Genes

30 pages, 759 KB

Open AccessEditor’s ChoiceReview

Genetic, Epigenetic, and Non-Genetic Factors in Testicular Dysgenesis Syndrome: A Narrative Review

by Alessandro Ciarloni, Nicola delli Muti, Sara Sacco, Nicola Ambo, Valentina Di Giacomi, Michele Perrone, Silvia Rossi, Marinella Balercia, Gianmaria Salvio and Giancarlo Balercia

Genes 2026, 17(1), 40; https://doi.org/10.3390/genes17010040 - 31 Dec 2025

Cited by 2 | Viewed by 2583

Abstract

Background: Testicular dysgenesis syndrome (TDS) is a complex disorder of the male reproductive system related to disfunction of the fetal testis. The clinical features of TDS may be evident at birth or infancy (cryptorchidism, hypospadias and/or reduced anogenital distance) or occur later in [...] Read more.

Background: Testicular dysgenesis syndrome (TDS) is a complex disorder of the male reproductive system related to disfunction of the fetal testis. The clinical features of TDS may be evident at birth or infancy (cryptorchidism, hypospadias and/or reduced anogenital distance) or occur later in adulthood (testis cancer, infertility). Genetic background seems to be important for genetic predisposition, with new genes being associated with components of the syndrome in last years. Interestingly, the incidence of clinical manifestations of TDS has been increasing in many countries in recent decades, suggesting that genetic predisposition alone cannot explain this trend. Consequently, the hypothesis of multifactorial etiopathogenesis is becoming increasingly accepted nowadays, with environmental factors probably acting during early developmental stages in genetically predisposed individuals. Methods: In this narrative review, we aim to critically evaluate genetic and non-genetic factors involved in the pathogenesis of TDs. Results: Important associations with intrauterine growth disorders and maternal diseases (overweight/obesity and diabetes) as well as lifestyle factors (e.g., smoking and alcohol abuse) were found. In such context, endocrine disruptors probably play a major role. These substances are widely used in industry and can exert estrogenic and antiandrogenic effects, potentially interfering with the development of the fetal gonad. Conclusions: Considering their possible impact on male sexual health, more attention should be focused on maternal modifiable factors to confirm with prospective studies the mixed results of available evidence. Full article

(This article belongs to the Special Issue The Genetics of Male Infertility and Clinical Implications)

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13 pages, 280 KB

Open AccessEditor’s ChoiceReview

Review of Genomic Drivers of Thyroid Cancer and Their Clinical Implications

by Sobrina Mohammed, Daniel Mettman, Axel Hugo Breier, Vaishali Patel and Mariana Garcia-Touza

Genes 2026, 17(1), 36; https://doi.org/10.3390/genes17010036 - 30 Dec 2025

Cited by 1 | Viewed by 1597

Abstract

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as [...] Read more.

Over the past several decades, rapid advances in molecular genomics have transformed our understanding of thyroid malignancies and are increasingly integrated into international clinical guidelines. Mutational profiles and epigenetic events are now recognized not only as diagnostic and prognostic tools but also as predictors of therapeutic response. Papillary, follicular, oncocytic, medullary, and anaplastic thyroid carcinomas harbor distinct early driver mutations, such as BRAFV600E, RAS, and fusion events (RET, NTRK, and ALK), that cooperate with secondary alterations (TERT promoter, TP53, PIK3CA, and CDKN2A/B loss) to drive dedifferentiation, metastasis, and therapeutic resistance. Insights from The Cancer Genome Atlas (TCGA) and transcriptomic scoring systems (e.g., BRAF–RAS score) now link genotype to tumor morphology, metastatic tropism, and radioactive iodine refractoriness. These molecular insights have been incorporated into updated risk stratification frameworks, preoperative surgical planning, and treatment algorithms, informing the selection of kinase inhibitors, redifferentiation strategies, and enrollment in genotype-directed clinical trials for radioiodine-refractory disease. This review synthesizes recent evidence connecting genomic alterations to clinical behavior and highlights their translation into evolving approaches for thyroid cancer management. Full article

(This article belongs to the Special Issue Genetics in Thyroid Cancer)

16 pages, 4926 KB

Open AccessEditor’s ChoiceArticle

Complete Chloroplast Genome Sequence and Phylogenetic Analysis of the Tibetan Medicinal Plant Soroseris hookeriana

by Tian Tian, Xiuying Lin, Yiming Wang and Jiuli Wang

Genes 2026, 17(1), 24; https://doi.org/10.3390/genes17010024 - 27 Dec 2025

Cited by 2 | Viewed by 708

Abstract

Background/Objectives: Soroseris hookeriana, a Tibetan medicinal plant endemic to the high-altitude Qinghai–Tibet Plateau, possesses significant pharmacological value but lacks fundamental genomic characterization. This study aims to generate and comparatively analyse its complete chloroplast genome. Methods: Total DNA was sequenced, assembled [...] Read more.

Background/Objectives: Soroseris hookeriana, a Tibetan medicinal plant endemic to the high-altitude Qinghai–Tibet Plateau, possesses significant pharmacological value but lacks fundamental genomic characterization. This study aims to generate and comparatively analyse its complete chloroplast genome. Methods: Total DNA was sequenced, assembled with GetOrganelle, annotated with CPGAVAS2, and compared with eight Asteraceae species; phylogenetic placement was inferred with IQ-TREE from 21 complete plastomes. Results: The circular chloroplast genome is 152,514 bp with a typical quadripartite structure (LSC 84,168 bp, SSC 18,528 bp, two IRs 24,909 bp each). It contains 132 unique genes (87 protein-coding, 37 tRNA, 8 rRNA; 18 duplicated in IRs yield 150 total copies). Twenty-three genes harbour introns; clpP and ycf3 have two. Overall GC content is 37.73%, elevated in IRs (43.12%). Codon usage shows strong A/U bias at the third position; 172 SSRs and 39 long repeats are detected. IR-SC boundaries exhibit the greatest inter-specific variation, notably in ycf1 and ndhF. Conclusions: The complete plastome robustly supports S. hookeriana and Stebbinsia umbrella as sister species (100% bootstrap) and provides essential genomic resources for species identification, population genetics, and studies of high-altitude adaptation. Full article

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

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16 pages, 1189 KB

Open AccessEditor’s ChoiceArticle

Brain Matters in Duchenne Muscular Dystrophy: DMD Mutation Sites and Their Association with Neurological Comorbidities Through Isoform Impairment

by Teodora Barbarii, Raluca Anca Tudorache, Dana Craiu, Elena Neagu, Lacramioara Aurelia Brinduse, Carmen Magdalena Burloiu, Catrinel Mihaela Iliescu, Magdalena Budisteanu, Ioana Minciu, Diana Gabriela Barca, Carmen Sandu, Oana Tarta-Arsene, Cristina Pomeran, Cristina Motoescu, Alice Dica, Cristina Anghelescu, Dana Surlica, Adrian Ioan Toma and Niculina Butoianu

Genes 2026, 17(1), 12; https://doi.org/10.3390/genes17010012 - 24 Dec 2025

Cited by 1 | Viewed by 1895

Abstract

Background: Duchenne/Becker muscular dystrophy (DMD/BMD) is associated with a wide spectrum of brain-related comorbidities. Methods: This retrospective study assesses the neuropsychiatric profile of DMD/BMD patients and the hypothesis of a functional-versus-structural approach of dystrophin gene variants/impaired isoforms in relation to brain comorbidities. Patients with documented [...] Read more.

Background: Duchenne/Becker muscular dystrophy (DMD/BMD) is associated with a wide spectrum of brain-related comorbidities. Methods: This retrospective study assesses the neuropsychiatric profile of DMD/BMD patients and the hypothesis of a functional-versus-structural approach of dystrophin gene variants/impaired isoforms in relation to brain comorbidities. Patients with documented mutation in the DMD gene and neuropsychiatric assessments were included. Seven comorbidities were analyzed based on variant location and dystrophin brain isoform disruption. The clustering of comorbidities and genotype–phenotype correlations were studied. Results: 264 DMD/BMD patients met inclusion criteria. 22 variants have never been described before. A high prevalence of neuropsychiatric comorbidities was identified in the cohort with higher values in patients with distal mutations. The number of comorbidities increased with the number of brain dystrophin isoforms predicted to be lost. Functional-versus-structural comparison revealed that Dp140 5′UTR variants might not affect protein expression. Epilepsy and intellectual disability (ID) showed significant association in this cohort. Neuropsychiatric phenotype varied greatly in patients with identical variants, even between siblings. Conclusions: This is one of the largest European cohorts for which all these comorbidities were studied in association with DMD gene mutation site and the first study of this kind performed on the Eastern European DMD/BMD population. Our group analyzed, for the first time, Dp140 5′UTR variants in relation to all neuropsychiatric phenotypes and showed that epilepsy and ID are strongly associated in DMD/DMB patients. Full article

(This article belongs to the Special Issue Genetic Diagnosis and Treatment of Duchenne Muscular Dystrophy)

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16 pages, 1206 KB

Open AccessEditor’s ChoiceArticle

Exercise, APOE Genotype, and Testosterone Modulate Gut Microbiome–Cognition Associations in Prostate Cancer Survivors

by Jacob Raber, Abigail O’Niel, Kristin D. Kasschau, Alexandra Pederson, Naomi Robinson, Carolyn Guidarelli, Christopher Chalmers, Kerri Winters-Stone and Thomas J. Sharpton

Genes 2025, 16(12), 1507; https://doi.org/10.3390/genes16121507 - 16 Dec 2025

Cited by 2 | Viewed by 1441

Abstract

Background: Men treated with androgen deprivation therapy (ADT) for prostate cancer are at risk for cognitive decline. Patient genetics and endocrine state may shape gut microbiome features that relate to cognition. Methods: We studied a subsample of 79 prostate cancer survivors with prior [...] Read more.

Background: Men treated with androgen deprivation therapy (ADT) for prostate cancer are at risk for cognitive decline. Patient genetics and endocrine state may shape gut microbiome features that relate to cognition. Methods: We studied a subsample of 79 prostate cancer survivors with prior ADT exposure previously enrolled in a randomized controlled exercise trial comparing three training modalities (strength training, Tai Chi training, or stretching control) who completed an additional food-frequency questionnaire and remote Montreal Cognitive Assessment (MoCA) and provided saliva and stool for APOE genotyping, salivary testosterone, and 16S rRNA sequencing. We used beta regression for MoCA (scaled 0–1), linear models for testosterone, alpha diversity regressions, PERMANOVA for beta diversity, and DESeq2 for genus-level differential abundance, with false-discovery correction. Results: Compared to post-stretching control, post-strength training testing was associated with higher MoCA scores whereas post-Tai Chi testing was not. APOE ε4 carriers exhibited a greater testosterone increase with strength training than non-carriers. Testosterone, and its interactions with exercise modality and APOE ε2 status, was related to presence/absence-based community structure; APOE ε4 interacted with exercise intervention to influence alpha diversity. At the genus level, exercise was linked to lower levels of Bacteroidota taxa (including Muribaculaceae) and higher levels of Enterobacteriaceae; APOE ε4 status was linked to higher Megamonas and lower Rikenellaceae RC9 levels; and higher salivary testosterone levels were linked to higher Prevotellaceae taxa and Succinivibrio levels. Higher MoCA scores were associated with lower abundances of several Firmicutes genera. Conclusions: Endocrine state and APOE genotype may condition the gut microbiome’s response to exercise intervention in ADT-treated prostate cancer survivors, with downstream associations with cognition. These findings could inform precision survivorship strategies pairing strength training with genotype- and hormone-informed microbiome monitoring to optimize cognitive performance. Full article

(This article belongs to the Special Issue Unveiling Human Microbiome Composition and Functions to Improve Health and Disease Research)

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26 pages, 800 KB

Open AccessEditor’s ChoiceReview

SIRT3-Mediated Mitochondrial Regulation and Driver Tissues in Systemic Aging

by Kate Šešelja, Ena Šimunić, Sandra Sobočanec, Iva I. Podgorski, Marija Pinterić, Marijana Popović Hadžija, Tihomir Balog and Robert Belužić

Genes 2025, 16(12), 1497; https://doi.org/10.3390/genes16121497 - 15 Dec 2025

Cited by 9 | Viewed by 2736

Abstract

Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This [...] Read more.

Mitochondrial dysfunction is a defining hallmark of aging that connects redox imbalance, metabolic decline, and inflammatory signaling across organ systems. The mitochondrial deacetylase SIRT3 preserves oxidative metabolism and proteostasis, yet its age-related decline transforms metabolically demanding organs into sources of pro-senescent cues. This review synthesizes evidence showing how SIRT3 loss in select “driver tissues”—notably liver, adipose tissue, vascular endothelium, bone-marrow macrophages, and ovary—initiates systemic aging through the release of cytokines, oxidized metabolites, and extracellular vesicles. We discuss molecular routes and mediators of senescence propagation, including the senescence-associated secretory phenotype (SASP), mitochondrial-derived vesicles, and circulating mitochondrial DNA, as well as sex-specific modulation of SIRT3 by hormonal and intrinsic factors. By integrating multi-tissue and sex-dependent data, we outline a framework in which SIRT3 activity defines the mitochondrial threshold separating local adaptation from systemic aging spread. Targeting SIRT3 and its NAD⁺-dependent network may offer a unified strategy to restore mitochondrial quality, dampen chronic inflammation, and therefore recalibrate the aging dynamics of an organism. Full article

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

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18 pages, 313 KB

Open AccessEditor’s ChoiceReview

Underlying Mechanisms of GBA1 in Parkinson’s Disease and Dementia with Lewy Bodies: Narrative Review

by Anastasia Bougea

Genes 2025, 16(12), 1496; https://doi.org/10.3390/genes16121496 - 15 Dec 2025

Cited by 7 | Viewed by 1958

Abstract

Background/Objectives: Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of misfolded alpha-synuclein protein in the brain. Mutations in the glucocerebrosidase 1 (GBA1) gene have been identified as a significant genetic risk factor [...] Read more.

