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Genes, Volume 16, Issue 10 (October 2025) – 79 articles

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11 pages, 987 KB  
Article
Allelic Variations of the Waxy Gene and Their Associations with Indica–Japonica Differentiation and Amylose Content in Yunnan Local Rice Germplasm
by Ying Lv, Wei Deng, Xueqian Zuo, Duo Lan, Jing Tan, Jianhua Zhang, Yangjun Dong, Yuran Xu, Jinwen Zhang, Xiao Zhang, Jian Tu, Limei Kui, Anyu Gu, Xiqiong Shen and Xiaolin Li
Genes 2025, 16(10), 1198; https://doi.org/10.3390/genes16101198 (registering DOI) - 14 Oct 2025
Abstract
Objectives: To provide insights for breeding high-quality rice varieties, we analyzed local rice (Oryza sativa L.) germplasm from Yunnan Province, China, focusing on the relationships among Waxy gene alleles, indica–japonica differentiation, and amylose content (AC). Methods: We examined 201 local rice accessions. [...] Read more.
Objectives: To provide insights for breeding high-quality rice varieties, we analyzed local rice (Oryza sativa L.) germplasm from Yunnan Province, China, focusing on the relationships among Waxy gene alleles, indica–japonica differentiation, and amylose content (AC). Methods: We examined 201 local rice accessions. Two functional molecular markers for the Waxy gene were used to detect four alleles (Wxa, Wxb, Wxin, Wxmw). Additionally, 33 InDel markers were employed to classify indica–japonica attributes, and AC was measured according to GB/T 15683-2008. Results: We detected 175 accessions with Wxa, 20 with Wxb, 4 with Wxin, and 2 with Wxmw, indicating Wxa dominance and a diverse genetic basis at the Waxy locus. Indica–japonica classification identified 180 indica-type, 19 japonica-type, and 2 intermediate-type accessions, confirming predominant indica differentiation in Yunnan rice. Integrating Waxy allele detection, indica–japonica attributes, and AC showed that Wxa occurred primarily in indica rice with higher AC (mean 22.55%), comparable to Wxin (mean 24.33%); Wxb was mainly found in japonica rice with lower AC (mean 13.46%), similar to Wxmw (mean 15.65%). Conclusions: Local Yunnan rice exhibits Wxa predominance at the Waxy locus and clear indica differentiation. The observed associations between Waxy alleles, subspecies attributes, and AC provide useful references for marker-assisted breeding of premium rice and for exploiting indica–japonica heterosis. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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16 pages, 300 KB  
Article
Chromosome 12 and Environmental Factors in Parkinson’s Disease: An All of Us Data Analysis
by Kenta Abe and Karen Niemchick
Genes 2025, 16(10), 1197; https://doi.org/10.3390/genes16101197 - 13 Oct 2025
Abstract
Background/Objectives: Parkinson’s disease (PD) is a neurodegenerative disease that develops with age and is related to a decline in motor function. Studies suggest that the causes may be based on genetic dysfunction including PARK gene mutations and environmental factors. Methods: To explore those [...] Read more.
Background/Objectives: Parkinson’s disease (PD) is a neurodegenerative disease that develops with age and is related to a decline in motor function. Studies suggest that the causes may be based on genetic dysfunction including PARK gene mutations and environmental factors. Methods: To explore those factors, we used multivariable logistic regression to obtain odds ratios (ORs) and adjusted ORs by using the All of Us Dataset which contains genomic, blood test, and other environmental data. Results: On Chromosome 12, there were 3709 candidate genetic polymorphisms (GPs) that are associated with PD. Of those GPs, fourteen GPs had high ORs which are similar to the OR of the PARK8 gene G2019S mutation. Of those 3709 GPs, a 2.00-fold change in OR was observed in five GPs located at bases 53,711,362 (OR = 4.86, 95% CI [1.46, 16.18]), 31,281,818 (OR = 4.37, 95% CI [1.02, 18.82]), 101,921,705 (OR = 5.38, 95% CI [1.23, 23.51]), 47,968,795 (OR = 7.82, 95% CI [1.81, 33.83]), and 112,791,809 (OR = 8.05, 95% CI [1.85, 35.05]) by calcium, Vitamin D, and alcohol intake and were statistically significant. Conclusions: The results suggest that the progression of some PD caused by certain GPs can be delayed or prevented by the environmental factors above. In February 2025, All of Us released the CT Dataset v.8 which has a 50% increase in the number of participants. Potentially, it may be possible to research more GPs and environmental factors. In future studies, we would like to explore other environmental factors and GPs on other chromosomes. It is believed that specific GPs may tailor current treatments and qualify patients for clinical trials. Additionally, genetic knowledge may help increase accuracy in clinical trials. Full article
21 pages, 1288 KB  
Review
Linking Genotype to Clinical Features in SMC1A-Related Phenotypes: From Cornelia de Lange Syndrome to Developmental and Epileptic Encephalopathy, a Comprehensive Review
by Maria Francesca Astorino, Desirèe Speranza, Giovanni Luppino, Maria Angela La Rosa, Silvana Briuglia and Marco Calabrò
Genes 2025, 16(10), 1196; https://doi.org/10.3390/genes16101196 - 13 Oct 2025
Abstract
Germline mutations in the X-linked cohesin subunit gene SMC1A have been increasingly recognized as a cause of developmental and epileptic encephalopathy (DEE); however, the underlying basis of its marked phenotypic heterogeneity remains elusive. In our narrative review, starting from all literature-reported clinical cases [...] Read more.
Germline mutations in the X-linked cohesin subunit gene SMC1A have been increasingly recognized as a cause of developmental and epileptic encephalopathy (DEE); however, the underlying basis of its marked phenotypic heterogeneity remains elusive. In our narrative review, starting from all literature-reported clinical cases of SMC1A-related DEE, we propose an integrative framework summarizing all the clinical and genetic features, stratified by mutation type, mosaic fraction, and X-chromosome inactivation (XCI) patterns to provide valuable support for genetic diagnosis and variants, found to date. Also, we discuss how somatic mosaicism and epigenetic variability underlie the clinical diversity of SMC1A-associated epilepsy and systematically describe the entire phenotypic spectrum, from early-onset, therapy-resistant seizures to milder intellectual disability profiles. We further examine how SMC1A mutations perturb cohesin’s canonical roles in chromatin loop formation and sister-chromatid cohesion, leading to widespread transcriptional dysregulation of neurodevelopmental gene networks. Evidence that XCI skewing can ameliorate or exacerbate neuronal cohesin deficits and, thus modulate seizure threshold, is presented. Full article
(This article belongs to the Special Issue Molecular Basis and Genetics of Intellectual Disability)
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12 pages, 616 KB  
Article
A Genome-Wide Association Study Identifying Novel Genetic Markers of Response to Treatment with Interleukin-23 Inhibitors in Psoriasis
by Sophia Zachari, Kalliopi Liadaki, Angeliki Planaki, Efterpi Zafiriou, Olga Kouvarou, Kalliopi Gerogianni, Themistoklis Giannoulis, Zissis Mamuris, Dimitrios P. Bogdanos, Nicholas K. Moschonas and Theologia Sarafidou
Genes 2025, 16(10), 1195; https://doi.org/10.3390/genes16101195 - 13 Oct 2025
Abstract
Background/Objectives: The advent of biologics targeting key inflammatory pathways has significantly advanced psoriasis treatment. Among them, the Interleukin-23 inhibitors Guselkumab and Risankizumab have demonstrated high efficacy and rapid clinical response in both clinical trials and real-world studies. However, up to 30% of [...] Read more.
