occurrence of CU and ATS. The hives were successfully attenuated by oral intake of effervescent potassium chloride during physical activity. This observation raises the possibility that chronic inducible urticaria may represent a previously unrecognized cutaneous ATS manifestation and suggests a potential pathophysiological link between potassium-channel dysfunction and mast cell activation. Distinguishing whether hives are an isolated symptom or part of a broader syndrome is critically important, as it might be crucial for the patient outcome. Full article

(This article belongs to the Special Issue The Function and Molecular Mechanism for Immune Responses in Human Diseases)

► Show Figures

Figure 1

22 pages, 3531 KB

Open AccessArticle

H3K27me3 Dynamic Turnover as a Gate Keeper of Defence Gene Expression in Arabidopsis

by Evangelia-Niki Pentari, Rory Osborne, Alonso Javier Pardal and Vardis Ntoukakis

Genes 2026, 17(8), 975; https://doi.org/10.3390/genes17080975 - 19 Aug 2026

Viewed by 523

Abstract

Background: Histone 3 lysine 27 tri-methylation (H3K27me3) is a chromatin mark typically associated with transcriptional repression. Histone demethylation, and particularly the removal of H3K27me3, has been linked to abiotic stress tolerance in plants. However, less is known about its role in biotic stress [...] Read more.

Background: Histone 3 lysine 27 tri-methylation (H3K27me3) is a chromatin mark typically associated with transcriptional repression. Histone demethylation, and particularly the removal of H3K27me3, has been linked to abiotic stress tolerance in plants. However, less is known about its role in biotic stress responses. Methods: We exploited immunity-related transcriptomics data combined with chromatin-state data to identify an association between chromatin modifications and plant immunity in Arabidopsis thaliana. We also measured the expression and H3K27me3 levels at immune-responsive loci, at Col-0 and at histone deacetylase mutants. Results: We identified H3K27me3 as a mark correlated with the silencing of defence gene loci. Moreover, we showed that the expression of a subset of flg22-induced genes is repressed by H3K27me3 prior to elicitation, and that expression negatively correlates with the mark upon activation of immunity. Notably, our studies also revealed a role for the H3K27 demethylase REF6 in plant defence. Loss of REF6 allows ectopic H3K27me3 deposition at target genes, revealing that these loci are actively regulated by the demethylase. Conclusions: Our data provide insight into the regulation of plant immune responses through chromatin dynamics. Full article

(This article belongs to the Special Issue Chromatin Modifications and RNA-Based Regulation of Gene Expression)

► Show Figures

Figure 1

25 pages, 7603 KB

Open AccessArticle

Longitudinal Transcriptomic Remodeling of Adipose Tissue After Bariatric Surgery Revealed by Differential Expression and Explainable Machine Learning

by Soumaya Allouch, Md. Shaheenur Islam Sumon, Aisha Naeem, Claus Vinter Bødker Hviid, Zumin Shi, Muhammad E. H. Chowdhury and Shona Pedersen

Genes 2026, 17(8), 974; https://doi.org/10.3390/genes17080974 - 19 Aug 2026

Viewed by 317

Abstract

Background: Bariatric surgery improves metabolic health, but long-term transcriptomic remodeling of white adipose tissue (WAT) after Roux-en-Y gastric bypass (RYGB) remains incompletely defined. This study aimed to characterize longitudinal WAT gene-expression patterns after RYGB and prioritize candidate signatures of post-surgical adaptation using a [...] Read more.

Background: Bariatric surgery improves metabolic health, but long-term transcriptomic remodeling of white adipose tissue (WAT) after Roux-en-Y gastric bypass (RYGB) remains incompletely defined. This study aimed to characterize longitudinal WAT gene-expression patterns after RYGB and prioritize candidate signatures of post-surgical adaptation using a publicly available dataset. Methods: We analyzed subcutaneous WAT transcriptomic data from women with obesity who underwent RYGB, with samples collected before surgery and at 2 and 5 years after surgery. Differential expression analysis was integrated with pathway enrichment, supervised machine-learning-based feature prioritization and classification, and SHAP-based model interpretation. Results: Differential expression and machine-learning analyses showed clear separation between baseline and post-surgery transcriptomic states. Pathway-level findings indicated reduced inflammatory and immune-related signaling, particularly across pathways related to phagosome function, lysosomal activity, antigen presentation, and host-defense responses after surgery. Gene-level analyses additionally suggested extracellular-matrix and metabolic remodeling. Machine-learning models distinguished baseline from post-surgery samples, while SHAP analysis identified genes with the strongest contributions to model predictions. Importantly, several statistically prioritized genes also showed high SHAP attribution, demonstrating concordance between univariate statistical significance and multivariate predictive relevance. This convergence suggests that the models captured biologically meaningful surgery-associated signals rather than purely data-driven classification artifacts. Conclusions: This study advances the interpretation of longitudinal adipose-tissue transcriptomic remodeling after RYGB by combining differential expression, pathway enrichment, supervised machine learning, and explainable AI within a unified framework. The integrated workflow prioritized candidate long-term remodeling genes, particularly immune/inflammatory and extracellular-matrix-related transcriptomic signatures, that warrant validation in independent cohorts. Full article

(This article belongs to the Section Bioinformatics)

► Show Figures

Figure 1

33 pages, 753 KB

Open AccessReview

RNA Modifications Modulate Biomolecular Condensates in Stress and Disease

by Y. Sprecher, M. Sevilla-Sharon and S. Moshitch-Moshkovitz

Genes 2026, 17(8), 973; https://doi.org/10.3390/genes17080973 - 19 Aug 2026

Viewed by 640

Abstract

Biomolecular condensates are dynamic membraneless organelles composed of proteins and RNAs that assemble through multivalent interactions and provide cells with powerful means to regulate gene expression in space and time. Different epitranscriptomic marks such as m⁶A, m¹A, and m [...] Read more.

Biomolecular condensates are dynamic membraneless organelles composed of proteins and RNAs that assemble through multivalent interactions and provide cells with powerful means to regulate gene expression in space and time. Different epitranscriptomic marks such as m⁶A, m¹A, and m⁵C can reshape RNA structure—binding interfaces and multivalency and, in this manner, tuning which transcripts nucleate or partition into specific condensates and influencing their material state. This review summarizes how individual RNA modifications and their associated proteins regulate the formation and function of BMCs such as stress granules, P-bodies, nuclear bodies and disease-linked condensates in cancer and neurodegeneration. It highlights emerging concepts of combinatorial “epitranscriptomic codes” and bidirectional feedback between condensates and RNA-modifying enzymes and discusses the current experimental and technical gaps that still limit our understanding of modification crosstalk and condensate topology. Full article

(This article belongs to the Special Issue RNA Biology and Diseases)

► Show Figures

Figure 1

2 pages, 130 KB

Open AccessRetraction

RETRACTED: Wigner et al. The Impact of Chronic Mild Stress and Agomelatine Treatment on the Expression Level and Methylation Status of Genes Involved in Tryptophan Catabolic Pathway in PBMCs and Brain Structures. Genes 2020, 11, 1093

by Paulina Wigner, Ewelina Synowiec, Paweł Jóźwiak, Piotr Czarny, Katarzyna Białek, Michal Bijak, Janusz Szemraj, Piotr Gruca, Mariusz Papp and Tomasz Sliwinski