Background/Objectives: Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB) are neurodegenerative disorders characterized by the accumulation of misfolded alpha-synuclein protein in the brain. Mutations in the glucocerebrosidase 1 (GBA1) gene have been identified as a significant genetic risk factor for both PD and DLB. GBA1 encodes for the lysosomal enzyme glucocerebrosidase, which is responsible for the breakdown of glucosylceramide (GC). Deficiencies in glucocerebrosidase activity lead to the accumulation of glucosylceramide within lysosomes, contributing to lysosomal dysfunction and impaired protein degradation. The aim of this narrative review is to update the underlying mechanisms by which GBA1 mutations contribute to the pathogenesis of PD and DLB. Methods: A comprehensive literature search was conducted across four major electronic databases (PubMed, Web of Science (Core Collection), Scopus, and Embase) from inception to 8 November 2025. The initial search identified approximately 1650 articles in total, with the number of hits from each database being as follows: PubMed (~450), Web of Science (~380), Scopus (~520), and Embase (~300). Results: The mechanism by which mutations in the GBA1 gene contribute to PD involves both loss-of- function and gain-of-function pathways, which are not mutually exclusive. Typically, GBA1 mutations lead to a loss of function by reducing the activity of the GCase enzyme, impairing the autophagy- lysosomal pathway and leading to α-synuclein accumulation. However, some mutant forms (GBA1L444P) of the GCase enzyme can also acquire a toxic gain of function, contributing to α-synuclein aggregation through mechanisms like endoplasmic reticulum stress and misfolding. While Venglustat effectively reduced GC levels, a key marker associated with GBA1-PD, the lack of clinical improvement led to the discontinuation of its development for this indication. Conclusions: GBA1-mediated lysosomal and lipid dysregulation represents a key pathogenic axis in PD and DLB. Understanding these mechanisms provides crucial insight into disease progression and highlights emerging therapeutic strategies—such as pharmacological chaperones, substrate reduction therapies, and gene-targeted approaches—aimed at restoring GCase function and lysosomal homeostasis to slow or prevent neurodegeneration. Full article

(This article belongs to the Special Issue Genetics and Epigenetics in Neurological Disorders)

21 pages, 717 KB

Open AccessEditor’s ChoiceReview

RET Gene Alterations in Clinical Practice: A Comprehensive Review and Database Update

by Claudio Ricciardi Tenore, Eugenia Tulli, Alessia Perrucci, Roberto Bertozzi, Ludovica Fortuna, Giulia Maneri, Concetta Santonocito, Andrea Urbani, Maria De Bonis and Angelo Minucci

Genes 2025, 16(12), 1472; https://doi.org/10.3390/genes16121472 - 9 Dec 2025

Cited by 4 | Viewed by 2161

Abstract

Background/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical [...] Read more.

Background/Objectives: The RET (Rearranged during Transfection) gene encodes a receptor tyrosine kinase. RET plays a critical role in embryonic development and postnatal physiology. This review provides a comprehensive overview of RET-associated disorders, focusing on the molecular mechanisms of RET activation, associated clinical phenotypes and therapeutic implications. In addition, we present an updated RET mutation database. Methods: RET mutation database is built through the integration and curation of data from two major RET mutation repositories: the Leiden Open Variation Database (LOVD) and the Cancer Knowledge Base (CKB) as well as information derived from the ClinVar database. Results: To date, 78 pathogenic RET mutations have been identified, among these, 71 (91.0%) are single nucleotide substitutions (missense variants), 2 (2.6%) are deletions, 1 (1.3%) are indels, 2 (2.6%) are nonsense mutations and 1 (1.3%) mutation affecting the introns. A pronounced clustering was observed in exons 10–11, accounting for ~60% of cases, suggesting a potential mutational hotspot with structural or functional relevance. Conclusions: Aberrant RET activation, resulting from activating missense variants, gene fusions, or overexpression, underlies a wide spectrum of human diseases. These include multiple endocrine neoplasia type 2A (MEN2A), medullary thyroid carcinoma (MTC), Hirschsprung disease, and pheochromocytoma. The existence and use of a database classifying variants in the RET gene plays a fundamental role in molecular diagnostics and personalized medicine. Full article

(This article belongs to the Section Bioinformatics)

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26 pages, 6524 KB

Open AccessEditor’s ChoiceArticle

Preliminary Assessment of Arnica montana L. Extract: Antimicrobial Activity Against Acinetobacter baumannii and Biofilm-Related Gene Expression Profiling

by Sylwia Andrzejczuk, Magdalena Sozoniuk and Danuta Sugier

Genes 2025, 16(12), 1473; https://doi.org/10.3390/genes16121473 - 9 Dec 2025

Cited by 2 | Viewed by 966

Abstract

Background/Objectives: Arnica montana L. is widely recognized for its diverse biological activities, including antimicrobial effects. This study aimed to evaluate the antimicrobial and antibiofilm activity of A. montana L. extracts against Acinetobacter baumannii, a pathogen of urgent public health concern due [...] Read more.

Background/Objectives: Arnica montana L. is widely recognized for its diverse biological activities, including antimicrobial effects. This study aimed to evaluate the antimicrobial and antibiofilm activity of A. montana L. extracts against Acinetobacter baumannii, a pathogen of urgent public health concern due to its increasing antibiotic resistance and capacity for biofilm formation. Methods: The antimicrobial activity of ethanolic (EtE) and aqueous (AqE) extracts of A. montana flowers was evaluated via the broth microdilution method. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC), and the MBC/MIC ratio were used. The effects of EtE on A. baumannii biofilm formation were assessed via a crystal violet assay. Additionally, transcriptional profiling of biofilm-associated genes following exposure to sub-MIC levels of the extract was conducted via RT-qPCR. Results: The anti-Acinetobacter activity of EtE was demonstrated (MIC = 234.4 and 468.75 µg/mL for A. baumannii ATCC BAA-3252 and ATCC 19606, respectively). The EtE exhibited bactericidal activity against both strains, whereas the AqE showed no activity. Additionally, EtE inhibited biofilm formation and significantly downregulated the expression of key biofilm-associated genes, including those of the csu operon and ompA. Conclusions: Arnica montana EtE demonstrated antimicrobial and antibiofilm activities against A. baumannii and inhibited biofilm development by suppressing the transcription of genes involved in pilus assembly and surface adherence, highlighting their essential role in biofilm formation. Full article

(This article belongs to the Special Issue Advances in Molecular Microbiology, Genetics, and Bioinformatics of Multiple-Drug-Resistant Bacteria in Public Health)

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25 pages, 812 KB

Open AccessEditor’s ChoiceReview

Artificial Intelligence-Driven Design of Antisense Oligonucleotides for Precision Medicine in Neuromuscular Disorders

by Jamie Leckie, Sunny Wu, Terryanne Standell and Toshifumi Yokota

Genes 2025, 16(12), 1468; https://doi.org/10.3390/genes16121468 - 8 Dec 2025

Cited by 2 | Viewed by 2654

Abstract

Rare neuromuscular disorders impose a significant burden on patients, caregivers, and the health care system, yet, effective disease-modifying therapies remain limited. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic strategy, enabling targeted modulation of gene expression through mechanisms such as exon skipping, [...] Read more.

Rare neuromuscular disorders impose a significant burden on patients, caregivers, and the health care system, yet, effective disease-modifying therapies remain limited. Antisense oligonucleotides (ASOs) have emerged as a promising therapeutic strategy, enabling targeted modulation of gene expression through mechanisms such as exon skipping, exon inclusion, and transcript degradation. However, the clinical efficacy of currently approved ASO therapies is often suboptimal. This limitation reflects not only poor target tissue uptake and delivery barriers, but also suboptimal design of ASO sequences and chemical modification patterns, which can compromise potency, safety, and translational robustness. Recent advances in machine learning have led to the development of ASO optimization platforms such as eSkipFinder and ASOptimizer, which aim to predict effective ASO sequences and chemistries for specific RNA targets. While these tools show considerable promise, their broader applicability remains limited due to a lack of comprehensive validation and the absence of integrated safety considerations. Further refinement and validation are necessary to improve their translational utility. Nevertheless, such platforms represent a critical advancement toward accelerating ASO development. By improving design precision, reducing reliance on extensive preclinical screening, and enabling researchers with limited ASO experience to generate optimized candidates, machine learning is poised to accelerate the development and clinical translation of ASO therapies for rare neuromuscular disorders. Full article

(This article belongs to the Special Issue AI and Neurogenomics: Innovations in Precision Medicine for Brain Disorders)

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31 pages, 567 KB

Open AccessEditor’s ChoiceReview

From Skin to Brain: Key Genetic Mediators Associating Cutaneous Inflammation and Neurodegenerative Diseases

by Vasiliki-Sofia Grech, Kleomenis Lotsaris, Vassiliki Kefala and Efstathios Rallis

Genes 2025, 16(12), 1463; https://doi.org/10.3390/genes16121463 - 8 Dec 2025

Cited by 4 | Viewed by 3252

Abstract

Chronic inflammatory skin diseases and neurodegenerative disorders share overlapping genetic, immunologic, and metabolic pathways that may predispose individuals to cognitive decline. This review synthesizes current human genomic, transcriptomic, and bioinformatic evidence linking psoriasis, rosacea, atopic dermatitis, and bullous pemphigoid with Alzheimer’s and Parkinson’s [...] Read more.

Chronic inflammatory skin diseases and neurodegenerative disorders share overlapping genetic, immunologic, and metabolic pathways that may predispose individuals to cognitive decline. This review synthesizes current human genomic, transcriptomic, and bioinformatic evidence linking psoriasis, rosacea, atopic dermatitis, and bullous pemphigoid with Alzheimer’s and Parkinson’s disease. Literature from PubMed, IEEE Xplore, and Google Scholar was examined, prioritizing studies integrating genomic, transcriptomic, and proteomic analyses. Among inflammatory dermatoses, psoriasis exhibits the strongest overlap with dementia genetics, with shared susceptibility loci including APOE, IL12B, and HLA-DRB5, and transcriptional regulators such as ZNF384 that converge on IL-17/TNF signaling. Rare-variant and pleiotropy analyses further implicate SETD1A and BC070367 in psoriasis–Parkinson’s comorbidity. Rosacea demonstrates upregulation of neurodegeneration-related proteins SNCA, GSK3B, and HSPA8, together with shared regulatory hubs (PPARG, STAT4, RORA) driving NF-κB/IL-17/TNF-dependent inflammation. In atopic dermatitis, rare FLG variants interacting with BACE1 suggest a mechanistic bridge between barrier dysfunction and amyloidogenic processing. Bullous pemphigoid reveals an HLA-DQB1*03:01-mediated immunogenetic link hypothesis and cross-reactive autoantibodies targeting BP180 (collagen XVII) and BP230, highlighting an autoimmune route of neurocutaneous interaction. Other inflammatory and neurodegenerative diseases with currently weak or limited genetic evidence are also discussed, as they may represent emerging biological pathways or potential therapeutic targets within the skin–brain connection in the future. The aim of this work is to help clarify these genetic links and to advocate for the routine cognitive assessment of affected patients, enabling early detection, improved long-term quality of life, and the potential for timely therapeutic intervention. Full article

(This article belongs to the Special Issue Genetics and Treatment in Neurodegenerative Diseases)

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40 pages, 1000 KB

Open AccessEditor’s ChoiceReview

Addiction Susceptibility: Genetic Factors, Personality Traits, and Epigenetic Interactions with the Gut Microbiome

by Alejandro Borrego-Ruiz and Juan J. Borrego

Genes 2025, 16(12), 1447; https://doi.org/10.3390/genes16121447 - 3 Dec 2025

Cited by 1 | Viewed by 5600

Abstract

Despite valuable insights into the individual roles of genetic factors and personality traits, their combined contribution to addiction susceptibility remains insufficiently characterized. Within this framework, the potential influence of epigenetic mechanisms, particularly those mediated by the gut microbiome, also remains underexplored. This comprehensive [...] Read more.

Despite valuable insights into the individual roles of genetic factors and personality traits, their combined contribution to addiction susceptibility remains insufficiently characterized. Within this framework, the potential influence of epigenetic mechanisms, particularly those mediated by the gut microbiome, also remains underexplored. This comprehensive review aims to address these gaps in an integrative manner by examining: (i) the association of gene regulation with personality traits; (ii) the genetics of substance use disorders; (iii) the roles of genes and personality in addiction; and (iv) epigenetic influences on addiction, with a particular focus on the role of the gut microbiome. Genetic influences on personality act primarily via regulatory variants that modulate gene expression during neurodevelopment, shaping cognitive, emotional, and behavioral traits that contribute to individual differences. Substance use disorders share partially overlapping genetic foundations, with specific loci, heritability estimates, and causal pathways differing across substances, reflecting both shared vulnerability and substance-specific genetic influences on addiction susceptibility. Impulsivity, novelty-seeking, and stress responsiveness are heritable personality traits that interact to shape susceptibility to substance use disorders, with genetic factors modulating risk across different forms of addiction. Environmental factors, early-life stress, and social influences interact with the gut microbiome to shape neurobiological and behavioral pathways that modulate addiction risk. These interactions highlight the multifactorial nature of substance use disorders, in which epigenetic, microbial, and psychosocial mechanisms converge to influence susceptibility, progression, and maintenance of addictive behaviors. Full article

(This article belongs to the Section Neurogenomics)

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22 pages, 1034 KB

Open AccessEditor’s ChoiceReview

The Utility of Genome-Wide Association Studies in Inherited Arrhythmias and Cardiomyopathies

by Saif Dababneh, Arya Ardehali, Jasleen Badesha and Zachary Laksman

Genes 2025, 16(12), 1448; https://doi.org/10.3390/genes16121448 - 3 Dec 2025

Cited by 4 | Viewed by 1229

Abstract

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given [...] Read more.