Background/Objectives: The advent of biologics targeting key inflammatory pathways has significantly advanced psoriasis treatment. Among them, the Interleukin-23 inhibitors Guselkumab and Risankizumab have demonstrated high efficacy and rapid clinical response in both clinical trials and real-world studies. However, up to 30% of patients fail to respond. This study aimed to identify pharmacogenetic markers associated with treatment response using a genome-wide association study (GWAS) and protein network-based approach. Methods: Fifty-three patients of Greek origin with moderate-to-severe plaque psoriasis were treated with Guselkumab or Risankizumab. Based on Psoriasis Area and Severity Index (PASI) improvement at 3 and 6 months, patients were categorized as responders or non-responders. Approximately 730,000 single-nucleotide polymorphisms (SNPs) were genotyped. After filtering, a GWAS was performed to identify variants associated with treatment response. Additionally, protein–protein interaction (PPI) network analysis was applied to the two Interleukin-23 subunits and SNPs within or near genes encoding Interleukin-23-interacting proteins to test for their association. Results: The GWAS identified two novel variants, rs73641950 and rs6627462, significantly associated with treatment response, with both surpassing the genome-wide significance threshold after Bonferroni correction. The PPI-based approach revealed rs13086445, located downstream of the Interleukin-12 subunit alpha (IL12A) gene, as another associated variant. All three SNPs lie in genomic regions with potential regulatory roles. Conclusions: This study identifies three novel genetic variants associated with response to Interleukin-23 inhibitors in psoriasis. These findings provide promising pharmacogenetic markers which, upon validation in larger, independent cohorts, will enable the translation of a patient’s genotype into a response phenotype, thereby guiding clinical decisions and improving drug effectiveness. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Treatment)
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23 pages, 1059 KB  
Review
Non-Protein-Coding RNA and Acute Kidney Injury: New Developments from Pathogenesis to Potential Biomarker
by Grazia Maria Virzì, Anna Clementi, Monica Zanella and Claudio Ronco
Genes 2025, 16(10), 1194; https://doi.org/10.3390/genes16101194 - 13 Oct 2025
Abstract
Acute Kidney Injury (AKI) is a critical medical condition characterized by a sudden and significant decline in renal function over a short timeframe. Commonly triggered by factors such as sepsis, ischemia–reperfusion injury, or nephrotoxic agents, AKI is linked to substantial rates of morbidity [...] Read more.
Acute Kidney Injury (AKI) is a critical medical condition characterized by a sudden and significant decline in renal function over a short timeframe. Commonly triggered by factors such as sepsis, ischemia–reperfusion injury, or nephrotoxic agents, AKI is linked to substantial rates of morbidity and mortality. In recent years, small non-coding RNAs have gained attention as promising biomarkers for the early diagnosis and potential treatment of AKI. Among them, microRNAs (miRNAs)—short RNA sequences of 21–25 nucleotides that regulate gene expression via sequence-specific binding—stand out due to their remarkable stability in biological fluids such as plasma and urine. Notably, certain miRNAs, including miR-21, miR-30, miR-494, and miR-29, have shown the ability to detect AKI earlier than traditional biomarkers like serum creatinine, offering the potential to enhance clinical decision-making. This narrative review aims to provide a comprehensive overview of the recent findings regarding the involvement of non-coding RNA, in particular microRNAs, in both the early diagnosis and therapeutic strategies for AKI. By highlighting their potential as sensitive biomarkers and novel treatment targets, this review seeks to contribute to advancing clinical approaches that improve patient outcomes. Ultimately, a deeper understanding and utilization of microRNAs could lead to the development of new diagnostic tools and targeted therapies for AKI, helping to prevent progression to chronic kidney disease and reduce associated mortality rates. However, further clinical studies and translational applications are still needed to validate these findings and implement them in patient care. Full article
(This article belongs to the Section RNA)
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12 pages, 865 KB  
Article
Genetic Variability in NKG2 Receptors and Their Ligands: Associations with SARS-CoV-2 Infection and COVID-19 Severity
by Jagoda Siemaszko, Katarzyna Grad, Jerzy Świerkot and Katarzyna Bogunia-Kubik
Genes 2025, 16(10), 1193; https://doi.org/10.3390/genes16101193 - 13 Oct 2025
Abstract
Background: The emergence of the COVID-19 pandemic has accelerated research into diverse immune response mechanisms. One key area of interest is the regulation of cytotoxic activity by Natural Killer (NK) cells. These cells rely on a dynamic interplay between activating and inhibitory surface [...] Read more.
Background: The emergence of the COVID-19 pandemic has accelerated research into diverse immune response mechanisms. One key area of interest is the regulation of cytotoxic activity by Natural Killer (NK) cells. These cells rely on a dynamic interplay between activating and inhibitory surface receptors that recognize specific ligands on target cells. Among these, receptors from the NKG2 family are particularly important, as maintaining their proper balance and function is essential for controlling NK cell cytotoxicity. Methods: In this study we employed qPCR to assess the genetic variability using single-nucleotide polymorphisms (SNPs) of NKG2A and NKG2D receptors and their ligands HLA-E and MICA/MICB. NKG2C deletion was determined by PCR-SSP, and serum-soluble levels of HLA-E and MICA/MICB molecules were measured by ELISA and Luminex methods. Results: Genotyping studies revealed that both NKG2A rs7301582 T and HLA-E rs1264457 A (HLA-E*01:01) alleles were predominant among infected individuals (OR = 2.21, p = 0.0258 and OR = 2.84, p = 0.0257, respectively). In contrast to MICB rs1065075 A, the MICA rs1051792 A (129Met) allele was most commonly found in hospitalized patients (OR = 14.95, p = 0.0114). The presence of the NKG2C del variant tended to be associated with an increased risk of SARS-CoV-2 infection (OR = 2.02, p = 0.0694). Moreover, higher concentrations of serum-soluble MICB was detected in infected individuals as compared to the control group (p = 0.008). Conclusions: Genetic variability of NK cell receptors and ligands as well as serum levels of their soluble forms showed associations with the risk of development of COVID-19 and the severity of its symptoms. Full article
(This article belongs to the Section Microbial Genetics and Genomics)
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22 pages, 1996 KB  
Article
Newborn MTHFR rs1801133 Variant and Extremely Low Birth Weight: A Case–Control Study and Meta-Analysis
by Bartosz Skulimowski, Anna Durska, Alicja Sobaniec, Anna Gotz-Więckowska and Ewa Strauss
Genes 2025, 16(10), 1192; https://doi.org/10.3390/genes16101192 - 13 Oct 2025
Abstract
Background: Extremely low birth weight (ELBW) and extremely low gestational age (ELGA) remain major challenges in neonatology, contributing to neonatal morbidity and mortality. This study aims to examine the association between functional variants of MTHFR and PON1, genes involved in homocysteine metabolism, [...] Read more.
