Genes

14 pages, 1838 KB

Open AccessArticle

Association of Obesity-Related Genetic Variants with Android Fat Patterning and Cardiometabolic Risk in Women

by Débora Sá, Maria Isabel Mendonça, Francisco Sousa, Gonçalo Abreu, Matilde Ferreira, Eva Henriques, Sónia Freitas, Mariana Rodrigues, Sofia Borges, Graça Guerra, António Drumond, Ana Célia Sousa and Roberto Palma dos Reis

Genes 2025, 16(9), 1019; https://doi.org/10.3390/genes16091019 - 28 Aug 2025

Abstract

Background/Objectives: The location and distribution of excess fat, rather than overall adiposity, are stronger predictors of cardiometabolic risk and are commonly assessed using the waist-to-hip ratio (WHR). Fat distribution in women has a heritable component, yet the genetic factors that influence it remain [...] Read more.

Background/Objectives: The location and distribution of excess fat, rather than overall adiposity, are stronger predictors of cardiometabolic risk and are commonly assessed using the waist-to-hip ratio (WHR). Fat distribution in women has a heritable component, yet the genetic factors that influence it remain poorly understood. We aim to assess the association between obesity-related polymorphisms with WHR and cardiometabolic risk in overweight and obese women. Methods: A cohort study was conducted in 512 women (56.1 ± 6.4 years; body mass index (BMI) ≥ 25 kg/m²). WHR was calculated, and participants were classified into android (WHR > 0.85) or gynoid (WHR ≤ 0.85) obesity groups. We genotyped 15 SNPs previously associated with obesity using TaqMan real-time PCR. Different genetic models (dominant, recessive, and allelic) were analysed, and bivariate and multivariate analyses were performed to compare the fat distribution groups. Results: Of the 15 SNPs studied, only 3 presented a significant association with WHR > 0.85. PSRC1 rs599839 in a dominant model (AA + GA vs. GG) with OR = 3.18 (p = 0.041), SLC30A8 rs1326634 in a recessive model (CC vs. TC + TT) (OR = 2.38; p = 0.004), both showing increased susceptibility to central obesity. KIF6 rs20455 offers protection in a recessive model (CC vs. TC + TT) with an OR of 0.47 (p = 0.043). After adjusted multivariate analysis, only SLC30A8 and diabetes remained independently associated with an increased risk of android obesity (OR = 2.50; p = 0.003 and OR = 3.63; p = 0.004, respectively). Conclusions: The SLC30A8 variant was significantly associated with android fat distribution and high cardiometabolic risk in overweight/obese women. Identifying genetic factors that influence fat distribution may help specify targeted lifestyle changes or pharmacological interventions to reduce risk. Full article

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

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13 pages, 3091 KB

Open AccessArticle

Identification of Novel Gene Cluster Potentially Associated with Insecticide Resistance in Anopheles gambiae s.l.

by Hyacinthe Dipina Ki, Mahamadi Kientega, Sabéré O. G. Yemien, Hamidou Maiga, Nouhoun Traoré, Koama Bayili, Moussa Namountougou and Abdoulaye Diabaté

Genes 2025, 16(9), 1018; https://doi.org/10.3390/genes16091018 - 28 Aug 2025

Abstract

Background/Objectives: Despite the increasing emergence of resistance, insecticide-based tools remain the primary method for malaria vector control in Africa. To maintain the effectiveness of these interventions, continuous monitoring and identification of novel resistance mechanisms is essential. This study aimed to investigate potential new [...] Read more.

Background/Objectives: Despite the increasing emergence of resistance, insecticide-based tools remain the primary method for malaria vector control in Africa. To maintain the effectiveness of these interventions, continuous monitoring and identification of novel resistance mechanisms is essential. This study aimed to investigate potential new insecticide resistance genes in the Anopheles gambiae complex. Methods: We analyzed whole-genome sequencing data from the An. gambiae 1000 Genomes Project. A broad range of genomic analysis techniques and tools were used to identify and explore genetic variation in the candidate resistance genes. Results: High haplotype homozygosity values, indicative of positive selection, were detected in a 2L chromosomal region corresponding to an aldehyde oxidase gene cluster (AGAP006220, AGAP006221, AGAP006224, AGAP006225, AGAP006226). Single nucleotide polymorphisms (SNPs) have been identified in these genes with frequencies up to 100%, including 569, 691, 1433, 978, and 811 non-synonymous SNPs in AGAP006220, AGAP006221, AGAP006224, AGAP006225, and AGAP006226, respectively. Copy number variations (CNVs) such as deletions and amplifications were also identified at low frequencies (<12%). Population structure analyses revealed adaptive and geographic gene flow between An. gambiae and An. coluzzii. Conclusions: This study provides evidence that aldehyde oxidase genes may contribute to insecticide resistance in An. gambiae s.l. populations. These results highlight the importance of genomic surveillance for detecting novel resistance loci and guiding the development of improved vector control strategies under changing ecological and evolutionary conditions. Full article