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as SCN5A for Brugada syndrome, and MYH7 and MYBPC3 for hypertrophic cardiomyopathy, which have revolutionized diagnosis, risk stratification, and medical management. Nonetheless, issues such as variable expressivity and penetrance, low yield of genetic testing, and relative lack of disease-modifying therapies remain significant hurdles for clinical management. The revolution of genome-wide association studies GWASs has transformed our understanding of inherited arrhythmias and cardiomyopathies, shifting the view of these disorders from a monogenic Mendelian inheritance towards a more complex, often polygenic inheritance with nuanced interplay between genetics and environment. Moreover, GWASs have enabled the quantification of polygenic predisposition to disease using polygenic risk scores, which are often complementary to and independent of monogenic risk. In this review, we highlight how GWASs have transformed the field of inherited arrhythmias and cardiomyopathies, with a particular focus on the polygenic risk scores developed and their clinical utility for the four disorders which have been impacted by GWASs—hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome. Full article

(This article belongs to the Special Issue Application of Genome-Wide Association Studies in Rare Diseases Research)

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20 pages, 888 KB

Open AccessEditor’s ChoiceReview

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

Cited by 2 | Viewed by 1754

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 AccessEditor’s ChoiceReview

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

Cited by 9 | Viewed by 3217

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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19 pages, 1128 KB

Open AccessEditor’s ChoiceArticle

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

Cited by 2 | Viewed by 949

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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60 pages, 604 KB

Open AccessEditor’s ChoiceReview

Sperm-Derived Extracellular Vesicles (Sperm-EVs), Emerging Biomarkers and Functional Modulators in Male Infertility and Assisted Reproduction

by Charalampos Voros, Fotios Chatzinikolaou, Georgios Papadimas, Spyridon Polykalas, Despoina Mavrogianni, Aristotelis-Marios Koulakmanidis, Diamantis Athanasiou, Vasiliki Kanaka, Maria Kanaka, Kyriakos Bananis, Antonia Athanasiou, Aikaterini Athanasiou, Ioannis Papapanagiotou, Dimitrios Vaitsis, Charalampos Tsimpoukelis, Maria Anastasia Daskalaki, Marianna Theodora, Nikolaos Thomakos, Panagiotis Antsaklis, Dimitrios Loutradis and Georgios Daskalakis Show full author list Hide full author list

Genes 2025, 16(12), 1400; https://doi.org/10.3390/genes16121400 - 22 Nov 2025

Cited by 4 | Viewed by 3053

Abstract

Background/Objectives: Approximately 50% of infertility cases are attributable to male factors; yet conventional semen examination can not identify the molecular abnormalities that hinder sperm functionality. Extracellular vesicles (EVs) derived from sperm, such as testicular EVs, prostasomes, and epididymosomes, have become important modulators of [...] Read more.

Background/Objectives: Approximately 50% of infertility cases are attributable to male factors; yet conventional semen examination can not identify the molecular abnormalities that hinder sperm functionality. Extracellular vesicles (EVs) derived from sperm, such as testicular EVs, prostasomes, and epididymosomes, have become important modulators of oocyte activation, sperm maturation, capacitation, acrosome stability, motility, and early embryonic development. This study aimed to evaluate the potential diagnostic and translational uses of sperm-associated extracellular vesicles (EVs) in male infertility and assisted reproduction, while also consolidating recent insights on their origins, composition, and functional significance. Methods: A focused narrative search of PubMed (2000–2025) was conducted using backward and forward citation tracking. Studies that qualified included human clinical cohorts, functional sperm extracellular vesicle tests, and omics analyses using MISEV-aligned extracellular vesicle isolation and characterisation methodologies. When human mechanistic understanding was constrained, knowledge from animal research was selectively integrated. Results: The cargo signatures specific to the source identified in sperm-derived and seminal EVs encompass proteins, small RNAs, lipids, and enzymatic modules that govern sperm maturation, capacitation, acrosome reaction, redox balance, calcium signalling, zona binding, and DNA integrity. Density-resolved seminal extracellular vesicle subfractions (EV-H/EV-M/EV-L) have unique functional and proteomic characteristics linked to progesterone-induced hyperactivation, oxidative stress, and motility. Asthenozoospermia and oligoasthenoteratozoospermia are associated with changes in extracellular vesicle composition, reduced embryonic developmental potential, compromised oocyte activation (related to PLCζ), and increased sperm DNA fragmentation. Numerous EV-related miRNA and protein signatures may predict TESE results, identify functional sperm anomalies not recognised by conventional semen analysis, and differentiate between obstructive and non-obstructive azoospermia. Conclusions: The available findings indicate that sperm-derived extracellular vesicles are significant functional regulators of sperm physiology and may serve as valuable non-invasive indicators for male infertility. The standardisation of EV isolation, characterisation, and clinical validation is essential prior to widespread use; nonetheless, their integration into liquid biopsy methods and assisted reproductive technology processes represents a significant improvement. Full article

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

23 pages, 4371 KB

Open AccessEditor’s ChoiceArticle

Molecular Characterization and Functional Effect on Canine Peripheral Blood Mononuclear Cells of an Uncharacterized Major Egg Antigen EGR-01664 from Echinococcus granulosus

by Juncheng Huang, Xinwen Bo, Xuke Chen, Jiaxin Zhao, Jianan Zhao, Linying Wei, Yanyan Zhang, Yan Sun and Zhengrong Wang

Genes 2025, 16(11), 1384; https://doi.org/10.3390/genes16111384 - 14 Nov 2025

Cited by 2 | Viewed by 924

Abstract

Background: Cystic echinococcosis (CE) is a globally distributed zoonosis triggered by the larval stage of Echinococcus granulosus (E. granulosus), impacting humans and an extensive array of mammalian intermediate hosts. EGR-01664 is the major egg antigen of E. granulosus, but almost [...] Read more.

Background: Cystic echinococcosis (CE) is a globally distributed zoonosis triggered by the larval stage of Echinococcus granulosus (E. granulosus), impacting humans and an extensive array of mammalian intermediate hosts. EGR-01664 is the major egg antigen of E. granulosus, but almost nothing is currently known about the function of EGR-01664 from E. granulosus. Methods: This study aimed to investigate the E. granulosus EGR-01664 gene (GenBank ID: 36337379), and the recombinant EGR-01664 protein was expressed successfully. Next, the transcription of the EGR-01664 gene across various developmental stages of E. granulosus was analyzed. Its spatial expression patterns in adult worms and protoscoleces were characterized using both quantitative PCR (qPCR) and immunofluorescence assays. Furthermore, the immunomodulatory effects of rEGR-01664 on cell proliferation, nitric oxide production, and cytokine secretion were examined by co-culturing the recombinant protein with canine PBMCs. Results: The rEGR-01664 could be recognized by sera from dogs infected with E. granulosus. Immunofluorescence assay (IFA) localization revealed the protein’s presence in the epidermis of protoscoleces, the adult epidermis, and some parenchymal tissues. qPCR revealed that EGR-01664 mRNA levels were significantly higher in protoscoleces compared to adults (p < 0.0001). At a concentration of 20 μg/mL, rEGR-01664 could significantly activate the transcription and expression of IL-10, TGF-β1, IL-17A, and Bax in canine PBMCs. However, with an increase in concentration, it inhibited the expression of IFN-γ, Bcl-2, GSDMD, IL-18, and IL-1β. These results suggest that the EGR-01664 gene plays a crucial role in the development, parasitism, and reproduction of E. granulosus. In vitro studies have shown that rEGR-01664 protein regulates the immune regulation function of canine PBMCs, suggesting its potential as a vaccine adjuvant or immunotherapy target. Conclusions: EGR-01664 may modulate canine PBMC functions to regulate host immune responses, thereby facilitating our understanding of how E. granulosus EGR-01664 contributes to the mechanism of parasitic immune evasion. Full article

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

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28 pages, 873 KB

Open AccessEditor’s ChoiceReview

Curing Sickle Cell Disease by Allogeneic Hematopoietic Stem Cell (HSC) Transplantation Toward In Vivo HSC Gene Therapy

by Rina Kansal

Genes 2025, 16(11), 1367; https://doi.org/10.3390/genes16111367 - 11 Nov 2025

Cited by 5 | Viewed by 3635

Abstract

Sickle cell disease comprises a group of prevalent inherited disorders defined by an underlying sickle cell allele that forms sickle hemoglobin. The incidence of this disease is rising, with more than 500,000 children born with it globally. The disease carries significant morbidity and [...] Read more.

Sickle cell disease comprises a group of prevalent inherited disorders defined by an underlying sickle cell allele that forms sickle hemoglobin. The incidence of this disease is rising, with more than 500,000 children born with it globally. The disease carries significant morbidity and mortality. Its only curative treatment was an allogeneic hematopoietic stem cell (HSC) transplant (HSCT) until late 2023, when two one-time gene therapies were approved for treating patients aged 12 years or older with severe sickle cell disease. This work aims to inform readers about these two gene therapies: one lentiviral-based and the other nonviral. The latter is based on the Nobel Prize-winning discovery of clustered, regularly interspaced, short, palindromic repeats (CRISPR)/CRISPR-associated (Cas)9 proteins and single-guide RNA (sgRNA)-based genome editing. Both approved gene therapies require an autologous HSCT with ex vivo genetically edited autologous hematopoietic stem and progenitor cells. Therefore, access to these gene therapies is limited to specialized centers with expertise in HSCTs. This review is meant for students, researchers, and clinical practitioners. It explains the basis for both approved gene therapies, their mechanisms of action, differences, risks, and other lentiviral-based and CRISPR-Cas9-based ex vivo gene therapies for sickle cell disease in clinical development. Additionally, it discusses the current state of preclinical studies for in vivo HSC gene therapy for sickle cell disease, which utilize advanced genome editing technologies developed after CRISPR-Cas9-sgRNA-based genome editing. In vivo HSC gene therapy, after it is clinically developed, would eliminate the need for an HSCT in receiving gene therapy and vastly increase access for numerous patients worldwide, even in low-income countries with the most significant disease burden. Full article

(This article belongs to the Special Issue Progress in Hematology: Non-Malignant, Pre-Malignant, and Malignant Disorders, and Genetically Based Therapies)

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15 pages, 569 KB

Open AccessEditor’s ChoiceSystematic Review

Genetic Assessment and Clinical Correlates in Severe Hypertriglyceridemia: A Systematic Review

by Carmine De Luca, Paola Ciciola, Guido D’Errico, Maria Donata Di Taranto, Giuliana Fortunato, Carina Gross, Jonathan Garn, Gabriella Iannuzzo, Matteo Di Minno and Ilenia Calcaterra

Genes 2025, 16(11), 1377; https://doi.org/10.3390/genes16111377 - 11 Nov 2025

Cited by 3 | Viewed by 2631

Abstract

Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed [...] Read more.

Background: Severe hypertriglyceridemia (SHTG) is associated with acute pancreatitis, metabolic dysfunction, and increased cardiovascular risk. Its genetic architecture ranges from rare biallelic variants causing familial chylomicronemia syndrome (FCS) to more prevalent polygenic or multifactorial chylomicronemia syndromes (MCS). Methods: We systematically reviewed scientific literature up to 2025 for studies reporting genetic data, clinical features, or therapeutic outcomes in adults with triglycerides (TG) ≥ 500 mg/dL. Extracted data were synthesized for genotype, polygenic risk score (PRS), TG levels, metabolic comorbidities, hepatic steatosis, pancreatitis, and treatment response. Results: Ten studies (n = 2521) were included. FCS due to biallelic LPL, APOC2, GPIHBP1, or LMF1 variants accounted for <5% of cases and showed extreme TG elevations (>2800 mg/dL) with pancreatitis prevalence (>70%). APOA5, APOC3, and APOB variants were associated with intermediate TG levels and high rates of metabolic dysfunction-associated steatotic liver disease (MASLD). Polygenic hypertriglyceridemia represented ~70–80% of cases, with TG ≈ 2200 mg/dL and pancreatitis prevalence 15–20%, largely modulated by metabolic triggers. MASLD was present in >70% of polygenic cases, supporting a “two-hit” model where hepatic overproduction of TG-rich lipoproteins amplifies TG excess. Interventional trials demonstrated TG reductions with APOC3 antisense therapy (70–80%) and ANGPTL3 inhibition (50–55%), while GLP-1RA significantly reduced hepatic fat (30–35%) and resolved NASH in up to 59% of patients. Conclusions: SHTG displays a genotype–phenotype gradient: FCS is linked to recurrent pancreatitis, whereas polygenic/MCS forms are closely associated with MASLD and metabolic dysfunction. These findings support a precision-medicine approach integrating genetic testing and PRS-guided strategies—prioritizing APOC3/ANGPTL3 inhibitors for FCS and combined TG-lowering plus metabolic therapies for MCS—to reduce pancreatitis recurrence and liver disease. Full article

(This article belongs to the Section Genetic Diagnosis)

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19 pages, 535 KB

Open AccessEditor’s ChoiceReview

Nutrigenomics and Epigenetics in the Dietary Management of Inflammatory Bowel Diseases

by Patrycja Musz, Gabriela Ryś, Weronika Fic, Aneta Sokal-Dembowska and Sara Jarmakiewicz-Czaja

Genes 2025, 16(11), 1368; https://doi.org/10.3390/genes16111368 - 11 Nov 2025

Cited by 2 | Viewed by 2809

Abstract

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic diseases with complex aetiology involving genetic, immunological, and environmental factors and intestinal microbiota disorders. Mutations in genes such as NOD2, ATG16L1, IRGM, TLR4, and IL23R disrupt the functioning of [...] Read more.