Background: Extremely low birth weight (ELBW) and extremely low gestational age (ELGA) remain major challenges in neonatology, contributing to neonatal morbidity and mortality. This study aims to examine the association between functional variants of MTHFR and PON1, genes involved in homocysteine metabolism, and the risk of ELGA, ELBW, and other complications of prematurity. A meta-analysis was also conducted to integrate literature data with the results of this study. Methods: The study included 377 premature infants, 164 mothers, and a population-based sample of 404 individuals. Genotyping was performed using TaqMan assays. Results: The fetal, but not maternal, MTHFR rs1801133 genotype was associated with ELBW (OR = 1.65; 95% CI: 1.09–2.51; p = 0.017, dominant model), bronchopulmonary dysplasia (p = 0.028), patent ductus arteriosus (p = 0.017), and neonatal mortality. The meta-analysis, which included five studies spanning 1156 cases and 1124 controls, confirmed the association between the neonatal MTHFR genotype and low birth weight (LBW), demonstrating an association of the rs1801133T allele with LBW in the TT homozygote model (vs. CT: OR = 1.41; 95% CI: 1.08–1.80; p = 0.0097). Subgroup analyses indicated that the rs1801133T allele is a protective factor against LBW in more developed countries, such as Canada and the UK (dominant model), whereas in other countries, such as China, Turkey, and Poland, it is a risk factor for LBW (recessive model). No association with PON1 variants with ELBW or ELGA was found. Conclusions: This study provides the first global evidence confirming that the neonatal MTHFR genotype contributes to LBW, underscoring the population-specific effects of this genetic variant. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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18 pages, 1496 KB  
Review
PRC2 Diversity in Neuronal Differentiation and Developmental Disorders
by Jasmine Akoto, Thomas Roule and Naiara Akizu
Genes 2025, 16(10), 1191; https://doi.org/10.3390/genes16101191 - 13 Oct 2025
Abstract
Advances in genetic studies have not only improved the diagnosis and treatment of neurodevelopmental disorders but also uncovered human-specific aspects of nervous system development. The generation of neuronal diversity in the human brain relies on tightly regulated epigenetic mechanisms, with Polycomb Repressive Complex [...] Read more.
Advances in genetic studies have not only improved the diagnosis and treatment of neurodevelopmental disorders but also uncovered human-specific aspects of nervous system development. The generation of neuronal diversity in the human brain relies on tightly regulated epigenetic mechanisms, with Polycomb Repressive Complex 2 (PRC2) emerging as a key player. In this review, we first summarize foundational studies that established the role of PRC2 in the epigenetic maintenance of transcriptional silencing. We then highlight recent insights into the increasing evolutionary complexity of PRC2 subcomplexes, their roles in neurodevelopment, and their contribution to human developmental disorders. Full article
(This article belongs to the Special Issue The Genetic and Epigenetic Basis of Neurodevelopmental Disorders)
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12 pages, 1269 KB  
Article
Familial NSD1 Exon 3 Deletion Associated with Phenotypic and Epigenetic Variability
by Sunwoo Liv Lee, Alison Foster, Dalit May, Ciara Batterton, Eguzkine Ochoa, Bryndis Yngvadottir, Ruth Armstrong, Meena Balasubramanian, Mary O’Driscoll, Marc Tischkowitz, France Docquier, Fay Rodger, Ezequiel Martin, Ana Toribio and Eamonn R. Maher
Genes 2025, 16(10), 1190; https://doi.org/10.3390/genes16101190 - 13 Oct 2025
Abstract
Background: Germline pathogenic variants in NSD1 cause Sotos syndrome, a developmental disorder characterised by overgrowth, intellectual disability, macrocephaly, developmental anomalies, and, in some cases, tumour development. Familial cases of Sotos syndrome are rare and genotype–phenotype correlations are not well described. NSD1, a lysine-specific [...] Read more.
Background: Germline pathogenic variants in NSD1 cause Sotos syndrome, a developmental disorder characterised by overgrowth, intellectual disability, macrocephaly, developmental anomalies, and, in some cases, tumour development. Familial cases of Sotos syndrome are rare and genotype–phenotype correlations are not well described. NSD1, a lysine-specific histone methyltransferase, is an important epigenetic regulator and pathogenic variants in NSD1 are associated with a distinctive blood DNA methylation pattern (episignature). We described a family with an NSD1 exon 3 deletion and an atypical clinical phenotype. Methods: DNA episignature profiling was undertaken with a next generation sequencing-based approach. Results: Within the family, the three affected individuals showed clinical variability with the proband being most severely affected, although none showed unequivocal macrocephaly or the characteristic facial features of Sotos syndrome. DNA methylation profiling was performed in the three affected family members, eight individuals with Sotos syndrome, and compared to control samples. The eight individuals with Sotos syndrome displayed genome-wide hypomethylation as previously described. DNA hypomethylation was also apparent in the three family members with the NSD1 exon 3 deletion with the proband being most similar to the episignature observed in confirmed Sotos syndrome patients. The two more mildly affected relatives had less pronounced DNA hypomethylation. Conclusions: A familial germline exon 3 NSD1 deletion was associated with mild Sotos syndrome phenotype with variable expressivity and a DNA methylation episignature that was less marked in milder cases than in individuals with classical Sotos syndrome. These findings support the use of methylation episignature analysis to explore intrafamilial variability in chromatin disorders. Full article
(This article belongs to the Special Issue Clinical Diagnosis and Analysis of Cancers)
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22 pages, 1001 KB  
Review
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
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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16 pages, 1085 KB  
Review
Dirty Ends: Formation, Repair, and Biological Relevance of Non-Canonical DNA Terminal Structures
by Seanmory Sothy and Linlin Zhao
Genes 2025, 16(10), 1188; https://doi.org/10.3390/genes16101188 - 13 Oct 2025
Abstract
Human DNA is continuously exposed to endogenous and exogenous agents that generate over 100,000 lesions per cell each day. In addition to damage to nucleobases, deoxyribose, and phosphate groups, a particularly harmful class of lesions involves non-canonical DNA termini—structures deviating from the canonical [...] Read more.
Human DNA is continuously exposed to endogenous and exogenous agents that generate over 100,000 lesions per cell each day. In addition to damage to nucleobases, deoxyribose, and phosphate groups, a particularly harmful class of lesions involves non-canonical DNA termini—structures deviating from the canonical 3′-hydroxyl and 5′-phosphate ends. These aberrant DNA ends can obstruct essential DNA transactions and, if left unrepaired, contribute to cytotoxicity and mutagenesis. Their biological significance is further highlighted by the severe pathologies linked to deficiencies in DNA end-processing enzymes, including inflammation, cancer predisposition syndromes, neurodegeneration, and aging. This review highlights recent advances in our understanding of the formation, prevalence, and repair mechanisms of several key non-canonical DNA end structures, including 3′-phosphate, 3′-phosphoglycolate, 3′-α,β-unsaturated aldehyde and its glutathione derivative, 5′-deoxyribose-5-phosphate, 2′-deoxyribonucleoside-5′-aldehyde, and 5′-adenosine monophosphate. These non-canonical DNA terminal structures arise from various sources, such as radical-induced oxidation of the 2-deoxyribose moiety and DNA repair pathways. While this review does not cover the full spectrum of non-canonical termini, the selected structures are emphasized based on quantitative data supporting their biological relevance. The review also discusses their broader implications in mitochondrial DNA maintenance and inflammatory signaling and highlights key knowledge gaps that warrant further investigation. Full article
(This article belongs to the Section Molecular Genetics and Genomics)
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16 pages, 296 KB  
Article
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
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)
16 pages, 3529 KB  
Article
Functional Validation of ALDOA in Regulating Muscle Cell Fate: Based on In Vitro Proliferation, Apoptosis, and Differentiation Experiments
by Hongzhen Cao, Jing Wang, Yunzhou Wang, Jingsen Huang, Wei Chen, Hui Tang, Junfeng Chen, Baosong Xing and Yongqing Zeng
Genes 2025, 16(10), 1186; https://doi.org/10.3390/genes16101186 - 12 Oct 2025
Abstract
Background/Objectives: This study systematically investigated the expression characteristics of the ALDOA gene in skeletal muscle cells and its effects on cell proliferation, apoptosis, and differentiation. Methods: We constructed an ALDOA overexpression vector and transfected it into C2C12 cells and porcine skeletal [...] Read more.
