Genes

21 pages, 1288 KB

Open AccessReview

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

Open AccessArticle

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

Open AccessReview

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

Open AccessArticle

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

Open AccessArticle

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

Open AccessReview

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

Open AccessArticle

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

Open AccessReview

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

Open AccessReview

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

Open AccessArticle

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

Open AccessArticle

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

Open AccessArticle

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

Open AccessArticle

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

Open AccessReview

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

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

(This article belongs to the Special Issue Inherited Retinal Dystrophies: Genetic Basis, Genetic Diagnosis and Therapy)

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14 pages, 1741 KB

Open AccessArticle

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

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

Open AccessBrief 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

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

Open AccessArticle

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

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

Open AccessArticle

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

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

Open AccessArticle

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

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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