Inflammatory bowel diseases (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic diseases with complex aetiology involving genetic, immunological, and environmental factors and intestinal microbiota disorders. Mutations in genes such as NOD2, ATG16L1, IRGM, TLR4, and IL23R disrupt the functioning of the intestinal barrier and the immune response, increasing susceptibility to chronic inflammation. Recent studies indicate that interactions between diet, gene expression, and epigenetic mechanisms play a key role in modulating the course of IBD, e.g., DNA methylation, histone modifications, and microRNA activity. The use of bioactive dietary components in combination with epigenome modulation is a promising tool in the treatment of IBD, enabling the reduction in chronic inflammation, improving intestinal barrier function, and supporting the immune response. Full article

(This article belongs to the Section Epigenomics)

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20 pages, 354 KB

Open AccessEditor’s ChoiceReview

Analysis of Human Degraded DNA in Forensic Genetics

by Irena Zupanič Pajnič

Genes 2025, 16(11), 1375; https://doi.org/10.3390/genes16111375 - 11 Nov 2025

Cited by 15 | Viewed by 5582

Abstract

Upon an organism’s death, enzymatic DNA repair ceases, exposing the genome to destructive factors such as free cellular nucleases and proliferating microorganisms, which can cause DNA loss. DNA preservation is highly dependent on environmental conditions, and less favorable environments accelerate degradation. Despite this, [...] Read more.

Upon an organism’s death, enzymatic DNA repair ceases, exposing the genome to destructive factors such as free cellular nucleases and proliferating microorganisms, which can cause DNA loss. DNA preservation is highly dependent on environmental conditions, and less favorable environments accelerate degradation. Despite this, advanced extraction and analytical methods now enable the study of poorly preserved and degraded DNA. DNA typing is a foundation of forensic genomics, enabling the identification of individuals and the individualization of biological evidence through the generation of unique genetic profiles. Although DNA is relatively stable, environmental exposure initiates its degradation into progressively shorter fragments, complicating analysis. The extent of DNA preservation in biological evidence depends on numerous factors, and this review focuses on the environmental factors—including temperature, humidity, ultraviolet radiation, pH, chemical agents, and microbial activity—as the most influential variables. In samples with degraded DNA, the maximum amplicon length achievable through polymerase chain reaction (PCR) is inherently limited. This review discusses genetic markers and analytical strategies improvements that enable the examination of highly degraded samples, particularly when conventional short tandem repeat (STR) typing fails. In these situations, successful identification requires targeting short DNA fragments, which are more likely to persist. Single-nucleotide polymorphisms (SNPs) are a valuable alternative, as their high allelic variability and short amplicon requirements make them more amenable to amplification from fragmented templates than STRs. Advances in next-generation sequencing (NGS) technologies have further enhanced this capacity by enabling high-resolution SNP profiling, thereby improving outcomes in challenging forensic cases. Full article

(This article belongs to the Special Issue Advances and Challenges in Forensic Genetics)

15 pages, 458 KB

Open AccessEditor’s ChoiceReview

GLP-1 Receptor Agonists in Solid Tumour Therapy: Exploring Their Anticancer Potential and Underlying Molecular Pathways

by Daniela Lucente, Stefania Bellino and Anna La Salvia

Genes 2025, 16(11), 1352; https://doi.org/10.3390/genes16111352 - 10 Nov 2025

Cited by 9 | Viewed by 3779

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed to treat type 2 diabetes mellitus, are now being investigated as agents in oncology. Recent preclinical studies have demonstrated their antitumor activity in several solid malignancies, including pancreatic, colorectal, breast, and prostate. Importantly, GLP-1 RAs [...] Read more.

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), initially developed to treat type 2 diabetes mellitus, are now being investigated as agents in oncology. Recent preclinical studies have demonstrated their antitumor activity in several solid malignancies, including pancreatic, colorectal, breast, and prostate. Importantly, GLP-1 RAs modulate key signalling pathways such as PI3K/Akt, PKA, and AMPK, and exert anti-inflammatory effects by reducing cytokine production and macrophage infiltration. Preclinical data support their antineoplastic activity in vitro and in vivo, particularly by inhibiting tumour growth and metastasis. Nevertheless, there are ongoing concerns about tumorigenic effects in certain cancer types. This review critically examines the molecular mechanisms by which GLP-1 RAs influence cancer cell proliferation, apoptosis, angiogenesis, and inflammation, and emphasizes the need for further clinical studies to determine their therapeutic relevance. It also proposes assessing GLP-1 RAs as adjuncts in the management of solid tumours. Full article

(This article belongs to the Section Pharmacogenetics)

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20 pages, 558 KB

Open AccessEditor’s ChoiceReview

Genetic Predisposition and Genetic Resilience Factors in Stress-Related Disorders During the Developmental Age: A Narrative Review

by Alessia Raffagnato, Arianna Raicich, Lisa Paiusco, Giulia Coser, Ilaria Bonemazzi, Andrea Gazzin, Maria Federica Pelizza, Caterina Ancora and Irene Toldo

Genes 2025, 16(11), 1362; https://doi.org/10.3390/genes16111362 - 10 Nov 2025

Cited by 4 | Viewed by 6080

Abstract

Background: Stress-related disorders, including PTSD, acute stress disorders, adjustment disorder, and attachment disorders, arise from complex interactions between genetic susceptibility and environmental stressors. While early environmental factors play a central role in the development of these disorders, there is growing evidence that genetic [...] Read more.

Background: Stress-related disorders, including PTSD, acute stress disorders, adjustment disorder, and attachment disorders, arise from complex interactions between genetic susceptibility and environmental stressors. While early environmental factors play a central role in the development of these disorders, there is growing evidence that genetic predisposition also contributes to individual differences in vulnerability and resilience. This narrative review examines current evidence on genetic predisposition and resilience mechanisms in stress-related psychopathology during developmental age. Methods: A literature search was performed using PubMed, Cochrane, MedRxiv, and Medline databases, focusing on studies published between 2010 and 2025, written in English, in the pediatric and adolescent population. Priority was given to original research articles and high-impact reviews. Studies were selected based on relevance to the genetic mechanisms underlying vulnerability and resilience to stress. 71 of 317 were selected. Two hundred forty-six articles were excluded due to a lack of relevance to the topic or because they included an adult population. Results: Polymorphisms and epigenetic modifications in genes involved in hypothalamus–pituitary–adrenal axis (FKBP5, NR3C1, ADCYAP1R1 and ACE), serotoninergic (SLC6A4 and HTR2A), noradrenergic and dopaminergic system (COMT and MAOA), BDNF, estrogen receptor and excitatory amino acid transporters are associated with increased risk of psychopathology following early trauma, but are also implicated in the development of resilience. Conclusions: Genetic factors influence both vulnerability and resilience to stress-related disorders. However, further studies based on the role of genetics are needed to advance precision and personalized medicine, which is still largely underexplored to this day in the field of stress-induced disorders. Full article

(This article belongs to the Special Issue Genetics of Neuropsychiatric Disorders)

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19 pages, 3001 KB

Open AccessEditor’s ChoiceArticle

Breeding Selection for U.S. Siberian Huskies Has Altered Genes Regulating Metabolism, Endurance, Development, Body Conformation, Immune Function, and Behavior

by Heather J. Huson, Krishnamoorthy Srikanth and Karolynn M. Ellis

Genes 2025, 16(11), 1355; https://doi.org/10.3390/genes16111355 - 10 Nov 2025

Cited by 2 | Viewed by 7031

Abstract

Background: The Siberian Husky has evolved as a versatile dog capable of traversing over 1600 km in extreme Arctic conditions, being a competitive show dog in the American Kennel Club, or a favorite pet for companionship. Modern genomics provides an opportunity to explore [...] Read more.

Background: The Siberian Husky has evolved as a versatile dog capable of traversing over 1600 km in extreme Arctic conditions, being a competitive show dog in the American Kennel Club, or a favorite pet for companionship. Modern genomics provides an opportunity to explore the biological implications of selection within the Siberian Husky breed for the purpose of sledding, show, or pet. Methods: We identified regions of genetic selection associated with sledding, show, or pet purposes using a whole-genome panel of 234 K SNPs from 237 Siberian Huskies. We assessed allelic variation using Wright’s F_ST and selective sweeps with runs of homozygosity (ROH). Results: Genomic and morphometric measurement principal component analyses identified population structure aligning with breeding purpose. In total, 118 SNPs demonstrated significant allelic variation (F_ST ≥ 0.6) and 22,598 ROH segments were identified within the Siberian Husky breed. ROH islands (n = 91) highlighted selective sweeps, whereas homozygosity association tests characterized regions of the genome under differential selection between populations. Genes within regions were assessed using GO and KEGG pathway analysis for biological insight. Pet dogs showed selection for olfactory performance genes, whereas show dogs were selected for immune function, tissue and nervous system development, and cytoskeletal motor activity. Sledding Siberian Huskies were selected for the development of muscle organs, lung vasculature, limbs, bones, eye structure, and pigmentation, plus genes influencing lipid metabolism and glucose transport. Conclusions: In all, this provides the first evidence of the biological impact of genetic selection within a breed for the distinct sledding, show, and pet purposes while simultaneously maintaining overall population uniformity to meet breed standards. Full article

(This article belongs to the Special Issue Genetics in Canines: From Evolution to Conservation)

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23 pages, 914 KB

Open AccessEditor’s ChoiceArticle

Genetic Analysis of Patients with Chronic Thromboembolic Pulmonary Hypertension (CTEPH): A Single-Center Observational Study

by Zsuzsanna Bereczky, Gábor Kolodzey, Sarolta Borsos, László Balogh, Petra Erzsébet Biró, Éva Molnár, Katalin Rázsó, Andrea Péter, Judit Barta and Tibor Szűk

Genes 2025, 16(11), 1336; https://doi.org/10.3390/genes16111336 - 6 Nov 2025

Cited by 4 | Viewed by 1713

Abstract

Background/Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, in which multiple genetic and environmental factors may contribute. This study aimed to identify potential genetic determinants in patients with CTEPH and to compare their occurrence to a control group, which included [...] Read more.

Background/Objectives: Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease, in which multiple genetic and environmental factors may contribute. This study aimed to identify potential genetic determinants in patients with CTEPH and to compare their occurrence to a control group, which included patients with pulmonary embolism who had not developed CTEPH. Methods: Tier 1 and 2 genes related to coagulation, fibrinolysis and platelet disorders—as recommended by the International Society on Thrombosis and Haemostasis—and genes associated with vascular conditions were analyzed in n = 15 patients with CTEPH and n = 17 controls using next-generation sequencing. Non-synonymous, rare variants were collected and interpreted. Results: As expected, no single gene or variant was consistently present among CTEPH patients. Instead, individuals carried different mutations and combinations of variants. We identified several variants that were not found in the control group. Candidate variants were detected in F12, F13A1, F13B, F5, KNG1, SERPIND1, THBD, ADAMTS13, VWF, STIM1, ETV6, THPO, MPL, SERPINA1, ENG, RASA1, ACVRL1, GDF2, NFE2, SOX17 and RNF213. We did not detect exclusive variants in FGA, CPB2, and BMPR2 although they were suggested as candidates in previous studies. Elevated factor VIII and von Willebrand factor in CTEPH could not be explained by mutations in VWF and F8. Conclusions: Our study supports the hypothesis of heterogeneous genetic background in CTEPH, involving multiple pathways such as coagulation, altered fibrinolysis and impaired angiogenesis. These results provide a basis for more detailed investigations into specific genes and variants potentially associated with CTEPH in larger cohorts. Full article

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

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17 pages, 2820 KB

Open AccessEditor’s ChoiceArticle

Oxford Nanopore Technologies [ONT] Sequencing: Clinical Validation in Genetically Heterogeneous Disorders

by Mario Urtis, Chiara Paganini, Viviana Vilardo, Antonio Tescari, Samantha Minetto, Claudia Cavaliere, Andrea Pilotto, Carmela Giorgianni, Alessia Cattaneo, Marilena Tagliani, Maurizia Grasso, Alexandra Smirnova, Payam Ebadi, Valentina Barzon, Valentina Favalli, Andrea Bimbocci, Marta Baragli, Alberto Magi, Alessandra Renieri and Eloisa Arbustini

Genes 2025, 16(11), 1325; https://doi.org/10.3390/genes16111325 - 3 Nov 2025

Cited by 1 | Viewed by 4494

Abstract

Background/Objectives: Short-read-sequencing (SRS) is currently the standard for genetic testing in inherited human diseases. Intrinsic limitations include PCR dependency, restricted read length, and challenges in identifying structural variants (SVs), copy number variations (CNVs), and intronic small variants (SNVs/indels). Long-read-sequencing (LRS) enables the [...] Read more.