Background/Objectives: This study systematically investigated the expression characteristics of the ALDOA gene in skeletal muscle cells and its effects on cell proliferation, apoptosis, and differentiation. Methods: We constructed an ALDOA overexpression vector and transfected it into C2C12 cells and porcine skeletal muscle satellite cells. Results: We found that ALDOA exhibited the highest expression in the longissimus dorsi muscle and was primarily localized in the cell nucleus. Overexpression of ALDOA significantly inhibited cell proliferation, induced G0/G1 phase arrest, and downregulated the expression of proliferation-related genes such as CDK2 and Cyclin D1. Concurrently, ALDOA overexpression markedly promoted apoptosis. Regarding differentiation, although ALDOA expression was upregulated during differentiation, its overexpression significantly suppressed the expression of myogenic differentiation-related genes (such as MYOD, MYOG, MEF2C), suggesting a negative regulatory role in differentiation control. Conclusions: This study reveals the multifaceted regulatory functions of ALDOA in skeletal muscle cells, providing experimental evidence for deepening the understanding of its mechanisms in muscle development and regeneration. This study provides the first functional evidence that ALDOA acts as a multifunctional regulator in skeletal muscle cells, negatively governing cell growth and fate decisions by inhibiting proliferation, promoting apoptosis, and impeding myogenic differentiation, thereby extending its role beyond glycolysis to direct governance of cellular processes. This study reveals for the first time that ALDOA possesses dual functions in muscle cells, regulating both metabolism and transcription. Full article
(This article belongs to the Special Issue Advances in Pig Genetic and Genomic Breeding)
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18 pages, 2929 KB  
Article
Comprehensive Analysis of Agronomic Traits, Saponin Accumulation, and SNP-Based Genetic Diversity in Different Cultivars of Panax notoginseng
by Yawen Wu, Guanjiao Wang, Ran Pu, Tian Bai, Hao Fan, Jingli Zhang and Shengchao Yang
Genes 2025, 16(10), 1185; https://doi.org/10.3390/genes16101185 - 12 Oct 2025
Abstract
Background: Given the need to optimize Panax notoginseng cultivation, screen high-quality germplasm, and clarify its insufficiently elucidated genetic–phenotype–quality associations (e.g., saponin accumulation), this study was conducted. Methods: Agronomic traits were measured, saponin accumulation was determined via high-performance liquid chromatography (HPLC), and [...] Read more.
Background: Given the need to optimize Panax notoginseng cultivation, screen high-quality germplasm, and clarify its insufficiently elucidated genetic–phenotype–quality associations (e.g., saponin accumulation), this study was conducted. Methods: Agronomic traits were measured, saponin accumulation was determined via high-performance liquid chromatography (HPLC), and comprehensive performance was evaluated through integrated cluster analysis and fuzzy membership function assessment; additionally, single-nucleotide polymorphism (SNP)-based genetic diversity analysis was conducted to explore the genetic basis of trait variations. Results: Agronomic traits exhibited coefficients of variation (CVs) of 2.95–18.12%, with primary root length showing the highest variability. Phenotypic cluster analysis divided the materials into three groups. Group I (“Miaoxiang No.1”, “Dianqi No.1”, “Miaoxiang Kangqi No.1”) was characterized by tall plants, sturdy stems, heavy roots, and long/large leaves. Saponin determination results revealed significant differences in notoginsenoside R1, ginsenoside Rb1, ginsenoside Re, ginsenoside Rd, and total saponins among cultivars (order: “Zijing” > “Dianqi No.1” > original cultivar > “Miaoxiang Kangqi No.1” > “Miaoxiang No.1” > “Miaoxiang No.2”), with “Zijing” having the highest total saponin accumulation (18.13%); no significant difference was observed in ginsenoside Rg1 accumulation. The GATK initially identified 16,329,600 SNPs, and 115,930 high-quality SNPs were retained after Samtools filtration. SNP-based Neighbor-joining (NJ) clustering grouped the cultivars into three categories, with the original cultivar clustered alone as one category. Through comprehensive evaluation, three superior germplasm lines (“Miaoxiang Kangqi No.1”, “Miaoxiang No.1”, “Dianqi No.1”) were identified. A significant negative correlation (p < 0.05) was found between compound leaf petiole length and saponin accumulation. Conclusions: This integrated analytical strategy clarifies the links between genetics, phenotype, and quality, providing a scientific foundation for P. notoginseng germplasm screening and facilitating future molecular breeding efforts. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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12 pages, 3188 KB  
Article
Gene Mapping and Molecular Marker Development for Controlling Purple-Leaf Trait in Pakchoi (Brassica rapa subsp. chinensis (L.) Hanelt)
by Bo Song, Qinyu Yang, Wenqi Zhang, Xiao Yang, Li Zhang, Lin Ouyang, Limei He, Longzheng Chen, Zange Jing, Tao Huang, Hai Xu, Yuejian Li and Qichang Yang
Genes 2025, 16(10), 1184; https://doi.org/10.3390/genes16101184 - 12 Oct 2025
Abstract
Purple pakchoi (Brassica rapa subsp. chinensis (L.) Hanelt) is rich in anthocyanins, which contribute to its significant edible, ornamental, and potential health-promoting value. The previous research on the purple-leaf trait of pakchoi was rather insufficient, key gene controlling the purple-leaf trait remains [...] Read more.
Purple pakchoi (Brassica rapa subsp. chinensis (L.) Hanelt) is rich in anthocyanins, which contribute to its significant edible, ornamental, and potential health-promoting value. The previous research on the purple-leaf trait of pakchoi was rather insufficient, key gene controlling the purple-leaf trait remains to be further elucidated. Fine mapping of the genes responsible for the purple-leaf trait is essential for establishing molecular marker-assisted breeding and facilitating genetic improvement. In this study, we used the inbred purple-leaf line ‘PQC’ and green-leaf line ‘HYYTC’ as parents to construct a six-generation genetic segregation population. We analyzed the inheritance pattern of the purple-leaf trait and combined Bulked Segregant Analysis Sequencing (BSA-seq) with penta-primer amplification refractory mutation system (PARMS) to map the causal gene. The main findings are as follows: the purple-leaf trait is controlled by a single dominant gene. Using BSA-seq and PARMS, the genes were mapped to a 470 kb region (31.18–31.65 Mb) on chromosome A03. Within this interval, 29 candidate genes were identified. Bra017888 which encoding trehalose phosphate synthase 10 (TPS10), was highlighted as a potential regulator of anthocyanin biosynthesis. A developed molecular marker, SNP31304070, based on the final candidate region, successfully distinguished between purple homozygous and purple heterozygous plants in the F2 and F3 populations, showing complete co-segregation with the trait. The marker could be applied to molecular-assisted breeding in purple pakchoi. Full article
(This article belongs to the Section Plant Genetics and Genomics)
21 pages, 618 KB  
Review
Inherited Retinal Diseases with High Myopia: A Review
by Cyndy Liu, Narin Sheri and Matthew D. Benson
Genes 2025, 16(10), 1183; https://doi.org/10.3390/genes16101183 - 11 Oct 2025
Viewed by 41
Abstract
Inherited retinal dystrophies (IRDs) are a diverse group of monogenic disorders associated with dysfunction of the retina. High myopia, commonly defined as a spherical equivalent ≤ −6.00 D or axial length ≥ 26.5 mm, is a recurring clinical feature across several IRDs, and [...] Read more.