Genes 2026, 17(8), 972; https://doi.org/10.3390/genes17080972 - 19 Aug 2026

Viewed by 301

Abstract

The journal retracts the article titled, “The Impact of Chronic Mild Stress and Agomelatine Treatment on the Expression Level and Methylation Status of Genes Involved in Tryptophan Catabolic Pathway in PBMCs and Brain Structures” [...] Full article

14 pages, 7140 KB

Open AccessArticle

Molecular Genetic Diagnosis of Spinal Muscular Atrophy: Clinical Utility, Challenges, and Lessons Learned from Illustrative Cases in a Single Center

by Jinli Bai, Qinglin Jiang, Hui Jiao, Yuwei Jin, Hong Wang, Xiushan Ge, Ying Gao, Xiaoyin Peng, Fang Song, Yujin Qu and Mei Diao

Genes 2026, 17(8), 971; https://doi.org/10.3390/genes17080971 - 19 Aug 2026

Viewed by 423

Abstract

Background: Spinal muscular atrophy (SMA) is mainly caused by biallelic SMN1 inactivation. While most patients carry homozygous deletions, 3–5% are compound heterozygotes, making molecular diagnosis challenging. Methods: A tiered diagnostic strategy was applied to 17 pediatric patients, combining copy number analyses (MLPA and [...] Read more.

Background: Spinal muscular atrophy (SMA) is mainly caused by biallelic SMN1 inactivation. While most patients carry homozygous deletions, 3–5% are compound heterozygotes, making molecular diagnosis challenging. Methods: A tiered diagnostic strategy was applied to 17 pediatric patients, combining copy number analyses (MLPA and targeted long-read sequencing, tLRS), sequence variant detection (RT-PCR cloning and sequencing, allele-specific long-range PCR with nested PCR, and tLRS), and structural variant analysis (ultra-long-read sequencing, Ultra-LRS). Results: Copy numbers were concordant between MLPA and tLRS. MLPA-suggested gene conversions were confirmed by tLRS, while discordant total copy numbers were resolved as large deletions by Ultra-LRS. RT-PCR cloning, and sequencing identified SMN1 variants in 11/12 cases and confirmed aberrant splicing in three cases, but failed for large deletions. AS-LR-PCR with nested PCR characterized the variants in 13/15 but failed in gene conversion cases. tLRS achieved definitive diagnosis in all cases, and Ultra-LRS precisely delineated breakpoint junctions of two large deletions. Conclusions: A hierarchical complementary strategy integrating copy number, sequence, and structural analyses is essential for the accurate diagnosis of compound heterozygous SMA. Full article

(This article belongs to the Special Issue Advances in Prenatal and Postnatal Genetic Testing: Precision Diagnosis for Genetic Disorders)

► Show Figures

Figure 1

17 pages, 8007 KB

Open AccessArticle

Strictosidine Synthase-like Gene NMS1 Is Required for Male Fertility in Rice by Regulating Tapetal Degradation

by Zhiyuan He, Anping Du, Nenggang Chen, Yulin Tang, Ping Wang, Longxiang Lu, Hui Li, Yulu Bai, Shicong Yu, Jing Liang, Xiaoqing Yan, Lei Zhou, Xiaolan Liu, Zhigang Pu and Binhua Hu

Genes 2026, 17(8), 970; https://doi.org/10.3390/genes17080970 - 19 Aug 2026

Viewed by 342

Abstract

Background: Male sterility is a critical trait for large-scale hybrid rice seed production, yet the genetic and molecular regulatory networks governing tapetal degradation during anther development remain incompletely understood. This study aimed to clone the causal gene underlying a novel rice non-pollen male [...] Read more.

Background: Male sterility is a critical trait for large-scale hybrid rice seed production, yet the genetic and molecular regulatory networks governing tapetal degradation during anther development remain incompletely understood. This study aimed to clone the causal gene underlying a novel rice non-pollen male sterility mutant and elucidate its role in tapetal development and microsporogenesis. Methods: The nms1 (non-pollen male sterility 1) sterile mutant was screened from the ethyl methanesulfonate (EMS)-mutagenized progeny of the elite indica restorer line Shuhui 498 (R498). Map-based cloning and whole-genome resequencing-assisted bulked segregant analysis were used to identify the causal variant. Gene function was verified via cytological observation, genetic complementation testing, RNA sequencing, and quantitative real-time PCR (qRT-PCR) to profile sterility-associated transcriptional changes. Results: Gene mapping identified a T635A single-nucleotide substitution within OsR498G0305626400.01 on chromosome 3, which encodes a strictosidine synthase-like protein. This nucleotide alteration causes a Val212Glu amino acid change and is associated with delayed tapetal degradation and pollen abortion. Transgenic complementation experiments verified that functional NMS1 restores fertility in nms1 mutant plants. Spatiotemporal expression analysis showed predominant NMS1 expression in late-developing spikelets. Furthermore, combined RNA sequencing and qRT-PCR analyses demonstrated that loss of NMS1 function leads to significant transcriptional dysregulation of key regulators of programmed cell death (PCD) in the tapetum (PTC2, TIP2) and pollen wall biosynthesis genes (TIP3, OsMS2). Conclusions: This study demonstrates that NMS1 plays a crucial role in coordinating tapetal degradation and microspore development in rice. The discovered functional SNP of NMS1 provides a novel theoretical foundation and a valuable sterile genetic resource for hybrid rice breeding. Full article

(This article belongs to the Special Issue Genetics and Genomics of Plant Reproductive Development)

► Show Figures

Figure 1

14 pages, 506 KB

Open AccessArticle

Genotypic Distribution of FGF4L2 in DTK-Registered Dachshunds in Germany: A Pilot Study

by Hanna Berls, Jan Peter Bach, Danika Bannasch, Peter J. Dickinson and Holger A. Volk

Genes 2026, 17(8), 969; https://doi.org/10.3390/genes17080969 - 19 Aug 2026

Viewed by 1334

Abstract

Background/Objectives: The fibroblast-growth-factor 4 retrogene insertion on chromosome 12 (FGF4L2) is known to be associated with chondrodystrophy and intervertebral disc disease (IVDD), which increases the risk of Hansen’s type I intervertebral disc extrusion (IVDE) in Dachshunds. While the FGF4L2 insertion is [...] Read more.

Background/Objectives: The fibroblast-growth-factor 4 retrogene insertion on chromosome 12 (FGF4L2) is known to be associated with chondrodystrophy and intervertebral disc disease (IVDD), which increases the risk of Hansen’s type I intervertebral disc extrusion (IVDE) in Dachshunds. While the FGF4L2 insertion is known to occur at high frequency within the breed, subgroup-specific data relating to coat-type and size categories remain limited. This pilot study aimed to determine the distribution of FGF4L2 and wild-type (N) alleles in a cohort of Dachshunds registered with the German Dachshund Club (DTK) and to evaluate differences among coat and size varieties. Methods: A total of 488 Dachshund samples from the DNA archive of the Deutscher Teckelklub 1888 e.V. (DTK) were analysed and genotyped. Genotype data was categorised according to coat-type and size variant. Allele and genotype frequencies were calculated for the overall population and for each subgroup. Results: The overall frequency of the FGF4L2 insertion allele was 96.51% (95% CI: 95.17–97.50). However, there were moderate differences between subgroups. The allele was nearly fixed in several coat and size variants. Standard wire-haired Dachshunds had the lowest allele frequency (89.09%) and were the only group in which homozygous wild-type individuals were observed. Heterozygous frequencies peaked in standard smooth-haired (16.7%) and standard wire-haired (14.5%) groups. Conclusions: Because the FGF4L2 frequency differs meaningfully between Dachshund varieties, grouping them into a single breed, as many studies do, can obscure the residual subgroup-specific genetic variation present in this population. Analysing the varieties separately provides a basis for future studies investigating factors that may interact with FGF4L2 in IVDE, thereby highlighting its multifactorial nature. It also reveals where wild-type alleles persist, making genotype-informed, variety-specific breeding a viable strategy for improving vertebral column health. However, variation in FGF4L2 allele frequency alone may not fully account for the recently reported differences in vertebral column health between Dachshund coat varieties. Full article