Background/Objectives: Short-read-sequencing (SRS) is currently the standard for genetic testing in inherited human diseases. Intrinsic limitations include PCR dependency, restricted read length, and challenges in identifying structural variants (SVs), copy number variations (CNVs), and intronic small variants (SNVs/indels). Long-read-sequencing (LRS) enables the sequencing of long DNA molecules, detection of deep intronic variants, rapid testing of few samples, and improved resolution of SVs, CNVs, and SNVs/indels. We therefore aimed to validate Oxford Nanopore Technologies (ONT) LRS for potential clinical application. Methods: We evaluated the ONT’s ability to detect pathogenic/likely pathogenic (P/LP) variants previously identified by SRS and confirmed via Sanger sequencing, Multiplex-Ligation-dependent-Probe-Amplification (MLPA), or quantitative-PCR (qPCR). In total, 509 samples were analyzed, including 393 with P/LP variants and 116 negative controls. We used CE-IVD panels HEVA pro, CARDIO pro, BRaCA panel, and ClinEX pro (4Bases-CH). Sequencing was performed on MinION, GridION, and PromethION-2 platforms. Data were analyzed using the 4eVAR pipeline. Results: ONT successfully identified all P/LP variants across the panels (sensitivity 100%); identified a previously missed CNV in ENG gene; precisely defined the breakpoints of a del(13q) (unsuspected and diagnosed as BRCA2 del ex2–14); improved the coverage profiles in difficult-to-map regions (e.g., ex1 TGFBR1, PSM2CL); expanded the coverage of out-of-target deep intronic regions; and allowed for the set-up of fast-track tests (<24 h) for urgent clinical needs. Conclusions: Our findings demonstrate that ONT LRS provides diagnostic performance comparable to SRS, with significant advantages in resolving complex and previously undetectable variants. Ongoing developments are further increasing read length, expanding detectable targets, and potential clinical applications. Full article

(This article belongs to the Section Bioinformatics)

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17 pages, 1351 KB

Open AccessEditor’s ChoiceArticle

Endometrial Signatures of Subfertility in Beef Heifers Reveal Dysregulation of MAPK Signaling and Ciliary Function

by Nicholas C. Kertz, Priyanka Banerjee, Paul W. Dyce, Soren P. Rodning and Wellison J. S. Diniz

Genes 2025, 16(11), 1323; https://doi.org/10.3390/genes16111323 - 3 Nov 2025

Cited by 2 | Viewed by 1001

Abstract

Background: Reproductive efficiency is a significant hurdle to the sustainability of the beef cattle industry. Method: This study employed transcriptomic profiling to investigate endometrial gene expression differences in heifers with divergent fertility outcomes. Caruncular endometrial samples from fertile (n = 7) and [...] Read more.

Background: Reproductive efficiency is a significant hurdle to the sustainability of the beef cattle industry. Method: This study employed transcriptomic profiling to investigate endometrial gene expression differences in heifers with divergent fertility outcomes. Caruncular endometrial samples from fertile (n = 7) and subfertile (n = 5) heifers were subjected to RNA-Seq analysis, yielding 894 differentially expressed genes (DEGs) (p ≤ 0.05 and |log2FC| ≥ 0.5). Results: The MAPK (Mitogen-activated protein kinase) and Rap1 (Ras-associated protein 1) signaling pathways and immune response regulation were identified among the over-represented pathways underlying the DEGs. Transcriptional regulators, such as DUSP2, DUSP10, and MAPK13, were downregulated in subfertile heifers, suggesting disrupted signal transduction and immune function. Gene co-expression network analysis showed network rewiring and increased connectivity of genes related to cilium organization, motility, and microtubule-based processes in the subfertile group. Over-represented hub genes were enriched in the subfertile endometrium, including DNAH2, DNAI2, DNAAF4, CCDC65, and the transcription factor FOXJ1. Our results suggest that impaired ciliary function and disrupted MAPK and immune signaling could potentially contribute to subfertility. Conclusions: This study highlights novel molecular signatures in the uterine endometrium that may serve as predictive markers of fertility potential in beef heifers, providing a foundation for targeted strategies to improve reproductive performance in cattle. Full article

(This article belongs to the Special Issue Research on Genetics and Breeding of Cattle)

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22 pages, 2074 KB

Open AccessEditor’s ChoiceReview

Non-Coding RNAs as Emerging Regulators in Kidney Pathophysiology: From Molecular Mechanisms to Therapeutic Potential

by Petar Todorović, Nikola Pavlović, Mirko Maglica, Patricija Bajt, Nela Kelam, Fila Raguž and Katarina Vukojević

Genes 2025, 16(11), 1328; https://doi.org/10.3390/genes16111328 - 3 Nov 2025

Cited by 4 | Viewed by 2028

Abstract

The kidney’s intricate physiology relies on finely tuned gene regulatory networks that coordinate cellular responses to metabolic, inflammatory, and fibrotic stress. Beyond protein-coding transcripts, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators [...] Read more.

The kidney’s intricate physiology relies on finely tuned gene regulatory networks that coordinate cellular responses to metabolic, inflammatory, and fibrotic stress. Beyond protein-coding transcripts, non-coding RNAs (ncRNAs), including microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), have emerged as pivotal regulators of renal biology. By modulating transcriptional, post-transcriptional, and epigenetic pathways, ncRNAs govern podocyte integrity, tubular adaptation, intercellular signaling, and immune activation. Dysregulation of these networks is now recognized as a hallmark of major kidney diseases, ranging from diabetic nephropathy and acute kidney injury to chronic kidney disease, glomerulopathies, and polycystic kidney disease. Mechanistic studies have revealed how pathogenic ncRNAs drive apoptosis, inflammation, fibrosis, and cystic remodeling, while protective ncRNAs mitigate these processes, highlighting their dual roles as both disease mediators and therapeutic targets. The exceptional stability of ncRNAs in urine, plasma, and exosomes further positions them as minimally invasive biomarkers with diagnostic and prognostic value. Translational advances include anti-miR and mimic-based therapies (e.g., lademirsen targeting miR-21, miR-29 mimics, anti-miR-17 oligonucleotides), alongside lncRNA silencing strategies, although challenges in delivery, safety, and redundancy remain significant. This review integrates molecular mechanisms with translational perspectives, providing a comprehensive synthesis of how ncRNAs shape renal pathophysiology. By bridging mechanistic insights with emerging diagnostic and therapeutic applications, we highlight the potential of ncRNAs to transform nephrology, paving the way for biomarker-driven precision medicine and novel interventions aimed at intercepting kidney injury at its regulatory roots. In clinical terms, ncRNA-based biomarkers and therapeutics promise earlier detection, more precise risk stratification, and individualized treatment selection within precision nephrology. Full article

(This article belongs to the Special Issue From Genetic to Molecular Basis of Kidney Diseases)

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13 pages, 609 KB

Open AccessEditor’s ChoiceReview

The miR-200 Family in Non-Small-Cell Lung Cancer: Molecular Mechanisms, Clinical Applications, and Therapeutic Implications

by Nobuaki Kobayashi, Yukihito Kajita, Fangfei Yang, Nobuhiko Fukuda, Kohei Somekawa, Ayami Kaneko and Seigo Katakura

Genes 2025, 16(11), 1312; https://doi.org/10.3390/genes16111312 - 2 Nov 2025

Cited by 3 | Viewed by 1490

Abstract

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, demanding improved biomarkers and therapeutic approaches. This review synthesizes the extensive evidence positioning the miR-200 family as a master regulator of NSCLC progression. We detail the core molecular circuitry centered on [...] Read more.

Non-small-cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality worldwide, demanding improved biomarkers and therapeutic approaches. This review synthesizes the extensive evidence positioning the miR-200 family as a master regulator of NSCLC progression. We detail the core molecular circuitry centered on the bistable, double-negative feedback loop between miR-200 and the ZEB1/ZEB2 transcription factors, which governs epithelial–mesenchymal transition (EMT). This review connects this central mechanism to critical clinical challenges, including the development of resistance to EGFR-targeted therapies and the regulation of immune evasion through PD-L1 expression and CD8+ T cell infiltration. We evaluate the strong clinical evidence for the miR-200 family’s utility as a diagnostic, prognostic, and predictive biomarker. Finally, we explore emerging therapeutic strategies that target this network, including miRNA replacement, epigenetic reactivation, and rational combinations with immunotherapy and targeted agents. We synthesize evidence positioning the miR-200/ZEB feedback circuit as a central regulatory node in NSCLC that links EMT with therapeutic resistance and immune evasion. Beyond summarizing associations, we interpret how this circuitry could inform biomarker development and rational combinations with targeted and immune therapies. Given heterogeneous study designs and non-standardized assays, translational claims remain provisional; we outline immediate priorities for assay harmonization and biomarker-stratified trials. Full article

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

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17 pages, 7468 KB

Open AccessEditor’s ChoiceArticle

Complete Chloroplast Genome and Phylogenomic Analysis of Davallia trichomanoides (Polypodiaceae)

by Yingying Wang, Ziqi Xiang, Keqin Liu, Yuan Lin and Siyuan Dong

Genes 2025, 16(11), 1310; https://doi.org/10.3390/genes16111310 - 1 Nov 2025

Cited by 1 | Viewed by 1066

Abstract

Background/Objectives: Chloroplast genomes (plastomes) are valuable for fern systematics, yet the epiphytic lineages have remained underexplored. Methods: The Davallia trichomanoides plastome was de novo assembled from Illumina data and annotated. Results: The plastome measures 154,217 bp with a GC content [...] Read more.

Background/Objectives: Chloroplast genomes (plastomes) are valuable for fern systematics, yet the epiphytic lineages have remained underexplored. Methods: The Davallia trichomanoides plastome was de novo assembled from Illumina data and annotated. Results: The plastome measures 154,217 bp with a GC content of 40.82% and contains 115 genes. Comparative analysis reveals two inverted repeat (IR) size classes (~24.0–24.6 kb vs. ~27.4–27.5 kb) and lineage-specific shifts at the IR junctions. For instance, the ndhF gene remains in the small single copy (SSC) region in D. trichomanoides and Drynaria acuminata, but it crosses into the IRb region in other species. We observed nucleotide diversity hotspots in the large single copy (LSC) and SSC regions. The IR regions are highly conserved. The ratios of nonsynonymous to synonymous substitutions (Ka/Ks) are mostly less than 1, indicating purifying selection. Phylogenetic analysis places D. trichomanoides as the sister to D. acuminata. Conclusions: This study highlights the stable plastome structure of D. trichomanoides and identifies candidate loci for barcoding. It also supports the stable placement of Davallia within the epiphytic Polypodiineae. Full article

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

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48 pages, 1189 KB

Open AccessEditor’s ChoiceReview

Toward a Multi-Trait Genetic Panel Targeting Training, Rehabilitation, and Chronic Disease Prevention: A Narrative Review

by Antonio Imperatore, Cristina Mennitti, Giulia De Fonzo, Raffaele Amitrano, Alessandro Gentile, Mariella Calvanese, Fernanda Iafusco, Serena Coppola, Mattia Digno, Paola Borrelli, Barbara Lombardo, Giulia Frisso, Roberto Berni Canani, Nadia Tinto, Valeria D’Argenio and Olga Scudiero

Genes 2025, 16(11), 1309; https://doi.org/10.3390/genes16111309 - 1 Nov 2025

Cited by 1 | Viewed by 3974

Abstract

Athletic performance results from complex interactions between genetic and environmental factors. This review compiles and synthesizes available literature on polymorphic genes associated with endurance, power, and strength performance, as well as their links to injury susceptibility and chronic metabolic diseases. Endurance performance is [...] Read more.

Athletic performance results from complex interactions between genetic and environmental factors. This review compiles and synthesizes available literature on polymorphic genes associated with endurance, power, and strength performance, as well as their links to injury susceptibility and chronic metabolic diseases. Endurance performance is modulated by ACE, PPARGC1A, HFE, UCP2, UCP3, CDKN1A, and PPARA, regulating mitochondrial biogenesis, oxygen utilization, and muscle fiber composition. Power performance involves ACTN3, MCT1, IGF1, AMPD1, AGT, and AGTR2, affecting anaerobic metabolism, lactate clearance, and fast-twitch fiber recruitment. Strength performance is influenced by AR, PPARG, ARK2N, MMS22L, LRPPRC, PHACTR1, and MTHFR, related to androgen signaling, muscle hypertrophy, and recovery. Injury-related genes (COL1A1, COL5A1, IL6, VEGFA, NOG) and metabolic risk genes (FTO, PPARG, ADRB3) further highlight the clinical relevance of genomics. Collectively, these insights support the application of genetic information to personalize training, enhance performance, prevent injuries, and guide exercise interventions to mitigate metabolic disease risk. Full article

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

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23 pages, 1370 KB

Open AccessEditor’s ChoiceSystematic Review

PMP22-Related Neuropathies: A Systematic Review

by Carlo Alberto Cesaroni, Laura Caiazza, Giulia Pisanò, Martina Gnazzo, Giulia Sigona, Susanna Rizzi, Agnese Pantani, Daniele Frattini and Carlo Fusco

Genes 2025, 16(11), 1279; https://doi.org/10.3390/genes16111279 - 29 Oct 2025

Cited by 4 | Viewed by 4110

Abstract

Background. PMP22-related neuropathies comprise a spectrum of predominantly demyelinating disorders, most commonly Charcot–Marie–Tooth type 1A (CMT1A; 17p12 duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; 17p12 deletion), with rarer phenotypes due to PMP22 sequence variants (CMT1E, Dejerine–Sottas syndrome [DSS]). [...] Read more.