Inherited retinal dystrophies (IRDs) are a diverse group of monogenic disorders associated with dysfunction of the retina. High myopia, commonly defined as a spherical equivalent ≤ −6.00 D or axial length ≥ 26.5 mm, is a recurring clinical feature across several IRDs, and could serve as an early diagnostic clue. This review provides a summary of IRDs associated with high myopia to guide the clinician in establishing a molecular diagnosis for patients. We performed a comprehensive literature review of articles in PubMed, ScienceDirect, and JAMA Network to identify associations between monogenic IRDs and high myopia. Genes associated with IRDs and high myopia clustered into functional categories that included collagen/structural integrity (COL2A1, COL9A1, COL11A1, COL18A1, P3H2), phototransduction and visual cycle (PDE6C, PDE6H, GUCY2D, ARR3, RBP3), ciliary trafficking and microtubule-associated genes (RPGR, RP2, IFT140, CFAP418, FAM161A), synaptic ribbon and bipolar cell signaling (NYX, CACNA1F, TRPM1, GRM6, LRIT3, GPR179), opsin-related genes (OPN1LW, OPN1MW), and miscellaneous categories (VPS13B, ADAMTS18, LAMA1). Associations between IRDs and high myopia spanned stationary and progressive retinal disorders and included both cone-dominant and rod-dominant diseases. High myopia accompanied by other visual symptoms and signs such as nyctalopia, photophobia, or reduced best-corrected visual acuity should heighten suspicion for an underlying IRD. Earlier diagnosis of IRDs for patients could facilitate timely genetic counseling, participation in clinical trials, and interventions for patients to preserve vision.: Full article
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14 pages, 1741 KB  
Article
The p.Ile202Thr Substitution in TUBB2B Can Be Associated with Syndromic Presentation of Congenital Fibrosis of the Extraocular Muscles
by Cecilia Mancini, Luigi Chiriatti, Alessandro Bruselles, Paola D’ambrosio, Andrea Ciolfi, Marco Ferilli, Camilla Cappelletti, Mattia Carvetta, Francesca Clementina Radio, Viviana Cordeddu, Marcello Niceta, Marta Parrino, Rossella Capolino, Corrado Mammì, Rossana Senese, Mario Muto, Manuela Priolo and Marco Tartaglia
Genes 2025, 16(10), 1182; https://doi.org/10.3390/genes16101182 - 11 Oct 2025
Viewed by 53
Abstract
Background: Dominantly acting variants in TUBB2B have primarily been associated with cortical dysplasia complex with other brain malformations 7 (CDCBM7), a disorder in which cortical brain abnormalities are typically linked to developmental delay/intellectual disability (DD/ID) and seizures. While the majority of TUBB2B [...] Read more.
Background: Dominantly acting variants in TUBB2B have primarily been associated with cortical dysplasia complex with other brain malformations 7 (CDCBM7), a disorder in which cortical brain abnormalities are typically linked to developmental delay/intellectual disability (DD/ID) and seizures. While the majority of TUBB2B pathogenic variants have been linked to isolated CDCBM7, only one family with CDCBM7 and congenital fibrosis of the extraocular muscles (CFEOM) has been reported so far. We describe a second individual with a severe phenotype of CFEOM combined with CDCBM7 carrying a pathogenic TUBB2B missense variant previously reported in two individuals with isolated CDCBM7. Methods: A trio-based WGS analysis was performed. The structural impact of the identified substitution was assessed by using the UCSF Chimera (v.1.17.3) software and PyMOL docking plugin DockingPie tool. Results: WGS analysis identified a de novo missense TUBB2B variant (p.Ile202Thr, NM_178012.5), previously associated with isolated CDCBM7. Structural analysis and docking simulations revealed that Ile202 contributes to establishing a proper hydrophobic environment required to stabilize GTP/GDP in the β-tubulin pocket. p.Ile202Thr was predicted to disrupt these interactions. Conclusions: Our findings broaden the mutational spectrum of TUBB2B-related CFEOM, targeting a different functional domain of the protein, and further document the occurrence of phenotypic heterogeneity. We also highlight the limitations of exome sequencing in accurately mapping TUBB2B coding exons due to its high sequence homology with TUBB2A and suggest targeted or genome analyses when clinical suspicion is strong. Full article
(This article belongs to the Special Issue Advances in Genetic Analysis of Congenital Disorders)
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7 pages, 1052 KB  
Brief Report
A New Variant in the NALCN Channel Is Responsible for Cerebellar Ataxia and Cognitive Impairment
by Rute Luísa Cabrita Pinto, Roberto Fancellu, Tiziana Benzi Markushi, Silvia Viaggi, Barbara Testa, Giuseppina Conteduca, Lane Fitzsimmons, Domenico Coviello and Angela Elvira Covone
Genes 2025, 16(10), 1181; https://doi.org/10.3390/genes16101181 - 11 Oct 2025
Viewed by 78
Abstract
Background/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form [...] Read more.
Background/Objectives: CLIFAHDD syndrome (OMIM # 616266) is a rare neurodevelopmental disorder caused by mutations in the NALCN gene. It is characterized by hypotonia, developmental delay, and congenital contractures of the limbs and face. We report a 33-year-old Italian woman with a mild form of CLIFAHDD who exhibited early-onset language difficulties and mild intellectual disability and later developed gait and balance impairments in adulthood. Methods and Results: Whole Exome Sequencing (WES) identified a novel missense variant c.1514A>T; p.(Lys505Met) in the NALCN gene. The allele frequency of this variant is not detected (MAF = 0.0), the variant is classified as likely pathogenic according to ACMG criteria, and predicted to be probably damaging by PolyPhen-2. It affects a critical residue within the second pore-forming domain of the NALCN channel, potentially altering lipid interactions and channel regulation. Sanger sequencing and segregation analysis confirmed the variant to be heterozygous and de novo. Conclusions: The patient’s milder symptoms and later onset, compared to severe pediatric cases, suggest that the clinical spectrum of CLIFAHDD syndrome may be broader than previously recognized. These findings underscore the potential influence of mutation location on disease presentation and severity. Full article
(This article belongs to the Section Genetic Diagnosis)
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15 pages, 882 KB  
Article
Evidence of Mixed Selection Acting on the MHC Class II DQA Gene in Captive Thai Elephant Populations
by Trifan Budi, Marie Roselle Enguito, Worapong Singchat, Thitipong Panthum, Ton Huu Duc Nguyen, Aingorn Chaiyes, Narongrit Muangmai, Darren K. Griffin, Prateep Duengkae and Kornsorn Srikulnath
Genes 2025, 16(10), 1180; https://doi.org/10.3390/genes16101180 - 10 Oct 2025
Viewed by 222
Abstract
Background: The health and viability of captive elephants, which are central to off-site conservation efforts and health management in Thailand, is threatened by emerging infectious diseases. This is partly due to genetic differences in immune-related genes, especially in the major histocompatibility complex (MHC) [...] Read more.