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

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14 pages, 3164 KB

Open AccessArticle

Chloroplast Genome Evolution and Codon Usage In the Medicinal Plant Pothos chinensis (Araceae)

by Hua Chen and Jisi Zhang

Genes 2025, 16(9), 1017; https://doi.org/10.3390/genes16091017 - 28 Aug 2025

Abstract

Background/Objectives: Pothos chinensis is commonly used as traditional medicine in China and India. Codon usage analysis is a good way to understand plants’ evolution. However, there is no report about the codon usage bias of chloroplast genomes in P. chinensis. Methods: In [...] Read more.

Background/Objectives: Pothos chinensis is commonly used as traditional medicine in China and India. Codon usage analysis is a good way to understand plants’ evolution. However, there is no report about the codon usage bias of chloroplast genomes in P. chinensis. Methods: In this study, the chloroplast genome of the medicinal plant P. chinensis was newly obtained. Comparative analyses, DNA barcoding investigation, codon usage bias, and phylogenetic reconstruction were conducted to reveal the chloroplast genome characteristics of P. chinensis. Results: The length of the chloroplast genome of P. chinensis was 165,165 bp. A total of 134 genes were annotated, i.e., 90 protein-coding genes, 36 transfer RNA genes, and eight ribosomal RNA genes. Compared to its sister group Anthurium andraeanum, the length of the large single-copy region (LSC) had been expanded, while the small single-copy region (SSC) had been contracted. Within P. chinensis and P. scandens there were no obvious differences in the length of LSC, SSC, and two inverted repeat regions. Based on Pi values, seven hypervariable regions of whole plastomes were identified. The analysis of codons showed that an average frequency of the 50 candidate genes was 35.30%, and these genes preferred A/U-ending codons. The average effective number of codon (ENC) value was 45.49, which indicated weak codon usage bias. ENCs had a highly significant positive correlation with GC3. Fourteen optimal codons had been identified, 11 of which ended with A/U. The results of the neutrality plot, ENC-plot, and PR2-plot analysis indicated that natural selection might have a significant impact on codon usage patterns. Conclusions: Taken together, our study unraveled the codon usage patterns in P. chinensis and provided valuable genetic information for the genus Pothos. Full article

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

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25 pages, 4801 KB

Open AccessArticle

Genotype–Phenotype Correlations in PRPH2 Retinopathies: A Comprehensive Analysis of 36 Patients from the Oxford Eye Hospital, UK

by Saoud Al-Khuzaei, Mital Shah, Arun Reginald, Edna Baba, Morag Shanks, Penny Clouston, Robert E. MacLaren, Stephanie Halford, Samantha R. De Silva and Susan M. Downes

Genes 2025, 16(9), 1016; https://doi.org/10.3390/genes16091016 - 27 Aug 2025

Abstract

Purpose: To investigate genotype–phenotype correlations in PRPH2-retinopathies in a cohort of 36 patients from the Oxford Eye Hospital and report on novel pathogenic variants. Methods: Clinical data, including best corrected visual acuities (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) imaging, [...] Read more.