Background. PMP22-related neuropathies comprise a spectrum of predominantly demyelinating disorders, most commonly Charcot–Marie–Tooth type 1A (CMT1A; 17p12 duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; 17p12 deletion), with rarer phenotypes due to PMP22 sequence variants (CMT1E, Dejerine–Sottas syndrome [DSS]). Methods. We conducted a PRISMA-compliant systematic review (PROSPERO ID: 1139921) of PubMed and Scopus (January 2015–August 2025). Eligible studies reported genetically confirmed PMP22-related neuropathies with clinical and/or neurophysiological data. Owing to heterogeneous reporting, we synthesized pooled counts and proportions without meta-analysis, explicitly tracking missing denominators. Results. One hundred twenty-seven studies (n = 4493 patients) were included. Sex was available for 995 patients (males 53.8% [535/995]; females 46.2% [460/995]); mean age at onset was 23.7 years in males and 16.4 years in females. Phenotypic classification was reported for 4431/4493 (75.4% CMT1A, 20.9% HNPP, 2.6% CMT1E, 1.2% DSS). Across phenotypes, weakness/foot drop was the leading presenting symptom when considering only cohorts that explicitly reported it (e.g., 65.3% in CMT1A; 76.0% in HNPP); sensory complaints (numbness, paresthesia/dysesthesia) were variably documented. Neurophysiology consistently showed demyelinating patterns, with median and ulnar nerves most frequently abnormal among assessed nerves; in HNPP, deep peroneal and sural involvement were also common in evaluated subsets. Comorbidities clustered by phenotype: orthopedic/neuromuscular features (pes cavus/hammer toes, scoliosis/kyphosis, tremor) in CMT1A and DSS; broader metabolic/autoimmune and neurodevelopmental associations in HNPP; and higher syndromic/ocular/hearing involvement in CMT1E. Genetically, 75.6% (3241/4291) had 17p12 duplication, 19.6% (835/4291) 17p12 deletion, and 4.8% (215/4291) PMP22 sequence variants with marked allelic heterogeneity. Among 2571 cases with available methods, MLPA was most used (41.9%), followed by NGS (20.4%) and Sanger sequencing (17.8%). Main limitations include heterogeneous and incomplete reporting across studies (especially symptoms and nerve-specific data) and the absence of a formal risk-of-bias appraisal, which preclude meta-analysis and may skew phenotype proportions toward more frequently reported entities (e.g., CMT1A). Conclusions. Recent literature confirms that PMP22 copy-number variants account for the vast majority of cases, while sequence-level variants underpin a minority with distinct phenotypes (notably CMT1E/DSS). Routine MLPA, complemented by targeted/NGS, optimizes diagnostic yield. Standardized reporting of nerve-conduction parameters and symptom denominators is urgently needed to enable robust cross-study comparisons in both pediatric and adult populations. Full article

(This article belongs to the Section Neurogenomics)

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18 pages, 3198 KB

Open AccessEditor’s ChoiceArticle

Chloroplast Genome Features and Phylogeny of Two Nationally Protected Medicinal Plants, Euchresta tubulosa and Euchresta japonica: Molecular Resources for Identification and Conservation

by Dabao Yin, Xue Li, Zhongchun Xiao and Li Zhou

Genes 2025, 16(11), 1286; https://doi.org/10.3390/genes16111286 - 29 Oct 2025

Cited by 3 | Viewed by 1224

Abstract

[Objectives]: By performing genome assembly, annotation, comparative characterization, and phylogenetic analysis on the complete chloroplast genomes of E. tubulosa and E. japonica—two medicinal plants belonging to the genus Euchresta—this study aims to identify their differential genes, thereby providing fundamental research for [...] Read more.

[Objectives]: By performing genome assembly, annotation, comparative characterization, and phylogenetic analysis on the complete chloroplast genomes of E. tubulosa and E. japonica—two medicinal plants belonging to the genus Euchresta—this study aims to identify their differential genes, thereby providing fundamental research for screening candidate genes as DNA barcodes for species identification and facilitating the conservation of these endangered species. [Methods]: Illumina PE150 sequencing was performed. Chloroplast genomes (plastomes) were assembled and annotated with GetOrganelle/SPAdes. Comparative analyses assessed gene content, IR/LSC/SSC structure, repeat profiles, and codon-usage bias. Using related Fabaceae as references, we conducted mVISTA alignments and sliding-window nucleotide diversity (Pi) analyses to identify candidate DNA barcodes. Phylogenies from whole-plastome sequences were inferred with Maximum Likelihood, Bayesian Inference, and Maximum Parsimony. [Results]: The plastomes measured 153,960 bp (E. japonica) and 150,146 bp (E. tubulosa), with GC contents of 36.30% and 36.20%, respectively, each exhibiting a typical quadripartite structure. IR/SC boundaries were highly conserved without evident expansion or contraction. Repeat statistics were 20/30 palindromic repeats, 57/64 tandem repeats, and 156/159 simple sequence repeats (SSRs) in E. japonica/E. tubulosa, respectively. Leucine was the most frequently encoded amino acid, cysteine the least, and codon usage favored A/U at third positions. Five hypervariable loci—rps19, psbA, trnK, matK, and rps16 (Pi > 0.03)—were identified as candidate DNA barcodes. All trees consistently placed both species within Papilionoideae (Fabaceae) and recovered the closest relationship to Sophora macrocarpa. [Conclusions]: This study provides, for the first time, complete plastomes and candidate barcoding regions for two protected Euchresta species, supplying foundational resources for species identification, resource assessment, and conservation planning. Full article

(This article belongs to the Special Issue 5Gs in Crop Genetic and Genomic Improvement: 2025–2026)

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10 pages, 209 KB

Open AccessEditor’s ChoiceArticle

Cardiac Genetic Variants in Sudden, Unexpected Death in Epilepsy: From Challenging DNA Extraction Methods to Updated NGS Panels for Improved Genetic Analysis

by Alessia Bernini Di Michele, Valerio Onofri, Filomena Melchionda, Lucia Fiordelmondo, Eleonora Ciarimboli, Marco Palpacelli, Sara Sablone, Chiara Turchi and Mauro Pesaresi

Genes 2025, 16(11), 1272; https://doi.org/10.3390/genes16111272 - 28 Oct 2025

Cited by 2 | Viewed by 891

Abstract

Background/Objectives: SUDEP is the sudden, unexpected death of someone with epilepsy, and occurs mainly during sleep or at rest, or when the individual does not seem to have experienced a convulsive seizure. The cause of death in SUDEP is still unknown, and it [...] Read more.

Background/Objectives: SUDEP is the sudden, unexpected death of someone with epilepsy, and occurs mainly during sleep or at rest, or when the individual does not seem to have experienced a convulsive seizure. The cause of death in SUDEP is still unknown, and it may differ between cases. Cardiac factors are among the most prevalent causes observed in SUDEP. Therefore, within the forensic medicine framework, identifying well-known DNA markers involved in cardiac sudden and unexpected death would aid in understanding the cause of SUDEP, as well as in finding cardiac risk markers in patients with epilepsy. The purpose of this study was to identify any genetic variants by analyzing blood and formalin-fixed paraffin-embedded (FFPE) tissue samples, utilizing next-generation sequencing techniques. Methods: We investigated five cases of SUDEP that were examined at the Legal Medicine department of Ancona (Italy). Peripheral blood or FFPE cardiac tissues were collected, and different DNA extraction methods were performed. In particular, this study underlines a new extraction method from FFPE tissue, adapting the Casework kit for forensic application to our purpose. Later, about one hundred genes correlated to inherited cardiac diseases were sequenced through the Ion PGM System and Ion GeneStudio S5 Systems. Results: Bioinformatic analysis showed some genetic variants of unknown significance (VUS) on genes involved in SUDEP: RYR2, SCN8A, and AKAP9. Conclusions: As expected, very low coverage of the target base was observed for FFPE tissue samples because of the complexity of the biological material. Therefore, the presence of any significant variants in unamplified regions cannot be excluded in the FFPE samples. As suggested by the literature, the variants found in the blood samples are potentially associated with SUDEP. Full article

(This article belongs to the Special Issue Advanced Research in Forensic Genetics)

20 pages, 1181 KB

Open AccessEditor’s ChoiceReview

RNAi-Based Bioinsecticides for Controlling Vector-Borne Diseases

by Krystal Maya-Maldonado, Antonio Celestino-Montes and Victor Cardoso-Jaime

Genes 2025, 16(11), 1276; https://doi.org/10.3390/genes16111276 - 28 Oct 2025

Cited by 4 | Viewed by 3365

Abstract

Vector-borne diseases account for 17% of all infectious diseases. The most effective strategies for controlling these diseases have focused on decreasing the vector population, primarily through the use of insecticides. Many insecticides have no specific targets, harming pollinators and beneficial insects. Additionally, the [...] Read more.

Vector-borne diseases account for 17% of all infectious diseases. The most effective strategies for controlling these diseases have focused on decreasing the vector population, primarily through the use of insecticides. Many insecticides have no specific targets, harming pollinators and beneficial insects. Additionally, the vector populations are developing resistance, reducing the effectiveness of these strategies and increasing ecological damage. Double-strand RNA (dsRNA) is widely used in insects to study gene function by knocking down their expression. Recently, this technology has been applied to develop RNAi-based insecticides for controlling agricultural pests. These biopesticides demonstrate high specificity, as insects do not develop resistance to them, and they cause minimal ecological damage. These pesticides knock down the expression of key genes related to vital functions, development, and reproduction, which affects the insect life cycle and consequently decreases their populations. This review focuses on using RNA interference (RNAi)-based insecticides for controlling major insect vectors, including mosquitoes, kissing bugs, and ticks. We examine the advancements and challenges associated with this technology, considering the complex life cycles and feeding behavior of these insects. Furthermore, we discuss gaps in knowledge about vector biology and delivery strategies for dsRNA, which need to be addressed to enhance the application and efficiency of this emerging technology for controlling vector-borne diseases. Full article

(This article belongs to the Section RNA)

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17 pages, 1063 KB

Open AccessEditor’s ChoiceReview

Secondary Mitochondrial Dysfunction in Gaucher Disease Type I, II and III—Review of the Experimental and Clinical Evidence

by Mollie Dewsbury, Tyler Purcell, Derralynn Hughes, Aimee Donald, Iain P. Hargreaves and Karolina M. Stepien

Genes 2025, 16(11), 1269; https://doi.org/10.3390/genes16111269 - 28 Oct 2025

Cited by 3 | Viewed by 1977

Abstract

Gaucher disease (GD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The pathogenic defects result in a misfolded protein, which can trigger endoplasmic reticulum stress and an unfolded protein response [...] Read more.

Gaucher disease (GD) is an autosomal recessive metabolic disorder caused by pathogenic variants in the GBA1 gene, which encodes the lysosomal hydrolase β-glucocerebrosidase (GCase). The pathogenic defects result in a misfolded protein, which can trigger endoplasmic reticulum stress and an unfolded protein response within the affected cells. The reduced enzyme activity leads to accumulation of its substrates, glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph), within lysosomes or macrophages and with prominent disease manifestations in reticuloendothelial tissues such as liver, spleen and bone marrow. GCase defects alter both the mitochondria and the lysosome. In the lysosome, reduced GCase activity leads to glycosphingolipid build-up, disrupting lysosomal function and autophagy, thereby activating α-synuclein accumulation. GCase can also be imported into the mitochondria, where it fosters the integrity and function of mitochondrial respiratory chain (MRC) complex I. Thus, the reduced GCase activity impairs the normal mitochondrial function and increases oxidative stress in this organelle, which may contribute to cell death. However, further studies are required to confirm this mechanism of MRC dysfunction. In this review we have systematically evaluated the evidence for oxidative stress in individuals affected by GD, as well as the currently available therapies and adjunctive therapies. Therapies targeting oxidative stress may prove useful as adjuvant treatments for GD. Full article

(This article belongs to the Special Issue 15th Anniversary of Genes: Feature Papers in the “Molecular Genetics and Genomics” Section)

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14 pages, 3627 KB

Open AccessEditor’s ChoiceArticle

Comparative Analysis of Chloroplast Genome Sequences and Phylogeny in Three Macadamia integrifolia Cultivars

by Jihua Guo, Zhuanmiao Kang, Zhongchun Xiao, Chunyan Zhong, Guidong Miao, Pei Zhang, Weiwei Zhao, Rongrong Su and Kecan Xia

Genes 2025, 16(11), 1248; https://doi.org/10.3390/genes16111248 - 22 Oct 2025

Cited by 2 | Viewed by 1132

Abstract

Background/Objectives: Macadamia integrifolia is a valuable subtropical fruit tree, yet genomic studies on its cultivars are limited. This study aims to elucidate the chloroplast genome features, variations, and phylogenetic relationships of three main cultivars (‘Guilin No. 1’, ‘Nanya No. 1’, ‘Qian’ao No. [...] Read more.

Background/Objectives: Macadamia integrifolia is a valuable subtropical fruit tree, yet genomic studies on its cultivars are limited. This study aims to elucidate the chloroplast genome features, variations, and phylogenetic relationships of three main cultivars (‘Guilin No. 1’, ‘Nanya No. 1’, ‘Qian’ao No. 1’) to support germplasm identification and breeding. Methods: chloroplast genomes of three M. integrifolia cultivars from Guangxi, Guangdong, and Guizhou were sequenced using Illumina technology, followed by assembly, annotation, and comparative analyses of structure, repeats, and codon usage. Phylogenetic relationships were reconstructed using complete genome sequences. Results: The three chloroplast genomes displayed typical quadripartite structures, with lengths of 159,714 bp, 159,195 bp, and 159,508 bp, and GC contents of 38.12%, 38.16%, and 38.14%, respectively. Each encoded 135 genes. Codon usage was biased towards A/U-ending codons. We identified 81, 87, and 80 SSRs and 26, 21, and 20 long repeats, respectively. IR boundary regions were highly conserved. Phylogenetically, the cultivars showed close relationships with M. integrifolia, Macadamia tetraphylla, and Macadamiaternifolia, forming a sister clade to Platanus occidentalis. Conclusions: This study provides essential chloroplast genomic resources for three M. integrifolia cultivars, revealing conserved structures and specific variations. The findings offer crucial insights for the genus's genetic diversity, supporting future germplasm evaluation and phylogenetic research. Full article

(This article belongs to the Special Issue 5Gs in Crop Genetic and Genomic Improvement: 2025–2026)

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18 pages, 545 KB

Open AccessEditor’s ChoiceReview

Imprinting Disorders and Epigenetic Alterations in Children Conceived by Assisted Reproductive Technologies: Mechanisms, Clinical Outcomes, and Prenatal Diagnosis

by Antonella Gambadauro, Valeria Chirico, Francesca Galletta, Ferdinando Gulino, Roberto Chimenz, Giorgia Serraino, Immacolata Rulli, Alessandro Manganaro, Eloisa Gitto and Lucia Marseglia

Genes 2025, 16(10), 1242; https://doi.org/10.3390/genes16101242 - 21 Oct 2025

Cited by 4 | Viewed by 5640

Abstract

Assisted reproductive technologies (ARTs) have revolutionized infertility treatment, leading to the birth of over 10 million children worldwide. Despite their success, increasing concerns have been expressed regarding the potential long-term outcomes of ART-conceived individuals, particularly in relation to imprinting disorders (IDs). IDs result [...] Read more.