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

► Show Figures

Figure 1

19 pages, 8438 KB

Open AccessArticle

Genome-Wide Characterization of the WIP Transcription Factor Gene Family in Soybean and Physiological Responses to Salt Stress

by Tianjiao Gao, Shuping Yan, Sobhi F. Lamlom, Huilong Hong, Tiantian Huang, Guoqing Li, Narentuya Chen, Chunlei Zhang, Honglei Ren, Qiang Qiu and Lichun Huang

Genes 2026, 17(8), 968; https://doi.org/10.3390/genes17080968 - 18 Aug 2026

Viewed by 361

Abstract

Background/Objectives: Soybean (Glycine max) productivity is increasingly constrained by soil salinity. WIP transcription factors, a subfamily of C2H2-type zinc finger proteins, regulate cell division, differentiation, and tissue patterning in several plant species, but this gene family had not previously been systematically [...] Read more.

Background/Objectives: Soybean (Glycine max) productivity is increasingly constrained by soil salinity. WIP transcription factors, a subfamily of C2H2-type zinc finger proteins, regulate cell division, differentiation, and tissue patterning in several plant species, but this gene family had not previously been systematically characterized in soybean or any other major legume crop. This study aimed to identify and characterize the GmWIP gene family genome-wide and evaluate its potential involvement in the soybean salt-stress response. Methods: Genome-wide identification of GmWIP genes was performed using sequence similarity and domain-based searches against the Wm82.gnm4.ann1 reference genome, followed by characterization of physicochemical properties, chromosomal distribution, phylogenetic relationships, gene duplication, conserved motifs, gene structure, and promoter cis-acting elements. Tissue-specific expression was examined using transcriptome data, and GmWIP responses to salt stress were profiled by RT-qPCR in roots, stems, and leaves of a salt-tolerant cultivar (HN531) and a salt-sensitive cultivar (HN563), alongside physiological measurements of oxidative stress and osmotic adjustment. Results: Thirty GmWIP genes were identified, with molecular weights from 26.90 to 57.52 kDa, distributed unevenly across 15 soybean chromosomes, with chromosomes 11, 12, and 13 forming a major hotspot (53.3% of the family). Duplication analysis detected 54 reconciled segmental duplicate gene pairs, all exhibiting Ka/Ks values < 1 (ranging from 0.0351 to 0.4471; mean 0.214), consistent with purifying selection acting on this gene set. GmWIP promoters were enriched for ABRE, MBS, and MeJA cis-acting elements. RT-qPCR showed genotype- and tissue-dependent differential expression under salt stress (e.g., up to 14.9-fold induction of GmWIP22 in HN531 stems), paralleled by superior proline accumulation (+45%), soluble sugars, and CAT activity (+38%) alongside reduced MDA accumulation in the tolerant cultivar. Conclusions: The GmWIP gene family has expanded substantially in soybean relative to previously characterized species and shows genotype-dependent transcriptional responses to salt stress, suggesting that specific GmWIP members are candidate regulators of salt tolerance and warrant further functional investigation. Full article

(This article belongs to the Special Issue Abiotic Stress in Plant: Molecular Genetics and Genomics)

► Show Figures

Figure 1

16 pages, 275 KB

Open AccessArticle

GWAS-Informed Candidate Genetic Variants and Gene–Gene/Gene–Environment Interaction Patterns Associated with Intervertebral Disc Degeneration: A Chinese Han Case–Control Study

by Ridan Lei, Mengyuan Zhang, Manjun Luo, Xiaorui Ruan, Jianhui Wei, Ziye Li and Jiabi Qin

Genes 2026, 17(8), 967; https://doi.org/10.3390/genes17080967 - 18 Aug 2026

Viewed by 382

Abstract

Background/Objectives: Intervertebral disc degeneration (IDD) is a multifactorial spinal degenerative condition influenced by inherited susceptibility and environmental exposures. Genetic evidence from Chinese Han populations remains limited. This study aimed to evaluate GWAS-informed and previously reported candidate single-nucleotide polymorphisms (SNPs) associated with IDD and [...] Read more.

Background/Objectives: Intervertebral disc degeneration (IDD) is a multifactorial spinal degenerative condition influenced by inherited susceptibility and environmental exposures. Genetic evidence from Chinese Han populations remains limited. This study aimed to evaluate GWAS-informed and previously reported candidate single-nucleotide polymorphisms (SNPs) associated with IDD and to explore potential gene–gene and gene–environment interaction patterns. Methods: A hospital-based case–control study was conducted in 1951 unrelated Chinese Han participants, including 929 patients with magnetic resonance imaging-confirmed IDD and 1022 control subjects without evident IDD. Candidate SNPs were genotyped using the MassARRAY platform. Multivariable logistic regression was used to assess genetic associations under different genetic models, and linkage disequilibrium, haplotype associations, additive and multiplicative interactions, and generalized multifactor dimensionality reduction (GMDR) were further evaluated. Results: Of the 60 initially selected candidate SNPs, 49 passed quality control and were retained for association analyses. Several variants showed nominal associations with IDD susceptibility. Representative associations included MMP3 rs591058 under the recessive model (OR = 1.37, 95% CI: 1.06–1.79, p = 0.019) and VDR rs2228570 under the dominant model (OR = 1.52, 95% CI: 1.10–2.11, p = 0.012), whereas the CCDC26 rs6651255–rs7816342 AC haplotype showed a protective association (OR = 0.87, 95% CI: 0.76–0.99, p = 0.046). Exploratory interaction analyses suggested possible gene–gene interactions involving ACAN, IL1B, VDR, CASP3, and CEP162/RIPPLY2, as well as gene–environment interactions involving smoking, weight-bearing workload, and duration of bending work. Conclusions: This study provides preliminary genetic epidemiological evidence that GWAS-informed candidate variants and exploratory interaction patterns may be associated with IDD susceptibility in the Chinese Han population. These findings require further replication and functional validation. Full article

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

16 pages, 4728 KB

Open AccessArticle

miR-27b-3p Exacerbates VCD-Induced KGN Cell Injury by Targeting PAPPA to Suppress IGF-1 Release and Inhibit the PI3K/AKT Pathway

by Manyu Zhang, Xiangyu Meng, Mengdi Shi and Pengling Ge

Genes 2026, 17(8), 966; https://doi.org/10.3390/genes17080966 - 18 Aug 2026

Viewed by 344

Abstract

Background/Objectives: While currently termed premature ovarian insufficiency (POI), premature ovarian failure (POF) remains a prominent driver of female infertility with a molecular pathogenesis that is still lacking comprehensive clarification. In in vitro studies, the pathology of POI is commonly simulated through a well-characterized [...] Read more.