Background: The health and viability of captive elephants, which are central to off-site conservation efforts and health management in Thailand, is threatened by emerging infectious diseases. This is partly due to genetic differences in immune-related genes, especially in the major histocompatibility complex (MHC) and, among these, loci such as DQA play a crucial role in immune surveillance. Data pertaining to MHC polymorphisms in elephants are scarce, and thus this study investigated such polymorphisms and selection signatures in a partial fragment of exon 2 of the MHC Class II DQA gene. Methods: The approach we used targeted next-generation sequencing and diversity analyses of individuals from three captive elephant camps in Northern Thailand. Results: Eight alleles containing 11 SNPs were identified in the exon 2 fragment, encompassing both silent and missense mutations, some of which may influence immune function. Notably, the allele Elma-DQA*TH3, which is identical to Loaf-DQA*01 and Elma-DQA*01, previously reported as the most common alleles in Loxodonta and Elephas, was found at low frequencies. This shift may reflect local selective pressures that shape MHC allele distributions. Evidence of mixed selection (both positive and balancing) was detected in the partial fragment of DQA exon 2, suggesting a dynamic interplay between evolutionary forces. Positive selection likely reflects an adaptation to emerging or locally prevalent pathogens, whereas balancing selection maintains allelic diversity over time to enable a broad immunological response. Conclusions: Our findings reveal immunogenetic variations in captive Thai elephants, and provides insights into host–pathogen interactions that inform conservation and health strategies with the aim of improving disease resilience. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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18 pages, 577 KB  
Article
Impact of Xenobiotic Detoxification Gene Polymorphisms on Steady-State Plasma Concentrations of Apixaban and the Development of Hemorrhagic Complications in Older Patients with Non-Valvular Atrial Fibrillation
by Andrey P. Kondrakhin, Sherzod P. Abdullaev, Ivan V. Sychev, Pavel O. Bochkov, Svetlana N. Tuchkova, Karin B. Mirzaev, Maksim L. Maksimov and Dmitry A. Sychev
Genes 2025, 16(10), 1179; https://doi.org/10.3390/genes16101179 - 10 Oct 2025
Viewed by 170
Abstract
Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual [...] Read more.
Background: Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia and is associated with a fivefold increase in stroke risk. Direct oral anticoagulants (DOACs), including apixaban, are now the preferred therapy for stroke prevention in patients with non-valvular AF (NVAF). However, interindividual variability in drug response and safety remains a major challenge, particularly in elderly patients with comorbidities and polypharmacy. Genetic polymorphisms in drug-metabolizing enzymes and transporters may contribute to variability in apixaban exposure and bleeding risk. This study aimed to evaluate the association of polymorphisms in ABCB1, CYP3A4, and CYP3A5 with steady-state plasma concentrations of apixaban (Cssmin) and hemorrhagic complications in elderly patients with NVAF. Methods: This cross-sectional study included 197 patients (mean age 83 ± 8 years; 67% women) with NVAF treated with apixaban (5 mg twice daily). Genotyping of ABCB1 (rs1045642, rs2032582, rs1128503), CYP3A4*22 (rs35599367), and CYP3A5*3 (rs776746) was performed using allele-specific real-time PCR. Cssmin of apixaban was determined by high-performance liquid chromatography coupled with tandem mass spectrometry. Associations with bleeding events were evaluated. Results: Bleeding events were recorded in 40 patients (20.3%). An association signal was observed for ABCB1 rs1045642, where carriers of the CC genotype had a higher risk of bleeding compared with alternative alleles (OR = 2.805; 95% CI: 1.326–5.935; p = 0.006). After correction for multiple testing, the association remained significant only under the log-additive model (OR = 1.93 per C allele; 95% CI: 1.17–3.20; q = 0.0275; p_adj = 0.044), while recessive and codominant effects did not withstand Bonferroni adjustment. No significant associations were observed for rs2032582, rs1128503, CYP3A4*22, or CYP3A5*3. None of the studied polymorphisms, including rs1045642, significantly affected Cssmin. Concomitant therapy, particularly with antiarrhythmic drugs and statins (rosuvastatin), also increased bleeding risk. Conclusions: The findings highlight the potential contribution of ABCB1 rs1045642 and specific drug–drug interactions to the risk of hemorrhagic complications in elderly NVAF patients receiving apixaban. Full article
(This article belongs to the Special Issue Pharmacogenomics and Personalized Treatment)
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31 pages, 5243 KB  
Article
Conserved Blood Transcriptome Patterns Highlight microRNA and Hub Gene Drivers of Neurodegeneration
by Jhyme Lou O. De La Cerna, Nicholas Dale D. Talubo, Brian Harvey Avanceña Villanueva, Po-Wei Tsai and Lemmuel L. Tayo
Genes 2025, 16(10), 1178; https://doi.org/10.3390/genes16101178 - 10 Oct 2025
Viewed by 287
Abstract
Background/Objectives: Neurodegenerative diseases (NDs) such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), and Amyotrophic Lateral Sclerosis (ALS) are clinically distinct but share overlapping molecular mechanisms. Methods: To identify conserved systemic signatures, we analyzed blood RNA-Seq datasets using Weighted Gene Co-Expression Network Analysis [...] Read more.
Background/Objectives: Neurodegenerative diseases (NDs) such as Alzheimer’s (AD), Parkinson’s (PD), Huntington’s (HD), and Amyotrophic Lateral Sclerosis (ALS) are clinically distinct but share overlapping molecular mechanisms. Methods: To identify conserved systemic signatures, we analyzed blood RNA-Seq datasets using Weighted Gene Co-Expression Network Analysis (WGCNA), differential expression, pathway enrichment, and miRNA–mRNA network mapping. Results: Two modules, the red and turquoise, showed strong preservation across diseases. The red module was enriched for cytoskeletal and metabolic regulation, while the turquoise module involved immune, stress-response, and proteostatic pathways. Discussion: Key hub genes, such as HMGCR, ACTR2, MYD88, PTEN, EP300, and regulatory miRNAs like miR-29, miR-132, and miR-146a, formed interconnected networks reflecting shared molecular vulnerabilities. The absence of classical heat shock proteins in preserved blood modules highlights tissue-specific expression differences between blood and neural systems. Several hub genes overlap with known pharmacological targets, suggesting potential in translational relevance. Conclusions: Together, these findings reveal conserved blood-based transcriptional modules that suggest parallel central neurodegenerative processes and may support future biomarker development and possible therapeutic exploration. Full article
(This article belongs to the Section Neurogenomics)
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18 pages, 586 KB  
Article
Genetic Alteration Profiling in North Macedonian Lung Cancer Patients
by Aleksandar Eftimov, Rubens Jovanovic, Slavica Kostadinova Kunovska, Magdalena Bogdanovska Todorovska, Boro Ilievski, Panche Zdravkovski, Selim Komina, Blagica Krstevska, Simonida Crvenkova, Marija Simonovska and Gordana Petrushevska
Genes 2025, 16(10), 1177; https://doi.org/10.3390/genes16101177 - 10 Oct 2025
Viewed by 92
Abstract
Background/Objectives: Late diagnosis and inefficient treatment regimens lead to poor prognosis, with a low 5-year survival rate for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). New targeted therapeutic agents can be developed and introduced only by first discovering new [...] Read more.