Assisted reproductive technologies (ARTs) have revolutionized infertility treatment, leading to the birth of over 10 million children worldwide. Despite their success, increasing concerns have been expressed regarding the potential long-term outcomes of ART-conceived individuals, particularly in relation to imprinting disorders (IDs). IDs result from the abnormal expression of imprinted genes, which are expressed in a parent-of-origin-specific manner and regulated by epigenetic mechanisms (e.g., DNA methylation). Disruption of these processes, through environmental, genetic, or procedural factors, can lead to disorders such as Beckwith–Wiedemann syndrome (BWS), Silver–Russell syndrome (SRS), Angelman syndrome (AS), and Prader–Willi syndrome (PWS). These syndromes are characterized by distinct clinical features, including growth abnormalities, neurodevelopmental delay, endocrine dysfunction, and cancer predisposition. ART procedures, especially ovarian hyperstimulation, in vitro fertilization (IVF), and embryo culture, coincide with critical periods of epigenetic reprogramming and may contribute to epimutations in imprinting control regions. In this review, we explored epidemiology, molecular mechanisms, and prenatal diagnostic strategies related to these four IDs in the context of ART. The findings suggest a higher prevalence of BWS and SRS in ART-conceived children. The data regarding AS and PWS are more controversial, with conflicting results across populations and methodologies. Although a causal link between ART and IDs remains debated, evidence suggests the potential contribution of ART procedures to epigenetic dysregulation in susceptible individuals. Further large-scale, methodologically rigorous studies will be essential to clarify this association and inform safer ART practices. Full article

(This article belongs to the Special Issue Genes and Pediatrics)

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20 pages, 4116 KB

Open AccessEditor’s ChoiceArticle

Stability Matters: Revealing Causal Roles of G-Quadruplexes (G4s) in Regulation of Chromatin and Transcription

by Ke Xiao, Rongxin Zhang, Tiantong Tao, Huiling Shu, Hao Huang, Xiao Sun and Jing Tu

Genes 2025, 16(10), 1231; https://doi.org/10.3390/genes16101231 - 17 Oct 2025

Cited by 4 | Viewed by 1480

Abstract

Background: G-quadruplexes (G4s) are non-canonical higher-order nucleic acid structures that form at guanine-rich motifs, with features spanning both secondary and tertiary structural levels. These dynamic structures play pivotal roles in diverse cellular processes. Endogenous G4s (eG4s) function through their dynamically formed structures, prompting [...] Read more.

Background: G-quadruplexes (G4s) are non-canonical higher-order nucleic acid structures that form at guanine-rich motifs, with features spanning both secondary and tertiary structural levels. These dynamic structures play pivotal roles in diverse cellular processes. Endogenous G4s (eG4s) function through their dynamically formed structures, prompting the hypothesis that their thermostability, as a key structural property, may critically influence their functionality. This study investigates the relationship between G4 stability and other functional genomic signals within eG4 regions and examines its broader impact on chromatin organization and transcriptional regulation. Methods: We developed a mapping strategy to associate in vitro-derived thermostability metrics and multi-omics functional signals with eG4 regions. A stability-centric analytical framework combining correlation analysis and causal inference using the Bayesian networks was applied to decipher causal relationships between G4 stability and the other related signals. We further analyzed the association between the stability of transcription start site (TSS)-proximal eG4s and the biological functions of their downstream genes. Results: Our analyses demonstrate that G4 thermostability exerts causal effects on epigenetic states and transcription factor binding, thereby influencing chromatin and transcription regulation. We further show distinct network architectures for G4-binding versus non-binding transcription factors. Additionally, we find that TSS-proximal eG4s are enriched in genes involved in core proliferation and stress-response pathways, suggesting that eG4s may serve as regulatory elements facilitating rapid stress responses through genome-wide coordination. Conclusions: These findings establish thermostability—though measured in vitro—as an intrinsic property that shapes eG4 functionality. Our study not only provides novel insights into the functional relevance of G4 thermostability but also introduces a generalizable framework for high-throughput G4 data interpretation, significantly advancing the functional decoding of eG4s across biological contexts. Full article

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

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66 pages, 1748 KB

Open AccessEditor’s ChoiceReview

Transcriptional Activation Mechanisms and Target Genes of the Oncogene Product Tax of Human T-Cell Leukemia Virus Type 1

by Mashiro Shirasawa, Rinka Nakajima, Yaxuan Zhou, Mariana Fikriyanti, Ritsuko Iwanaga, Andrew P. Bradford, Kenta Kurayoshi, Keigo Araki and Kiyoshi Ohtani

Genes 2025, 16(10), 1221; https://doi.org/10.3390/genes16101221 - 15 Oct 2025

Cited by 4 | Viewed by 2262

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). The trans-activator protein Tax of HTLV-1 is thought to play a crucial role in the early-stage transformation of the virus-infected cells. Tax is a multi-functional protein and [...] Read more.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATL). The trans-activator protein Tax of HTLV-1 is thought to play a crucial role in the early-stage transformation of the virus-infected cells. Tax is a multi-functional protein and modulates cellular signaling pathways that promote proliferation and survival of HTLV-1-infected cells, primarily through the trans-activation of cellular target genes. Tax interacts with a variety of host cell factors including signal transducers and transcription factors, leading to the activation of transcription factors such as CREB, NF-κB, and SRF and activates both its own promoter and those of a variety of host cellular genes. Tax activates its own promoter mainly through CREB and host cellular genes through NF-κB, SRF, and CREB. Accumulating evidence indicates that the Tax-mediated trans-activation of target genes through NF-κB plays an essential role in the transformation of HTLV-1 infected cells. However, the repertoire of Tax target genes, especially those crucial for leukemogenesis, are not known in detail. In this review, we summarize transcriptional activation mechanisms and target genes of Tax, especially focusing on transformation, to facilitate understanding of the underlying mechanisms of leukemogenesis induced by HTLV-1 infection. Full article

(This article belongs to the Special Issue Progress in Hematology: Non-Malignant, Pre-Malignant, and Malignant Disorders, and Genetically Based Therapies)

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23 pages, 2734 KB

Open AccessEditor’s ChoiceArticle

Epigenetic Modulation and Neuroprotective Effects of Neurofabine-C in a Transgenic Model of Alzheimer’s Disease

by Ivan Carrera, Vinogran Naidoo, Lola Corzo, Olaia Martínez-Iglesias and Ramón Cacabelos

Genes 2025, 16(10), 1214; https://doi.org/10.3390/genes16101214 - 15 Oct 2025

Cited by 1 | Viewed by 4111

Abstract

Background: Currently, there are limited therapeutic or preventative strategies for neurodegenerative disorders due to the challenges in alleviating the progressive neuronal loss and neuroinflammation which are the primary characteristics of these diseases, ultimately leading to cell death and functional impairment. Cocoa-derived flavanols [...] Read more.

Background: Currently, there are limited therapeutic or preventative strategies for neurodegenerative disorders due to the challenges in alleviating the progressive neuronal loss and neuroinflammation which are the primary characteristics of these diseases, ultimately leading to cell death and functional impairment. Cocoa-derived flavanols (Theobroma cacao) have been studied as potential bioactive compounds to modify and reverse various inflammation-associated diseases because of their remarkable antioxidant properties and capacity to modulate metabolic imbalance and reactive inflammatory responses. The faba bean (Vicia faba) extract obtained through nondenaturing biotechnological processes is a potent dopamine (DA) enhancer that has shown promising results as a neuroprotective agent against degeneration. Objective: This study will examine the synergistic effects of Neurofabine-C, a hybrid compound derived from cocoa and faba bean extracts, on various brain biomarkers in mice related to inflammatory, metabolic, and neurodegenerative processes. Methods: A triple-transgenic mouse model of neurodegeneration was treated with Neurofabine-C, and biomolecular data were obtained by performing biochemical and immunohistochemical analysis. Results: Neurofabine-C prevented neuronal degeneration (NeuN), mitigated the neuro-inflammatory processes triggered (decreased expression of reactive astrocytes (GFAP)), and induced an increase in neurogenesis in the treated cortical mice brain (PAX6). Epigenetic analysis revealed significant chromatin remodeling in the hippocampus. Neuroprotective genes, including FOXO3, ATM, and TRP73, were upregulated, whereas the expression of HIF1α and APOE decreased. In parallel, DNMT3A expression increased 20-fold, HDAC3 decreased by 60%, and global 5-methylcytosine levels increased four-fold. These coordinated changes suggest that Neurofabine-C promotes neuroprotective programs through enhanced DNA methylation and reduced histone deacetylation. Conclusions: The findings indicate that Neurofabine-C exhibits multiple neuroprotective mechanisms, making it a potent bioproduct for mitigating neuroinflammatory processes associated with neurodegenerative disorders. Full article

(This article belongs to the Section Neurogenomics)

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16 pages, 751 KB

Open AccessEditor’s ChoiceReview

Genetic Therapy of Fuchs Endothelial Corneal Dystrophy: Where Are We? A Review

by Spela Stunf Pukl

Genes 2025, 16(10), 1222; https://doi.org/10.3390/genes16101222 - 15 Oct 2025

Cited by 1 | Viewed by 2104

Abstract

Objectives: The incidence of Fuchs endothelial corneal dystrophy (FECD) is growing, and with it, the unmet need for a corneal transplant. Among alternative treatment modalities, only genetic therapy represents a causal therapy. Methods: Following the SNARA protocol, the PubMed and ClinicalTrials databases were [...] Read more.

Objectives: The incidence of Fuchs endothelial corneal dystrophy (FECD) is growing, and with it, the unmet need for a corneal transplant. Among alternative treatment modalities, only genetic therapy represents a causal therapy. Methods: Following the SNARA protocol, the PubMed and ClinicalTrials databases were searched using the keywords Fuchs endothelial corneal dystrophy, FECD, genetic therapy, and CRISPR-Cas9. Results: FECD is polyfactorial disease and mutations or polymorphisms in at least 15 different genes were connected to the disease. For the early-onset form of the disease, exclusive connection to mutations in COL8A2 was confirmed, while for the late-onset form, the most characteristic mutation is the expansion of the CTG18.1 triplet in the TCF4 gene, making these two possible targets. While the CRISPR-Cas9 approach represents the mainstay of genetic therapy development recently, the application of this method to FECD contains several obstacles, studied in preclinical settings. DT-168 and the Ad-Cas9-Col8a2gRNA molecules were developed for FECD treatment and preclinically tested, and phase I and II clinical studies for DT-168 are also already being performed. Conclusions: The review of the literature proved that genetic therapy for FECD is at the level of preclinical research and that there are several specific challenges connected to the target genetic mutation as well as the delivery of possible treatment and duration of the effect. Further studies in the field might bring solutions in the future for alternative treatments for this common corneal disease. Full article

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

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15 pages, 262 KB

Open AccessEditor’s ChoiceReview

How Close Are We to Achieving Durable and Efficacious Gene Therapy for Hemophilia A and B?

by Patrycja Sosnowska-Sienkiewicz and Danuta Januszkiewicz-Lewandowska

Genes 2025, 16(10), 1200; https://doi.org/10.3390/genes16101200 - 14 Oct 2025

Cited by 3 | Viewed by 3468

Abstract

Hemophilia, an X-linked recessive bleeding disorder, results from mutations in the F8 or F9 genes, leading to factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency. While conventional treatment relies on regular factor replacement therapy, gene therapy has emerged as a promising [...] Read more.

Hemophilia, an X-linked recessive bleeding disorder, results from mutations in the F8 or F9 genes, leading to factor VIII (hemophilia A) or factor IX (hemophilia B) deficiency. While conventional treatment relies on regular factor replacement therapy, gene therapy has emerged as a promising alternative, offering the potential for sustained endogenous factor production after a single administration. This review provides an in-depth analysis of recent advances in gene therapy for both hemophilia A and B, with a focus on AAV-mediated liver-directed approaches and other approved modalities. Key limitations—such as vector immunogenicity, hepatic toxicity, waning transgene expression, and limited re-dosing capacity—are discussed. Additional gene delivery platforms, including lentiviral and retroviral vectors, genome editing techniques (e.g., CRISPR/Cas9), and non-viral systems like transposons and lipid nanoparticles, are also examined. Although gene therapy for hemophilia B demonstrates greater clinical durability, hemophilia A presents unique challenges due to factor VIII’s size, poor expression efficiency, and the need for higher vector doses. Future efforts will focus on overcoming immune barriers, improving delivery technologies, and developing approaches suitable for pediatric patients and individuals with pre-existing immunity. This review provides not only a descriptive overview but also a critical comparison of gene therapy approaches for hemophilia A and B. We emphasize that the durability of response is currently superior in hemophilia B, whereas hemophilia A still faces unique barriers, including declining FVIII expression and higher immunogenicity. By analyzing cross-platform challenges (AAV, lentiviral, CRISPR, and emerging LNPs), we highlight the most promising strategies for overcoming these limitations and provide a forward-looking perspective on the future of gene therapy. Full article

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

16 pages, 296 KB

Open AccessEditor’s ChoiceArticle

A Genome-Wide Association Study in Psoriasis Patients Reveals Variants Associated with Response to Treatment with Interleukin-17A Pathway Inhibitors

by Dimitra Ioakeimidou, Efterpi Zafiriou, Themistoklis Giannoulis, Olga Kouvarou, Kalliopi Gerogianni, Dimitrios P. Bogdanos, Theologia Sarafidou and Kalliopi Liadaki

Genes 2025, 16(10), 1187; https://doi.org/10.3390/genes16101187 - 13 Oct 2025

Cited by 2 | Viewed by 1963

Abstract

Background/Objectives: Psoriasis is currently treated with biologics targeting the IL-17A signaling, which plays a major role in immune response and keratinocyte hyperproliferation. These include inhibitors of IL-17A and/or its heterodimer with IL-17F (Secukinumab, Ixekinumab and Bimekizumab) and the receptor IL17-RA (Brodalumab). Although these [...] Read more.