Background/Objectives: While currently termed premature ovarian insufficiency (POI), premature ovarian failure (POF) remains a prominent driver of female infertility with a molecular pathogenesis that is still lacking comprehensive clarification. In in vitro studies, the pathology of POI is commonly simulated through a well-characterized model involving VCD (4-vinylcyclohexene diepoxide)-mediated cytotoxicity within KGN-derived human granulosa cells. However, the key regulatory molecular networks involved in this process are still poorly characterized. Although microRNAs (miRNAs) have emerged as critical regulators in ovarian function decline, the specific role and underlying mechanism of miR-27b-3p in POI remain elusive. Methods: A VCD-induced KGN cell injury model was established by treating cells with 1.0 mM VCD for 24 h. Cell viability, apoptosis rate, and miR-27b-3p expression were assessed by CCK-8 assay, flow cytometry, and RT-qPCR, respectively. Overexpression and targeted suppression of miR-27b-3p were achieved by introducing its specific mimics and inhibitors, respectively. Target identification was conducted via bioinformatic prediction, EdU incorporation, Western blot, and dual-luciferase reporter assays. Functional rescue experiments were carried out by co-transfection with a PAPPA-overexpressing plasmid (oe-PAPPA). IGF-1 secretion was quantified by ELISA, and phosphorylation of IGF1R and AKT was analyzed by Western blot to determine whether miR-27b-3p modulates cellular phenotypes via the PAPPA–IGF-1–PI3K/AKT axis. Exogenous IGF-1 supplementation was further applied to confirm pathway dependence. Results: VCD treatment dose-dependently restrained cellular growth and stimulated apoptotic pathways in KGN cells; paralleling these phenotypic changes, miR-27b-3p abundance was remarkably increased. Ectopic expression of miR-27b-3p exacerbated VCD-induced growth inhibition and apoptosis, whereas its inhibition conferred cytoprotective effects. Through the integration of computational predictions and dual-luciferase reporter systems, PAPPA was definitively established as a direct downstream target of miR-27b-3p. miR-27b-3p negatively regulated both PAPPA mRNA and protein levels, thereby impairing PAPPA-mediated cleavage of IGF-binding proteins (e.g., IGFBP4) and subsequent release of free IGF-1. This led to reduced IGF-1 secretion and significantly diminished phosphorylation of IGF1R and AKT. Remarkably, PAPPA overexpression effectively reversed the detrimental effects of miR-27b-3p, and exogenous IGF-1 supplementation similarly attenuated miR-27b-3p–mediated proliferation arrest and pro-apoptotic phenotypes. Conclusions: This study uncovers a novel pathogenic mechanism whereby miR-27b-3p exacerbates VCD-induced granulosa cell injury by directly targeting PAPPA, suppressing IGF-1 release, and consequently inhibiting the PI3K/AKT pro-survival signaling pathway. A novel perspective on the fundamental basis of POI is established by this research, which further posits therapeutic manipulation of the miR-27b-3p/PAPPA/IGF-1 module as a prospective treatment for disrupted ovarian function. Full article

(This article belongs to the Special Issue Targeting RNA Coding Mechanisms in Disease Molecular Pathways)

► Show Figures

Figure 1

21 pages, 1263 KB

Open AccessReview

Genetic Architecture of Synaptic Failure in Dementia with Lewy Bodies: From α-Synuclein Proteoforms to GBA1-Mediated Plasticity Deficits

by Anastasia Bougea

Genes 2026, 17(8), 965; https://doi.org/10.3390/genes17080965 - 18 Aug 2026

Viewed by 456

Abstract

Dementia with Lewy bodies (DLB) is increasingly conceptualised not merely as a disorder of neuronal death but as a primary synaptopathy in which the functional collapse of synaptic transmission and plasticity precedes, and predicts, neurodegeneration and clinical decline. Two genetic determinants dominate the [...] Read more.

Dementia with Lewy bodies (DLB) is increasingly conceptualised not merely as a disorder of neuronal death but as a primary synaptopathy in which the functional collapse of synaptic transmission and plasticity precedes, and predicts, neurodegeneration and clinical decline. Two genetic determinants dominate the heritable risk architecture of DLB: the α-synuclein gene SNCA, in which both copy-number variation and missense mutations exert dose- and conformation-dependent effects, and GBA1, encoding the lysosomal hydrolase glucocerebrosidase (GCase), the single most influential genetic risk factor for the disease. Here we synthesise evidence that these loci converge on a shared pathogenic endpoint—the impairment of activity-dependent synaptic plasticity. We argue that GBA1 loss-of-function and the resulting accumulation of glucosylceramide stabilise specific neurotoxic α-synuclein proteoforms, including soluble oligomers and self-templating conformational strains bearing defined post-translational modifications. These proteoforms are trafficked to, and enriched within, presynaptic terminals, where they disrupt SNARE-complex assembly and synaptic-vesicle dynamics, while postsynaptically they perturb NMDA and AMPA receptor trafficking, dysregulate dendritic calcium, and compromise synaptic mitochondrial bioenergetics. The net consequence is a metaplastic shift away from long-term potentiation (LTP) and toward aberrant long-term depression (LTD), a signature of synaptic failure detectable before frank pathology. We map these molecular events onto disease-relevant circuits—particularly the cholinergic basal forebrain and hippocampal–cortical and thalamocortical networks—and relate them to the defining neuropsychiatric features of DLB, including cognitive fluctuations and recurrent visual hallucinations. Finally, we evaluate emerging therapeutic strategies that target the GBA1–α-synuclein axis and that aim to restore synaptic plasticity directly. Positioning DLB within the framework of genetically determined plasticity deficits clarifies its kinship with other neuropsychiatric disorders and identifies the synapse as the most tractable node for early, disease-modifying intervention. We further examine how GBA1 allele severity and zygosity grade the phenotype, which genetic and environmental factors modify penetrance in carriers, and what distinguishes this synaptopathy from those driven by PSEN1/PSEN2, MAPT, or HTT, and we summarise the therapeutic pipeline—including enzyme augmentation and adeno-associated viral GBA1 gene therapy—that targets it. Full article

(This article belongs to the Special Issue Genetic Mechanisms of Synaptic Plasticity in Neuropsychiatric Disorders)

► Show Figures

Figure 1

30 pages, 2329 KB

Open AccessReview

Epigenetic Skeletal Muscle Memory: The Impact of Physical Activity on Aging and Post-Injury Regeneration

by Antoni Godlewski, Marcin Wróblewski, Julia Kuk, Magdalena Moritz, Filip Dobrak, Renata Kołodziejska and Alina Woźniak

Genes 2026, 17(8), 964; https://doi.org/10.3390/genes17080964 - 17 Aug 2026

Viewed by 917

Abstract

Skeletal muscle retains adaptive information from previous mechanical loading, enabling faster responses to subsequent training and regenerative challenges. This review synthesizes current evidence on the cellular and epigenetic mechanisms underlying skeletal muscle memory and examines how these mechanisms are modified by aging and [...] Read more.