Background/Objectives: Late diagnosis and inefficient treatment regimens lead to poor prognosis, with a low 5-year survival rate for both non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). New targeted therapeutic agents can be developed and introduced only by first discovering new driver oncogenes and with a thorough investigation of the known driver genes. The aim of the current study is to investigate the prevalence of alterations in the eight most frequently altered genes in lung cancer—BRAF, EGFR, KRAS, ALK, ROS1, HER2, PD-L1 and PIK3CA. Methods: Real-time polymerase chain reaction (RT-PCR) was used to detect KRAS and EGFR mutations, multiplex PCR and microarray hybridization for KRAS/BRAF/PIK3CA mutations. Immunohistochemical analysis was performed for the detection of ALK, HER2/NEU, ROS-1 and PD-L1 alterations. Results: Overall, 221/603 patients (36.65%) had at least one genetic alteration, of which 22 patients (3.65%) had two genetic alterations and two patients had more than two genetic alterations. Additionally, 50 patients were identified with one or more KRAS mutations (8.29%), 45 patients with EGFR mutations (7.46%), and 1.82% with PIK3CA mutations and 0.66% with BRAF mutations. Furthermore, 50% of the co-occurring alterations were either on KRAS and PIK3CA genes (3/6), on KRAS and BRAF genes (2/6, 33.33%) or on EGFR and PIK3CA genes (1/6, 16.67%), and 10.45% of the patients exhibited PD-L1 overexpression, 5.31% ALK rearrangements, and 2.36% HER2/NEU expression, with no ROS-1 rearrangements detected. Conclusions: Comprehensive testing for somatic alterations in EGFR, BRAF, KRAS, and PIK3CA is significant in guiding therapeutic decisions in lung cancer management. Such testing should be routinely conducted to establish a thorough genetic profile of lung cancers in a manner that is both time-efficient and cost-effective. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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13 pages, 5646 KB  
Article
Analysis of the TGF-β1 of a Tibetan Plateau Schizothoracine Fish (Gymnocypris dobula) Revealed Enhanced Cytoprotection in Hypoxic Environments
by Ziyu Le, Xiaohui Wu, Yang Liu, Qianghua Xu and Congcong Wang
Genes 2025, 16(10), 1176; https://doi.org/10.3390/genes16101176 - 10 Oct 2025
Viewed by 158
Abstract
Background: The Tibetan Plateau, which is known for its high elevation and low oxygen levels, presents a challenging environment for its inhabitants. To adapt to these hypoxic conditions, species of Schizothoracine, a subfamily of Cyprinidae, have developed unique physiological mechanisms and [...] Read more.
Background: The Tibetan Plateau, which is known for its high elevation and low oxygen levels, presents a challenging environment for its inhabitants. To adapt to these hypoxic conditions, species of Schizothoracine, a subfamily of Cyprinidae, have developed unique physiological mechanisms and functions. Transforming growth factor-β (TGF-β) is a multifunctional cytokine involved in the regulation of cell growth, differentiation, apoptosis, and the cellular immune response. However, its specific role in adaptation to hypoxia remains poorly understood. Methods: In this study, we aimed to characterize the TGF-β1 gene in Gymnocypris dobula (Gd) and Schizothorax prenanti (Sp) and to test whether TGF-β1 contributes to hypoxia adaptation in plateau Schizothoracine fish. The predicted protein for Gd-TGF-β1 contains several primary domains, including cwf21 (cdc5 protein 21), GYF (Glycine-Tyrosine-Phenylalanine), FN1 (Fibronectin 1), a conservative domain, and a signal peptide. Results: The results of tissue distribution revealed that the mRNA level of TGF-β1 in brain, heart, muscle, skin, gills, and spleen—which are key tissues involved in oxygen sensing, transport, and physiological adaptation to hypoxic environments—was significantly lower in G. dobula than that in S. prenanti. Western blotting analysis revealed that the expression of activated TGF-β1 in G. dobula was significantly higher than that in S. prenanti. To investigate whether TGF-β1 in G. dobula possesses hypoxic adaptive features, Gd-TGF-β1 and Sp-TGF-β1 were cloned into an expression vector and transfected into 293-T cells, which are widely used due to their ease of culture, high transfectability, and well-characterized properties. We found that the survival rate of cells transfected with Gd-TGF-β1 was significantly higher than that of cells transfected with Sp-TGF-β1 after hypoxia treatment. Conclusions: These findings suggest that G. dobula may promote hypoxic adaptation through the activation and increased expression of TGF-β1. Changes in TGF-β1 expression may play a role in the adaptation of G. dobula to hypoxic conditions. Full article
(This article belongs to the Section Animal Genetics and Genomics)
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17 pages, 6547 KB  
Article
Unraveling Phylogenetic Relationships Among Six Miscanthus Andersson (Poaceae) Species Through Chloroplast Genome Analysis
by Ji Eun Kim, Yang Su Kim, Gyu Young Chung, Hyeok Jae Choi, Chang-Gee Jang, Hoe Jin Kim and Chae Sun Na
Genes 2025, 16(10), 1175; https://doi.org/10.3390/genes16101175 - 10 Oct 2025
Viewed by 189
Abstract
Background/Objectives: Miscanthus Andersson, a genus of perennial grasses that includes wild relatives of key crop species, remains poorly characterized in terms of genetic diversity and evolutionary relationships. The aim of this study was to elucidate the phylogenetic structure of Miscanthus through comparative genomic [...] Read more.
Background/Objectives: Miscanthus Andersson, a genus of perennial grasses that includes wild relatives of key crop species, remains poorly characterized in terms of genetic diversity and evolutionary relationships. The aim of this study was to elucidate the phylogenetic structure of Miscanthus through comparative genomic analysis of the chloroplast genomes of six Korean species. Methods: Complete chloroplast genomes were assembled and analyzed for six Miscanthus species. Informative nucleotide motifs and their associated gene locations were identified as potential markers, and their phylogenetic relationships with related crops were examined. Results: The chloroplast genomes exhibited a conserved quadripartite structure, with genome sizes and GC contents within typical ranges. Analysis of codon usage showed a preference for A/U-ending codons, consistent with patterns in other angiosperms. Simple sequence repeats and long repeats demonstrated non-random distributions, indicating their value as molecular markers for phylogenetic and population studies. Comparative analyses confirmed structural conservation across Miscanthus species, whereas variation in non-coding regions provided important phylogenetic signals. Phylogenetic reconstruction based on 21 chloroplast genomes revealed four major clades, corroborating previous findings and highlighting complex evolutionary relationships within Miscanthus, including close affinities between African and Himalayan species and the genus Saccharum L. Conclusions: This study provides complete chloroplast genomes of six Miscanthus species, contributing to enhanced understanding of the relationships within the subtribe Saccharinae. The findings support the inclusion of Miscanthus species in the Korea Crop Wild Relatives inventory and highlight their potential as a genetic resource for breeding programs aimed at enhancing crop resilience to environmental stress. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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19 pages, 2308 KB  
Article
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
Viewed by 251
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  
Review
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
Viewed by 401
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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16 pages, 3299 KB  
Article
Association Mapping for Biomass and Kernel Traits in Doubled-Haploid Population Derived from Texas Wheat Cultivars
by Yahya Rauf, Zhen Wang, Kyle Parker, Shannon A. Baker, Jason A. Baker, Jackie C. Rudd, Qingwu Xue, Amir Ibrahim and Shuyu Liu
Genes 2025, 16(10), 1172; https://doi.org/10.3390/genes16101172 - 5 Oct 2025
Viewed by 807
Abstract
Background: Genetic improvement in wheat yield is the most focused research area for the breeding community to ensure sustainable production. Wheat kernel traits and biomass are considered key contributors to enhance crop yield. Methods: This study was designed to explore the genetic diversity [...] Read more.