Background/Objectives: Psoriasis is currently treated with biologics targeting the IL-17A signaling, which plays a major role in immune response and keratinocyte hyperproliferation. These include inhibitors of IL-17A and/or its heterodimer with IL-17F (Secukinumab, Ixekinumab and Bimekizumab) and the receptor IL17-RA (Brodalumab). Although these drugs are safe and highly effective, there is significant variability in response among patients. This can be partly attributed to the patients’ genetic background, thus pointing to the need to identify pharmacogenetic markers for treatment response. Methods: The study involved 88 Greek patients who were treated with inhibitors of the IL-17A signaling for at least 6 months. Patients were classified as responders and non-responders according to the change in Psoriasis Area Severity Index. A total of 730,000 variants were genotyped and analyzed for association with the 3-month and 6-month responses to treatment. Results: The analysis identified 21 variants which were associated with the response, showing statistical significance after Bonferroni correction. These include variants located in protein coding genes (TP63, NRG1, SCN8A, TAF9, TMEM9, SMIM36, SYT14, BPIFC, SEZ6L2, PCARE), as well as intergenic and long non-coding RNA intronic variants. The functional significance of the variants was assessed using in silico analysis and for several variants, a link with immune processes was proposed. Notably, rs11649499 status, which was associated with complete clinical remission at 3 months, may influence key lipid mediators involved in psoriasis. Conclusions: This GWAS identified novel variants that could be utilized upon validation in larger populations as predictive markers regarding patient response to drugs targeting the IL-17A pathway. Full article

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

22 pages, 1001 KB

Open AccessEditor’s ChoiceReview

Fluid Biomarkers in Hereditary Spastic Paraplegia: A Narrative Review and Integrative Framework for Complex Neurodegenerative Mechanisms

by Lorenzo Cipriano, Nunzio Setola, Melissa Barghigiani and Filippo Maria Santorelli

Genes 2025, 16(10), 1189; https://doi.org/10.3390/genes16101189 - 13 Oct 2025

Cited by 2 | Viewed by 1905

Abstract

Background: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders marked by progressive corticospinal tract dysfunction and wide phenotypic variability. Their genetic heterogeneity has so far limited the identification of biomarkers that are broadly applicable across different subtypes. Objective: We aim to [...] Read more.

Background: Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders marked by progressive corticospinal tract dysfunction and wide phenotypic variability. Their genetic heterogeneity has so far limited the identification of biomarkers that are broadly applicable across different subtypes. Objective: We aim to define a balanced review on the use of biomarkers in HSP. Methods: This review focuses on fluid biomarkers already available in clinical or research settings—primarily validated in other neurodegenerative diseases—and assesses their potential translation to the HSP context. Biomarkers such as neurofilament light chain, brain-derived tau, glial fibrillary acidic protein, and soluble TREM2 reflect key converging mechanisms of neurodegeneration, including axonal damage, neuronal loss, and glial activation. These shared downstream pathways represent promising targets for disease monitoring in HSP, independently of the underlying genetic mutation. Results: An integrative framework of fluid biomarkers could assist in defining disease progression and stratify patients in both clinical and research settings. Moreover, recent advances in ultrasensitive assays and remote sampling technologies, such as dried blood spot collection, offer concrete opportunities for minimally invasive, longitudinal monitoring. When combined with harmonized multicenter protocols and digital infrastructure, these tools could support scalable and patient-centered models of care. Conclusions: The integration of already available biomarkers into the HSP field may accelerate clinical translation and offer a feasible strategy to overcome the challenges posed by genetic and clinical heterogeneity. Full article

(This article belongs to the Section Neurogenomics)

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19 pages, 2308 KB

Open AccessEditor’s ChoiceArticle

Bridging Genotype to Phenotype in KMT5B-Related Syndrome: Evidence from RNA-Seq, ¹⁸FDG-PET, Clinical Deep Phenotyping in Two New Cases, and a Literature Review

by Davide Politano, Renato Borgatti, Giulia Borgonovi, Angelina Cistaro, Cesare Danesino, Piercarlo Fania, Gaia Garghetti, Andrea Guala, Isabella Orlando, Irene Giovanna Schiera, Claudia Scotti, Fabio Sirchia, Romina Romaniello, Gaia Visani, Denise Vurchio, Simona Mellone and Mara Giordano

Genes 2025, 16(10), 1174; https://doi.org/10.3390/genes16101174 - 9 Oct 2025

Cited by 1 | Viewed by 2556

Abstract

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: [...] Read more.

Background: Autosomal dominant intellectual developmental disorder 51 (MIM #617788) is caused by pathogenic variants in KMT5B, a histone methyltransferase essential for transcriptional repression and central nervous system development. The disorder manifests as a complex neurodevelopmental syndrome with variable neurological and systemic features. Methods: Two adolescents with nonsense KMT5B variants underwent detailed clinical, neuropsychological, and neuroimaging evaluations, including MRI and ¹⁸FDG PET/CT, analyzed with Statistical Parametric Mapping against matched controls. RNA sequencing was performed, and the literature was reviewed to assess genotype–phenotype correlations. Results: Both patients showed global developmental delay, progressing to autism spectrum disorder (ASD) and developmental coordination disorder (DCD), without intellectual disability (ID). The MRI was normal, but neuropsychological testing revealed executive function impairment, expressive language deficits, and behavioral disturbances. PET/CT consistently demonstrated cerebellar and temporal lobe hypometabolism, correlating with symptom severity. RNA sequencing identified shared dysregulated pathways, notably DDIT4 upregulation, linked to synaptic dysfunction and neuronal atrophy in animal models. Conclusions: The findings highlight cerebellar involvement in DCD and ASD, medial temporal lobe contribution to ASD and executive dysfunction, and DDIT4 as a possible molecular signature of KMT5B loss-of-function. An integrative multimodal approach refined genotype–phenotype correlations and revealed novel brain regions and pathways implicated in KMT5B-related disorders. Full article

(This article belongs to the Special Issue Genetics and Genomics of Autism Spectrum Disorders)

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11 pages, 523 KB

Open AccessEditor’s ChoiceReview

Physical Activity During Pregnancy and Gestational Weight Gain: Implications for Maternal–Fetal Epigenetic Programming and Long-Term Health

by Nektaria Zagorianakou, Stylianos Makrydimas, Efthalia Moustakli, Ioannis Mitrogiannis, Ermanno Vitale and George Makrydimas

Genes 2025, 16(10), 1173; https://doi.org/10.3390/genes16101173 - 6 Oct 2025

Cited by 1 | Viewed by 2687

Abstract

Background/Objectives: Gestational weight gain (GWG) is a crucial factor influencing mother and fetal health, as high GWG is associated with adverse pregnancy outcomes and an increased long-term risk of obesity and metabolic issues in the children. In addition to controlling weight, maternal [...] Read more.

Background/Objectives: Gestational weight gain (GWG) is a crucial factor influencing mother and fetal health, as high GWG is associated with adverse pregnancy outcomes and an increased long-term risk of obesity and metabolic issues in the children. In addition to controlling weight, maternal physical activity (PA) during pregnancy may influence fetal development through potential epigenetic mechanisms, including histone modifications, DNA methylation, and the production of non-coding RNA. Methods: This narrative review synthesizes evidence from randomized controlled trials (RCTs; n = 11, 3654 participants) investigating the impact of aerobic PA on GWG, while also highlighting emerging, primarily indirect findings on maternal–fetal epigenetic programming. Results: The majority of RCTs found that supervised PA interventions, especially when paired with nutritional counseling, decreased both the incidence of excessive GWG and total GWG. Enhancements in lipid metabolism, adipokine profiles, and maternal insulin sensitivity point to likely biochemical mechanisms that connect PA to epigenetic modification of fetal metabolic genes (e.g., IGF2, PGC-1α, LEP). Animal and observational studies suggest that maternal activity may influence offspring epigenetic pathways related to obesity and cardiometabolic conditions, although direct human evidence is limited. Conclusions: In addition to potentially changing gene–environment interactions throughout generations, prenatal PA is a low-cost, safe method of improving maternal and newborn health. Future RCTs ought to incorporate molecular endpoints to elucidate the epigenetic processes by which maternal exercise may provide long-term health benefits. Full article

(This article belongs to the Section Epigenomics)

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35 pages, 2877 KB

Open AccessEditor’s ChoiceReview

RNA-Targeting Techniques: A Comparative Analysis of Modern Approaches for RNA Manipulation in Cancer Research and Therapeutics

by Michaela A. Boti, Marios A. Diamantopoulos and Andreas Scorilas

Genes 2025, 16(10), 1168; https://doi.org/10.3390/genes16101168 - 2 Oct 2025

Cited by 9 | Viewed by 5390

Abstract

RNA-targeting techniques have emerged as powerful tools in cancer research and therapeutics, offering precise and programmable control over gene expression at the post-transcriptional level. Once viewed as passive intermediates in the central dogma, RNA molecules are now recognized as dynamic regulators of cellular [...] Read more.

RNA-targeting techniques have emerged as powerful tools in cancer research and therapeutics, offering precise and programmable control over gene expression at the post-transcriptional level. Once viewed as passive intermediates in the central dogma, RNA molecules are now recognized as dynamic regulators of cellular function, capable of influencing transcription, translation, and epigenetic regulation. Advances in high-throughput sequencing technologies, transcriptomics, and structural RNA biology have uncovered a diverse landscape of coding and non-coding RNAs involved in oncogenesis, drug resistance, and tumor progression. In response, several RNA-targeting strategies have been developed to modulate these transcripts, including antisense oligonucleotides (ASOs), RNA interference (RNAi), CRISPR-Cas13 systems, small molecules, and aptamers. This review provides a comparative analysis of these technologies, highlighting their molecular mechanisms, therapeutic potential, and current limitations. Emphasis is placed on the translational progress of RNA-targeting agents, including recent FDA approvals and ongoing clinical trials for cancer indications. Through a critical comparison of these strategies, this review underscores the growing significance of RNA-targeting technologies as a foundation for next-generation cancer therapeutics and precision oncology. Full article

(This article belongs to the Section RNA)

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27 pages, 2302 KB

Open AccessEditor’s ChoiceReview

Crossroads of Iron Metabolism and Inflammation in Colorectal Carcinogenesis: Molecular Mechanisms and Therapeutic Perspectives

by Nahid Ahmadi, Gihani Vidanapathirana and Vinod Gopalan

Genes 2025, 16(10), 1166; https://doi.org/10.3390/genes16101166 - 1 Oct 2025

Cited by 7 | Viewed by 3354

Abstract

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and [...] Read more.

Background/Objectives: Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide. Iron metabolism and chronic inflammation are two interrelated processes that significantly influence the initiation and progression of CRC. Iron is essential for cell proliferation, but its excess promotes oxidative stress and DNA damage, while inflammation driven by cytokine-regulated pathways accelerates tumourigenesis. We therefore conducted this narrative review to collate the available evidence on the link between iron homeostasis and inflammatory signalling in CRC and highlight potential diagnostic and therapeutic applications. Methods: This narrative review of preclinical and clinical studies explores the molecular and cellular pathways that connect iron regulation and inflammation to CRC. Key regulatory molecules, such as the transferrin receptor (TFRC), ferroportin (SLC40A1), ferritin (FTH/FTL), hepcidin, and IL-6, were reviewed. Additionally, we summarised the findings of transcriptomic, epigenomic, and proteomic studies. Relevant therapeutic approaches, including iron chelation, ferroptosis induction, and anti-inflammatory strategies, were also discussed. Results: Evidence suggests that CRC cells exhibit altered iron metabolism, marked by the upregulation of transferrin receptor (TFRC), downregulation of ferroportin, and dysregulated expression of ferritin. Inflammatory mediators such as IL-6 activate hepcidin and STAT3 signalling, which reinforce intracellular iron retention and oxidative stress. Increased immune evasion, epithelial proliferation, and genomic instability appear to be linked to the interaction between inflammation and iron metabolism. Other promising biomarkers include ferritin, hepcidin, and composite gene expression signatures; however, their clinical application remains limited. Although several preclinical studies support the use of targeted iron therapies and combination approaches with anti-inflammatory agents or immunotherapy, there is a lack of comprehensive clinical validation confirming their efficacy and safety in humans. Conclusion: Although preclinical studies suggest that iron metabolism and inflammatory signalling form an interconnected axis closely linked to CRC, translating this pathway into reliable clinical biomarkers and effective therapeutic strategies remains a significant challenge. Future biomarker-guided clinical trials are essential to determine the clinical relevance and to establish precision medicine strategies targeting the iron–inflammation crosstalk in CRC. Full article

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

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