Skeletal muscle retains adaptive information from previous mechanical loading, enabling faster responses to subsequent training and regenerative challenges. This review synthesizes current evidence on the cellular and epigenetic mechanisms underlying skeletal muscle memory and examines how these mechanisms are modified by aging and post-injury regeneration. Muscle memory emerges from complementary structural and molecular components, including myonuclear retention, persistent DNA methylation changes, chromatin remodeling, transcriptional priming, non-coding RNA regulation, and mitochondrial epigenetic adaptations. These mechanisms interact with muscle satellite cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and extracellular matrix remodeling to maintain regenerative competence. During aging, epigenetic drift, chronic low-grade inflammation, altered macrophage states, MuSC dysfunction, persistent FAP activity, fibrosis, mitochondrial impairment, and anabolic resistance progressively reduce this plasticity, thereby contributing to sarcopenia. Training–detraining–retraining studies indicate that parts of the exercise-induced epigenetic landscape remain detectable after training cessation and can be reactivated during renewed loading, although the persistence and functional importance of individual molecular signatures remain incompletely defined. Physical exercise remains the most established intervention for preserving muscle function and epigenetic responsiveness, whereas caloric restriction, modulation of nutrient-sensing pathways, senolytic strategies, and direct targeting of epigenetic regulators remain promising but translationally less mature approaches. Overall, the preservation of epigenetic plasticity may be a key determinant of healthy skeletal muscle aging and effective regeneration. Full article

(This article belongs to the Special Issue Genetics and Genomics in Physical Activity, Sports and Injury)

► Show Figures

Figure 1

10 pages, 1662 KB

Open AccessArticle

Ocular Phenotypes and Novel SLC45A2 Variants in Patients with Oculocutaneous Albinism Type 4

by Chonglin Chen, Bingqi Wang, Ye Zheng, Junyi Liu and Xinping Yu

Genes 2026, 17(8), 963; https://doi.org/10.3390/genes17080963 - 17 Aug 2026

Viewed by 322

Abstract

Objectives: SLC45A2-related oculocutaneous albinism type 4 (OCA4) is a genetically defined subtype of albinism; however, its ocular phenotype remains incompletely characterized. This study aimed to describe the systemic, ophthalmic, and genetic features of patients with genetically confirmed SLC45A2-related OCA4. Methods: Ninety [...] Read more.

Objectives: SLC45A2-related oculocutaneous albinism type 4 (OCA4) is a genetically defined subtype of albinism; however, its ocular phenotype remains incompletely characterized. This study aimed to describe the systemic, ophthalmic, and genetic features of patients with genetically confirmed SLC45A2-related OCA4. Methods: Ninety patients with clinically diagnosed albinism were enrolled and underwent genetic testing. Patients with genetically confirmed SLC45A2-related OCA4 were included for further analysis. Demographic information, systemic pigmentation features, ophthalmic findings, and SLC45A2 variants were analyzed. Results: Five unrelated patients with genetically confirmed SLC45A2-related OCA4 were included, aged 5–33 years. Best-corrected visual acuity ranged from 0.1 to 1.0 logMAR, and spherical equivalent refractive error varied widely from −7.25 to +7.63 D. All patients exhibited iris transillumination defects and moderate-to-severe fundus hypopigmentation, both graded 2–3. Foveal hypoplasia was universally present, ranging from grade 1 to grade 4, with three patients showing grade 4 hypoplasia. Genetic analysis revealed nine disease-associated alleles representing eight distinct SLC45A2 variants: seven missense variants and one splice-altering variant. One patient carried a homozygous variant, and four carried compound heterozygous variants. Three novel variants were identified: c.1459C>G (p.Gln487Glu), c.137A>G (p.Glu46Gly), and c.561A>G. Conclusions: This study characterizes the ocular phenotype of SLC45A2-related OCA4, including iris transillumination defects, fundus hypopigmentation, and foveal hypoplasia of varying severity. Three novel SLC45A2 variants were identified, expanding the mutational spectrum of OCA4. Full article

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

► Show Figures

Figure 1

12 pages, 3057 KB

Open AccessArticle

Xq26.2 Contiguous Gene Deletion Involving FRMD7 and IGSF1: Highly Penetrant Infantile Nystagmus with Variable Endocrine Involvement

by Tomer Poleg, Lior Carmon, Elad Brav, Noam Hadar, Vadim Dolgin, Shirly Amar, Ginat Narkis, Ohad S. Birk and Libe Gradstein

Genes 2026, 17(8), 962; https://doi.org/10.3390/genes17080962 - 17 Aug 2026

Viewed by 339

Abstract

Background/Objectives: Contiguous Xq26.2 deletions involving FRMD7 and IGSF1 are rare and incompletely characterized. FRMD7 loss causes X-linked idiopathic infantile nystagmus (IIN), whereas IGSF1 loss causes central hypothyroidism and other pituitary-related abnormalities. We aimed to define the clinical and molecular spectrum of an Xq26.2 [...] Read more.

Background/Objectives: Contiguous Xq26.2 deletions involving FRMD7 and IGSF1 are rare and incompletely characterized. FRMD7 loss causes X-linked idiopathic infantile nystagmus (IIN), whereas IGSF1 loss causes central hypothyroidism and other pituitary-related abnormalities. We aimed to define the clinical and molecular spectrum of an Xq26.2 contiguous gene deletion in a large Bedouin kindred with infantile nystagmus. Methods: We clinically evaluated ten family members (3 males and 7 females); genomic analyses included chromosomal microarrays, whole-exome and whole-genome sequencing, breakpoint PCR, and Sanger sequencing. Results: We identified a novel 1.44-Mb Xq26.1-q26.2 deletion, NC_000023.11:g.130756102_132199443del (GRCh38), encompassing complete loss of FRMD7, IGSF1, ARHGAP36, OR13H1, and STK26 and partial deletion of the 5′ end of ENOX2. The deletion was molecularly confirmed in six family members. The kindred exhibited a broad phenotypic spectrum, from an asymptomatic confirmed female carrier to isolated nystagmus and combined ocular–endocrine manifestations. Nystagmus was highly penetrant, whereas endocrine abnormalities were less frequent and variable. Hypoprolactinemia occurred in one confirmed female carrier, and a confirmed hemizygous boy had low-normal free T4 without overt central hypothyroidism. The only relative with overt central hypothyroidism was not genotyped; therefore, co-segregation could not be established. Conclusions: These findings further delineate the clinical spectrum of Xq26.2 deletions, highlight marked intrafamilial variability, and support structural variant analysis in unexplained IIN and/or endocrine abnormalities. Longitudinal endocrine assessment of individuals with Xq26.2 deletions and at-risk relatives in affected families may enable early detection and treatment of hypothyroidism. Full article

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

► Show Figures

Figure 1

20 pages, 6914 KB

Open AccessArticle

EPHX2 Expression and Its Association with Prognosis, Metabolic Regulation, and Metastasis-Related Pathways in Lung Adenocarcinoma

by Şebnem Yıldırımcan Kadıçeşme

Genes 2026, 17(8), 961; https://doi.org/10.3390/genes17080961 - 16 Aug 2026

Viewed by 482

Abstract

Background/Objectives: Epoxide hydrolase 2 (EPHX2), which encodes soluble epoxide hydrolase (sEH), is involved in arachidonic acid metabolism and has been associated with inflammation, lipid metabolism, and tumor biology. However, its prognostic significance and biological associations in lung adenocarcinoma (LUAD) remain [...] Read more.