Background: Genetic improvement in wheat yield is the most focused research area for the breeding community to ensure sustainable production. Wheat kernel traits and biomass are considered key contributors to enhance crop yield. Methods: This study was designed to explore the genetic diversity of kernel and biomass traits in popular wheat varieties from the US Southern Great Plains using 264 doubled haploid (DH) lines mainly derived from TAM 114 or TAM 204. This population was evaluated in two field environments planted in alpha lattice design during the 2020 crop season. Kernel traits were collected using the hp Scanjet G4010 photo scanner for image capturing and GrainScan v3. software for image analysis. Biomass parameters were collected and processed manually. For genotyping genomic libraries were prepared and sequenced on Illumina NovaSeq 6000 to generate paired end reads of 150 bp. Sequences were aligned to the IWGSC RefSeq genome assembly v2.1 using the Burrows Wheeler Aligner for SNP calling. Results: A total of 59,482 polymorphic SNP markers were retained for genetic analysis after the filtration at 50% missing data and 5% minor allele frequency. To investigate the marker–trait association and the genomic regions, four genome-wide association study models were implemented using the R package GAPIT version 3.5. Based on the Bonferroni correction <8.41 × 10−7 was used as a threshold to declare marker-trait associations (MTAs) significant. The BLINK model identified 12 MTAs on chromosomes 1A, 2A, 2B, 4A, 4B, and 6B. Conclusions: The identified MTAs can be used to develop diagnostic markers for efficient selection and utilization in recombination breeding and cultivar development process. Full article
(This article belongs to the Section Plant Genetics and Genomics)
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8 pages, 570 KB  
Review
Genetic and Molecular Insights into the Links Between Heat Stroke, Alzheimer’s Disease, and Down Syndrome: A Mini-Review
by Hisahide Nishio, Hirokuni Negishi, Hiroyuki Awano and Jumpei Oba
Genes 2025, 16(10), 1171; https://doi.org/10.3390/genes16101171 - 5 Oct 2025
Viewed by 333
Abstract
Both epidemiological and animal model studies have revealed that heat stroke is closely related to the development or exacerbation of dementia disorders. The most common form of dementia is Alzheimer’s disease, which is characterized by the accumulation of amyloid-β protein in the central [...] Read more.
Both epidemiological and animal model studies have revealed that heat stroke is closely related to the development or exacerbation of dementia disorders. The most common form of dementia is Alzheimer’s disease, which is characterized by the accumulation of amyloid-β protein in the central nervous system. Notably, a whole-genome transcriptome analysis of heat stroke patients has identified the increased expression of amyloid-β precursor protein gene and the activation of amyloid processing pathways. This finding provides a molecular basis for the theory that heat stroke is a risk factor for dementia disorders. Down syndrome—a common chromosomal abnormality—is also a dementia disorder that is characterized by the overexpression of amyloid-β precursor protein gene and the accumulation of amyloid-β protein. Thus, heat stroke may also develop or exacerbate Alzheimer’s disease-like dementia in Down syndrome. For individuals with Down syndrome, heat stroke is therefore not only a life-threatening risk factor but may also be a risk factor for accelerating intellectual decline. Full article
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14 pages, 2539 KB  
Article
Transcriptomic and Clinical Profiling Reveals LGALS3 as a Prognostic Oncogene in Pancreatic Cancer
by Grazia Scuderi, Sanja Mijatovic, Danijela Maksimovic-Ivanic, Michelino Di Rosa, José Francisco Muñoz-Valle, Alexis Missael Vizcaíno-Quirarte, Gian Marco Leone, Katia Mangano, Paolo Fagone and Ferdinando Nicoletti
Genes 2025, 16(10), 1170; https://doi.org/10.3390/genes16101170 - 3 Oct 2025
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Abstract
Background/Objectives: Galectin-3 (Gal-3), encoded by LGALS3, is a β-galactoside-binding lectin involved in diverse tumor-associated processes, including immune modulation, cell cycle regulation, and stress adaptation. Despite its known roles in cancer biology, the full extent of its molecular functions and prognostic relevance across [...] Read more.
Background/Objectives: Galectin-3 (Gal-3), encoded by LGALS3, is a β-galactoside-binding lectin involved in diverse tumor-associated processes, including immune modulation, cell cycle regulation, and stress adaptation. Despite its known roles in cancer biology, the full extent of its molecular functions and prognostic relevance across tumor types remains incompletely understood. This study aimed to systematically investigate the transcriptomic impact of LGALS3 deletion and assess its clinical significance in cancer. Methods: We analyzed CRISPR-Cas9 knockout transcriptomic data from the SigCom LINCS database to characterize the consensus gene signature associated with LGALS3 loss using functional enrichment analyses. Pan-cancer survival analyses were conducted using TIMER2.0. Differential Gal-3 protein levels in ductal adenocarcinoma and normal pancreatic tissues were evaluated using the Human Protein Atlas. Finally, functional analyses were performed in pancreatic ductal adenocarcinoma (PDAC). Results: LGALS3 deletion across multiple cancer cell lines led to transcriptomic changes involving mitotic progression, stress responses, and axonal guidance pathways. High LGALS3 expression was significantly associated with worse overall survival in lower-grade glioma, PDAC, uveal melanoma, and kidney renal papillary cell carcinoma. LGALS3 knockout in YAPC cells recapitulated the pan-cancer findings, linking LGALS3 to cell morphogenesis and proliferation. Conclusions: These findings identify Galectin-3 as a key regulator of oncogenic programs and a potential prognostic biomarker in PDAC and other malignancies, with implications for therapeutic targeting. Full article
(This article belongs to the Section Human Genomics and Genetic Diseases)
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Article
Blackgrass (Alopecurus myosuroides Huds.) Multiple Resistance to ACCase- and ALS-Inhibitors and Its Competition with Winter Wheat
by Aristeidis P. Papapanagiotou, Ioannis Vasilakoglou, Maria V. Alvanou, Ioannis A. Giantsis, Panagiotis Madesis and Ilias G. Eleftherohorinos
Genes 2025, 16(10), 1169; https://doi.org/10.3390/genes16101169 - 3 Oct 2025
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Abstract
Background/Objectives: The herbicide resistance of blackgrass (Alopecurus myosuroides Huds.) is one of the most serious problems in the winter cereal monoculture in Europe. Recently, Greek farmers expressed complaints of reduced susceptibility of this weed to winter wheat herbicides. Keeping this in mind, [...] Read more.
Background/Objectives: The herbicide resistance of blackgrass (Alopecurus myosuroides Huds.) is one of the most serious problems in the winter cereal monoculture in Europe. Recently, Greek farmers expressed complaints of reduced susceptibility of this weed to winter wheat herbicides. Keeping this in mind, this study focused on the investigation of blackgrass resistance to herbicides at both phenotypic and molecular levels. Methods: Whole-plant rate-response pot assays were conducted to study the possible evolution of resistance (cross- or multiple-resistance) in a blackgrass population to ACCase- and ALS-inhibiting herbicides. Analysis of the ACCase gene sequence, herbicide metabolism study and competition with winter wheat studies were also conducted. Results: High levels of cross-resistance mainly to the ACCase post-emergence clodinafop-propargyl, medium to fenoxaprop-P-ethyl, cycloxydim, pinoxaden, as well as lower levels of resistance to ALS-inhibitors (mesosulfuron-methyl + iodosulfuron-methyl-sodium and pyroxsulam) were confirmed. In addition, the pre-emergence soil-applied herbicides chlorotoluron + diflufenican and prosulfocarb provided excellent control of the S and R blackgrass populations. The analysis of the ACCase gene sequence revealed a point mutation at position 1781, resulting in an amino acid substitution from isoleucine (Ile) to leucine (Leu). Furthermore, the combined application of the herbicides with piperonyl butoxide (PBO, applied 2 h before herbicide application) indicated that there was herbicide metabolism, which may be mediated by cytochrome P450. The R blackgrass population, when grown in competitive interaction with winter wheat, produced more tillers and aboveground fresh weight compared to the S population and caused greater reduction in winter wheat. Conclusions: The results suggest that a blackgrass population has developed multiple resistance to ACCase- and ALS-inhibiting herbicides, due to ACCase gene mutation and herbicide metabolism. No fitness cost and no compromised competitive ability associated with the blackgrass resistance were observed. Full article
(This article belongs to the Special Issue Forage and Grass Genetics and Genomics)
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