Background/Objectives: Epoxide hydrolase 2 (EPHX2), which encodes soluble epoxide hydrolase (sEH), is involved in arachidonic acid metabolism and has been associated with inflammation, lipid metabolism, and tumor biology. However, its prognostic significance and biological associations in lung adenocarcinoma (LUAD) remain unclear. This study aimed to investigate the expression profile, prognostic value, and molecular pathways of EPHX2 in LUAD using bioinformatics analyses. Methods: EPHX2 expression was evaluated using TNMplot, GEPIA2, and GEO datasets, while protein expression was assessed using the Human Protein Atlas and CPTAC/UALCAN platforms. Prognostic analyses were performed using Kaplan–Meier Plotter, GEPIA2, and Human Protein Atlas datasets. Co-expression and gene set enrichment analyses were conducted using LinkedOmics, and functional enrichment analyses were performed using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Reactome databases. Correlation and protein–protein interaction (PPI) analyses were evaluated using GEPIA2 and STRING. Results: EPHX2 expression was significantly reduced in LUAD tissues compared with normal lung tissues across datasets, and these findings were supported at the protein level. High EPHX2 expression was associated with better overall survival and retained independent prognostic significance in multivariate Cox analysis. Functional enrichment analyses demonstrated associations with lipid metabolism, arachidonic acid metabolism, cytochrome P450-related pathways, and oxidative processes. Correlation analyses suggested potential associations between EPHX2 and angiogenesis, extracellular matrix remodeling, and hypoxia-related pathways. Conclusions: Bioinformatics analyses suggest that EPHX2 may participate in metabolic and tumor progression-related regulatory networks and may serve as a prognostic biomarker in LUAD. Full article

(This article belongs to the Section Bioinformatics)

► Show Figures

Figure 1

10 pages, 2692 KB

Open AccessArticle

Race-Associated EGFR and KRAS Mutation Profiles in Lung Adenocarcinoma

by Lovyanne Vergel de Dios, Catherine Wu, Salique H. Shaham and Manish K. Tripathi

Genes 2026, 17(8), 960; https://doi.org/10.3390/genes17080960 - 16 Aug 2026

Viewed by 410

Abstract

Background: Lung adenocarcinoma (LUAD) is the most prevalent histologic subtype of non-small cell lung cancer (NSCLC) and exhibits considerable molecular heterogeneity. Among the most clinically significant driver alterations are mutations in EGFR and KRAS, both of which influence treatment selection and oncologic outcomes. [...] Read more.

Background: Lung adenocarcinoma (LUAD) is the most prevalent histologic subtype of non-small cell lung cancer (NSCLC) and exhibits considerable molecular heterogeneity. Among the most clinically significant driver alterations are mutations in EGFR and KRAS, both of which influence treatment selection and oncologic outcomes. The prevalence of these mutations varies by race, yet racial minority populations remain underrepresented in genomic studies. EGFR alterations are more frequently observed in Asian patients, while KRAS mutations predominate in non-Asian cohorts. This study aimed to characterize race-associated differences in driver mutation prevalence among Asian, Black, and White patients with LUAD. Methods: A retrospective secondary cohort analysis was performed using publicly available clinicogenomic data from the Lung Adenocarcinoma Met Organotropism cohort, accessed via cBioPortal, comprising 2653 tumor samples. Patients were stratified by self-reported race into Asian, Black, and White cohorts; cases with missing race data were denoted as either other or unknown. Mutation frequencies for EGFR, KRAS, and TP53 were extracted from OncoPrint cohort study views and compared descriptively across groups. Results: Distinct race-associated differences in driver mutation prevalence were observed. Asian patients exhibited the highest frequency of EGFR alterations (64%), compared with Black (41%) and White (28%) cohorts. In contrast, KRAS mutations were least prevalent in Asian patients (10%) and more frequent in White (33%) and Black (23%) cohorts, indicating an inverse distribution between Asian and non-Asian populations. TP53 mutation prevalence was similar in Asian (52%) and White (53%) cohorts but was notably higher in Black patients (65%). Conclusions: Asian patients with LUAD exhibit a distinct molecular profile characterized by EGFR predominance, with direct implications for eligibility for EGFR-targeted tyrosine kinase inhibitor therapy. Black patients may also benefit from EGFR-based targeted therapies, but lack of large genomic data on Black populations warrants further investigation. White cohorts display a KRAS-dominant mutation pattern, suggesting divergent tumorigenic pathways and the potential need for alternative therapeutic strategies. The elevated TP53 frequency in Black patients remains to be further characterized. These findings support integrating race-associated genomic profiling into precision oncology frameworks to improve treatment selection and reduce disparities in outcomes. Full article

(This article belongs to the Section Genetic Diagnosis)

► Show Figures

Figure 1

29 pages, 2627 KB

Open AccessArticle

Whole-Exome Sequencing Explores Host Genetic Susceptibility of COVID-19 Severity in Unvaccinated Vietnamese Patients Infected with the Delta Variant: A Hypothesis-Generating Study

by Hoai Thu Thi Nguyen, Thanh-Van Ta, Thuy Thi Le, Quyen-Diep Nguyen, Van Cao, Chan Dinh Khac Nguyen, Tuan Nguyen Duc and Ngoc-Lan Thi Nguyen

Genes 2026, 17(8), 959; https://doi.org/10.3390/genes17080959 - 15 Aug 2026

Viewed by 1138

Abstract

Background/Objectives: Host genetic variation contributes to the heterogeneous clinical outcomes of coronavirus disease 2019 (COVID-19), yet evidence from Southeast Asian populations remains limited. Methods: We investigated host genetic factors associated with COVID-19 severity in Vietnamese patients infected with the SARS-CoV-2 Delta [...] Read more.

Background/Objectives: Host genetic variation contributes to the heterogeneous clinical outcomes of coronavirus disease 2019 (COVID-19), yet evidence from Southeast Asian populations remains limited. Methods: We investigated host genetic factors associated with COVID-19 severity in Vietnamese patients infected with the SARS-CoV-2 Delta variant using whole-exome sequencing. A total of 48 unvaccinated patients were enrolled. During sample-level quality control, one sample was excluded because the genetically inferred sex was discordant with the information recorded in the clinical medical record, leaving 47 samples (23 severe/critical and 24 mild/asymptomatic) for downstream genetic analyses. Gene-based association analysis was performed using MAGMA, followed by functional enrichment and interaction network analyses with Metascape and GeneMANIA. Results: Population structure analysis showed that the study participants clustered closely with the East Asian (EAS) reference population. No individual variant reached the prespecified multiple-testing-adjusted threshold, and no gene-level association survived Benjamini–Hochberg correction. Using a nominal MAGMA gene-based p < 0.01 threshold solely for exploratory prioritization, 44 genes were selected for downstream functional analyses. Functional enrichment highlighted RNA processing and mRNA maturation, together with mitochondrial, metabolic, immune-regulatory, and cellular homeostasis pathways. Network topology analysis further identified several highly connected genes, including CPSF4, MRPS34, ATP5MF, BUD31, SNRPD3, and HDAC1. Conclusions: These hypothesis-generating findings are consistent with a potentially polygenic contribution to severe COVID-19 and provide an exploratory systems-level framework for understanding host genetic susceptibility in the Vietnamese population, while identifying biologically plausible candidate genes and pathways for future validation. Full article

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

► Show Figures

Figure 1

15 pages, 1099 KB

Open AccessArticle

Prenatal Substance Exposure Is Associated with Increased Placental DRD1 Dopamine Receptor Gene Expression and Striatal Gray Matter Volume in Children

by Tara E. Samson, Donato DeIngeniis, Maki S. Koyama, Roberto Bailey, Claire J. Brabander, Ariadna Cilleros Portet, Corina Lesseur, Ahmed Duke Shereen and Yoko Nomura

Genes 2026, 17(8), 958; https://doi.org/10.3390/genes17080958 - 15 Aug 2026

Viewed by 423

Abstract

Background/Objectives: Prenatal substance exposure (PSE) to alcohol, cannabis, and other psychoactive drugs affects over 500,000 pregnancies annually in the US and is consistently associated with adverse birth and childhood outcomes, but the underlying biological mechanisms are not well-understood. Given the dopaminergic system’s role [...] Read more.

Background/Objectives: Prenatal substance exposure (PSE) to alcohol, cannabis, and other psychoactive drugs affects over 500,000 pregnancies annually in the US and is consistently associated with adverse birth and childhood outcomes, but the underlying biological mechanisms are not well-understood. Given the dopaminergic system’s role in substance use and child development, this study aimed to examine and connect the effects of PSE on dopaminergic placental gene expression at birth and on striatal brain volumes in middle childhood. We hypothesized that PSE would lead to reduced dopamine receptor D1 (DRD1) gene expression and smaller striatal gray-matter volumes (GMVs) and that placental DRD1 gene expression would be positively associated with striatal GMV. Methods: PSE, placental gene expression, and T1-weighted MRI data were drawn from a pilot study (n = 34) within the longitudinal cohort Stress in Pregnancy study. PSE was defined by any amount of alcohol, tobacco, or cannabis use during pregnancy. Results: Unexpectedly, children with PSE had a trend toward increased placental DRD1 gene expression (β = 0.497, p = 0.056) and significantly larger GMV in the right putamen (β = 0.374, p = 0.018) and nucleus accumbens (NAc) (β = 0.389, p = 0.029) than unexposed children. Independent of PSE, higher placental DRD1 gene expression at birth was also associated with larger right NAc GMV (β = 0.617, p = 0.015) in middle childhood. Conclusions: These findings contrast prior cross-sectional work linking high-dosage PSE to smaller striatal volumes and inconsistent patterns of dopaminergic gene expression, suggesting potential compensatory placental mechanisms reflected in biological outcomes across child development. Full article

(This article belongs to the Special Issue Environmental Genomics and Low-Dose Induced Adaptive Response: Underlying Mechanisms from Cells to Organisms)

► Show Figures

Graphical abstract

28 pages, 12118 KB

Open AccessArticle

Integrated Bulk and Single-Cell Transcriptomic Analyses Identify a FOLR2⁺ Tissue-Resident Macrophage-Associated Lysophagy Gene Module in Heart Failure

by Qi Cheng, Yanli Wang, Deqiang Wang, Guoxing Wu, Biyun Liu, Qien Yuan and Fen Zhu

Genes 2026, 17(8), 957; https://doi.org/10.3390/genes17080957 - 15 Aug 2026

Viewed by 431

Abstract

Objectives: Heart failure (HF) arises from multiple interrelated pathological processes. Among these, lysosomal impairment and loss of autophagic homeostasis are increasingly recognized as important contributors to myocardial damage and ventricular remodeling. This study sought to identify lysophagy-associated signature genes in HF and [...] Read more.

Objectives: Heart failure (HF) arises from multiple interrelated pathological processes. Among these, lysosomal impairment and loss of autophagic homeostasis are increasingly recognized as important contributors to myocardial damage and ventricular remodeling. This study sought to identify lysophagy-associated signature genes in HF and to define their biological roles, cellular origins, and potential diagnostic relevance. Methods: Bulk myocardial transcriptome datasets, including GSE16499, GSE57338, and GSE76701, were integrated with the human cardiac single-cell dataset GSE145154. Differential expression analysis was first performed to identify lysophagy-related differentially expressed genes (DEGs). Candidate hub genes were then screened using support vector machine-recursive feature elimination (SVM-RFE) and least absolute shrinkage and selection operator (LASSO) regression. Functional enrichment analysis, Gene Set Enrichment Analysis (GSEA), immune infiltration assessment, single-cell transcriptomic mapping, and regulatory network analysis were subsequently conducted. The expression profiles of the selected genes were validated in a murine HF model, and VAMP8 overexpression assays were performed in H9c2 cells. Results: Five hub genes, namely VAMP8, STX2, MCOLN1, DERL1, and PTP4A2, were consistently and markedly decreased in failing myocardial tissue. These genes were mainly linked to SNARE-dependent vesicle trafficking and lysophagy regulation. A diagnostic model incorporating these hub genes demonstrated good discriminatory performance in both the training dataset and a small independent validation cohort, supporting further evaluation of their potential diagnostic value. Single-cell analysis further indicated that these genes were primarily enriched in cardiac FOLR2⁺ tissue-resident macrophages (TRMs). Pseudotime and cell–cell communication analyses associated this module with FOLR2⁺ TRM cell states and predicted interactions with cardiac stromal cells. In the HF mouse model, the mRNA levels of all five hub genes were decreased, with concurrent reductions in VAMP8, MCOLN1 and DERL1 protein expression. In Ang II/LLOMe-induced H9c2 cells, VAMP8 overexpression was associated with reduced cardiomyocyte injury, attenuation of changes in the abundance of lysosome- and autophagy-related proteins, and fewer ultrastructural abnormalities, suggesting a potential cardioprotective effect. Conclusions: VAMP8, STX2, MCOLN1, DERL1, and PTP4A2 were identified as candidate molecular markers of HF that reflect alterations in a lysophagy- and vesicular-transport-related program associated with FOLR2⁺ tissue-resident macrophages. These findings provide new insights into immune-microenvironment remodeling in HF and suggest potential directions for mechanistic and therapeutic investigations. Full article

(This article belongs to the Section Bioinformatics)

► Show Figures

Figure 1

19 pages, 1072 KB

Open AccessArticle

Population-Specific Genetic Markers of Prostate Cancer Risk in Kazakh Men: Association Analysis of 102 SNPs and Risk Prediction Modeling

by Kairat Kazbekov, Yerbol Zhapparov, Nasrulla Shanazarov, Valery Benberin, Sergey Zinchenko and Ainagul Kazbekova

Genes 2026, 17(8), 956; https://doi.org/10.3390/genes17080956 - 14 Aug 2026

Viewed by 314

Abstract

Background/Objectives: GWASs have identified more than 250 prostate cancer (PCa) predisposition loci, predominantly in European and partly Asian cohorts. The Kazakh population is markedly under-represented in international genetic studies, limiting existing risk models. This study aimed to analyze the distribution of 102 PCa-associated [...] Read more.

Background/Objectives: GWASs have identified more than 250 prostate cancer (PCa) predisposition loci, predominantly in European and partly Asian cohorts. The Kazakh population is markedly under-represented in international genetic studies, limiting existing risk models. This study aimed to analyze the distribution of 102 PCa-associated single-nucleotide polymorphism (SNP) genotypes and alleles and to identify reliable population-specific associations with PCa risk in Kazakh men. Methods: This retrospective case–control study included 941 Kazakh men (476 with histologically confirmed PCa and 465 cancer-free controls). Genomic DNA extracted from peripheral blood was genotyped with TaqMan^® OpenArray^® technology on a QuantStudio 12K Flex system. Associations were assessed by Pearson’s χ² test and logistic regression, with genotypic and allelic odds ratios (OR) and 95% confidence intervals (CI). Two-step multiple-testing correction (Bonferroni and Benjamini–Hochberg false-discovery rate, FDR) was applied. Predictive models were built using classification and regression trees (CART) and stepwise logistic regression. Results: Of 102 SNPs, 39 showed nominally significant genotypic differences; 12 remained significant after Bonferroni correction and 2 after FDR (14 in total). Several of the corrected loci were significant at both the genotypic and allelic level. Allelic ORs ranged from 0.37 (protective rs10187424 T allele) to 4.81 (rs1545985). A parsimonious seven-SNP autosomal logistic-regression model achieved an apparent AuROC of 0.84 (10-fold cross-validated 0.82); adding age as a covariate raised discrimination to 0.87. Ten of the fourteen significant loci remained significant after age adjustment, and six of these formed a core signal robust to both age imbalance and genotyping-quality concerns. Conclusions: This first large-scale SNP-association study in Kazakh men shows allele-frequency profiles resembling East Asian rather than European populations, confirming the need for population-specific genetic risk-assessment tools. The seven-SNP model showed high discriminatory power in the training set and requires external validation before clinical application. Full article

(This article belongs to the Special Issue Feature Papers in Human Genomics and Genetic Diseases 2026)

► Show Figures

Graphical abstract

21 pages, 3869 KB

Open AccessArticle

Real-World Diagnostic Yield and Longitudinal Dynamics of Fluorescence In Situ Hybridization in Hematologic Malignancies: A Five-Year Retrospective Analysis of 1357 Patient Samples

by Rosalba Fumo, Katia Scala, Sara Gaeta, Angela D’Ardia, Teresa Infante, Giuseppe Ciancia, Alessandro Caputo, Alessandra Rosati, Bianca Serio, Antonio D’Antonio, Pio Zeppa and Massimiliano Chetta

Genes 2026, 17(8), 955; https://doi.org/10.3390/genes17080955 - 14 Aug 2026

Viewed by 328

Abstract

Background/Objectives: Fluorescence in situ hybridization (FISH) is an established component of the diagnostic and prognostic workup of hematologic malignancies. However, most evidence supporting FISH interpretation originates from treatment-naïve diagnostic cohorts, providing limited insight into how cytogenetic findings evolve during longitudinal disease monitoring and [...] Read more.

Background/Objectives: Fluorescence in situ hybridization (FISH) is an established component of the diagnostic and prognostic workup of hematologic malignancies. However, most evidence supporting FISH interpretation originates from treatment-naïve diagnostic cohorts, providing limited insight into how cytogenetic findings evolve during longitudinal disease monitoring and therapeutic exposure. We retrospectively analyzed 1357 consecutive FISH assays performed in 1092 patients with hematologic malignancies between 2019 and 2023. Methods: Multivariable logistic regression identified predictors of aberration detection, while longitudinal analyses explored temporal changes in cytogenetic profiles among serially monitored patients. Observed abnormality rates were compared with published diagnostic benchmarks. Results: The cohort had a median age of 68 years and was predominantly composed of patients with myelodysplastic/myeloproliferative neoplasms (27.2%), multiple myeloma (26.9%), and chronic lymphocytic leukemia (21.6%). Overall, 29.2% of informative assays revealed cytogenetic abnormalities. Clinical indication was the strongest predictor of aberration detection. Compared with diagnostic samples, follow-up specimens showed significantly lower odds of abnormal findings (adjusted OR 0.48, 95% CI 0.36–0.64; p < 0.001), whereas relapse samples demonstrated higher odds (adjusted OR 1.82, 95% CI 1.28–2.59; p = 0.001). Increasing age was independently associated with abnormal FISH results (adjusted OR per decade 1.24, 95% CI 1.12–1.38; p < 0.001). Several canonical abnormalities occurred less frequently than expected from historical diagnostic series, including BCR::ABL1 within the chronic myeloid leukemia testing pathway and del(13q14) in both chronic lymphocytic leukemia and multiple myeloma. In contrast, del(17p), involving the TP53 locus, remained consistently represented across disease categories and was enriched in chronic lymphocytic leukemia relative to published diagnostic cohorts. Conclusions: Longitudinal assessment revealed increasing cytogenetic heterogeneity over time, with common lesions progressively declining and rare or complex abnormalities expanding from 16.3% to 36.7% of the observed cytogenetic landscape. The cytogenetic patterns detected by FISH in contemporary hematology practice are strongly associated with clinical context, disease stage, and treatment history; however, the cross-sectional and retrospective design precludes inference of causal influence. The divergence between real-world positivity rates and historical diagnostic benchmarks highlights the need for context-specific interpretation of cytogenetic findings. The persistence of TP53 loss across disease boundaries and the progressive diversification of aberrations over time underscore the dynamic nature of clonal evolution in hematologic malignancies. Full article

(This article belongs to the Special Issue Molecular Pathology and Genomic Analytics: Bioinformatics Innovations in Cancer Research)

► Show Figures

Figure 1

16 pages, 1146 KB

Open AccessReview

The Dysregulation of the Integrated Stress Response in Leukemic Stem Cells as a Marker of Treatment Sensitivity in Acute Myeloid Leukemia

by Giorgia Benedetta Dutti, Katia Mangialardi, Simona Rasola, Ludovico Sebastio, Francesco Tarantini, Cosimo Cumbo, Luisa Anelli, Antonella Zagaria, Nicoletta Coccaro, Angela Minervini, Giuseppina Tota, Immacolata Redavid, Maria Rosa Conserva, Pellegrino Musto and Francesco Albano

Genes 2026, 17(8), 954; https://doi.org/10.3390/genes17080954 - 14 Aug 2026

Viewed by 440

Abstract

Acute myeloid leukemia (AML) persistence is sustained by leukemic stem cells (LSCs) that survive metabolic deprivation, oxidative stress, hypoxia, proteotoxic burden, and therapeutic pressure. The integrated stress response (ISR) has emerged as a central adaptive network in this process. Through phosphorylation of a [...] Read more.

Acute myeloid leukemia (AML) persistence is sustained by leukemic stem cells (LSCs) that survive metabolic deprivation, oxidative stress, hypoxia, proteotoxic burden, and therapeutic pressure. The integrated stress response (ISR) has emerged as a central adaptive network in this process. Through phosphorylation of a subunit of eukaryotic initiation factor 2 (eIF2α) and selective translation of activating transcription factor 4 (ATF4), the ISR coordinates stress-responsive transcriptional programs that may either preserve cellular fitness or promote apoptotic commitment, depending on the intensity, duration, and biological context of activation. In AML, ATF4 occupies a critical position at the interface between stemness, metabolic adaptation, redox control, ferroptosis resistance, and treatment response. In primitive leukemic compartments, ISR–ATF4 signaling appears to support stress tolerance, amino acid metabolism, serine biosynthesis, autophagy, and leukemic persistence. At the same time, pharmacologic or sustained ISR activation may lower the apoptotic threshold by inducing pro-apoptotic mediators such as CHOP, PUMA, and NOXA, thereby modulating MCL-1 dependency and enhancing sensitivity to venetoclax-based strategies. Conversely, adaptive ISR signaling may promote resistance through mechanisms such as ATP-binding cassette subfamily B member 1 (ABCB1) enhancer activation and mitochondrial stress tolerance. This duality creates a therapeutic paradox: ISR–ATF4 signaling may need to be inhibited in adaptive, resistance-promoting states but amplified in apoptosis-permissive contexts. This review discusses the biological and therapeutic relevance of ISR–ATF4 dysregulation in AML and highlights the need for biomarkers capable of distinguishing adaptive ATF4 dependency from inducible apoptotic vulnerability. Full article

(This article belongs to the Special Issue Gene Regulatory Networks in Hematologic Malignancies and Cancer)

► Show Figures

Graphical abstract

Journal Menu

Journal Browser

Genes, Volume 17, Issue 8 (August 2026) – 139 articles

Further Information

Guidelines

MDPI Initiatives

Follow MDPI