Purpose: To investigate genotype–phenotype correlations in PRPH2-retinopathies in a cohort of 36 patients from the Oxford Eye Hospital and report on novel pathogenic variants. Methods: Clinical data, including best corrected visual acuities (BCVA), fundus autofluorescence (FAF), and optical coherence tomography (OCT) imaging, were analysed. Genetic testing was performed using next-generation sequencing (NGS). Results: In this cohort, 26 different PRPH2 variants, including 8 novel variants, were identified. Variants were clustered in the D2 loop of the protein. A diverse range of phenotypes were observed: pseudo-Stargardt pattern dystrophy (PSPD) (47.2%), adult-onset vitelliform macular dystrophy (AVMD) (22.2%), pattern dystrophy (PD) (25.0%), atypical macular dystrophy (2.8%), and retinitis pigmentosa (RP) (2.8%). The mean age of symptom onset was 44.0 ± 14.4 years. Mean BCVA was 0.20 ± 0.54 logMAR OD and 0.14 ± 0.29 logMAR OS at baseline and 0.33 ± 0.40 logMAR OD and 0.32 ± 0.40 logMAR OS after a mean follow up duration of 6.0 ± 3.2 years (range 1–11 years). A thickened ellipsoid zone (EZ) was noted in 34/36 patients with a mean EZ thickness of 44.3 ± 11.3 µm OD and 42.7 ± 11.6 µm OS. No clear genotype–phenotype correlations were observed. Conclusions: The significant phenotypic range described in this study is consistent with the previously reported phenotypic variability in PRPH2 retinopathy and emphasises the complexity of establishing genotype–phenotype correlations in this disease. The thickness of the EZ on OCT may serve as a useful biomarker in distinguishing PRPH2 retinopathy from other phenocopies. These findings contribute to improved understanding of PRPH2 retinopathy and help inform diagnosis and genetic counselling. Full article

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

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12 pages, 728 KB

Open AccessReview

Obesity and the Genome: Emerging Insights from Studies in 2024 and 2025

by Lindsey G. Yoo, Courtney L. Bordelon, David Mendoza and Jacqueline M. Stephens

Genes 2025, 16(9), 1015; https://doi.org/10.3390/genes16091015 - 27 Aug 2025

Abstract

Obesity is an epidemic that currently impacts many nations. The persistence of this disease is shaped by both genetic and epigenetic factors that extend beyond calorie balance. Research in the past year has revealed that epigenetic and cellular memory within adipose tissue can [...] Read more.

Obesity is an epidemic that currently impacts many nations. The persistence of this disease is shaped by both genetic and epigenetic factors that extend beyond calorie balance. Research in the past year has revealed that epigenetic and cellular memory within adipose tissue can predispose individuals to weight regain after initial fat loss, as shown by studies indicating persistent transcriptional and chromatin changes even after fat mass reduction. Independent studies also demonstrate long-lasting metabolic shifts, such as those triggered by glucose-dependent insulinotropic polypeptide receptor (GIPR)-induced thermogenesis and sarcolipin (SLN) stabilization that also support a form of “metabolic memory” that is associated with sustained weight loss. At the neural level, rare variants in synaptic genes like BSN (Bassoon presynaptic cytomatrix protein), a presynaptic scaffold protein, and APBA1 (amyloid beta precursor protein binding family A member 1), a neuronal adaptor involved in vesicular trafficking, disrupt communication in feeding circuits, elevating obesity risk and illustrating how synaptic integrity influences food intake regulation. Similarly, the spatial compartmentalization of metabolic signaling within neuronal cilia is emerging as crucial, with cilia-localized receptors G protein-coupled receptor 75 (GPR75) and G protein-coupled receptor 45 (GPR45) exerting opposing effects on energy balance and satiety. Meanwhile, genome-wide association studies (GWAS) have advanced through larger, more diverse cohorts and better integration of environmental and biological data. These studies have identified novel obesity-related loci and demonstrated the value of polygenic risk scores (PRS) in predicting treatment responses. For example, genetic variants in GLP-1R (glucagon-like peptide-1 receptor) and GIPR (glucose-dependent insulinotropic polypeptide receptor) may modulate the effectiveness of incretin-based therapies, while PRS for satiation can help match individuals to the most appropriate anti-obesity medications. This review focuses on studies in the last two years that highlight how advances in obesity genetics are driving a shift toward more personalized and mechanism-based treatment strategies. Full article

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

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19 pages, 968 KB

Open AccessReview

Beyond TLR4 and Its Alternative Lipopolysaccharide (LPS) Sensing Pathways in Zebrafish

by Dara V. Grebennikova, Umesh K. Shandilya and Niel A. Karrow

Genes 2025, 16(9), 1014; https://doi.org/10.3390/genes16091014 - 27 Aug 2025

Abstract

Due to their evolutionary divergence from mammals, zebrafish (Zf, Danio rerio), which are frequently employed in biomedical research, provide a distinctive viewpoint on innate immune systems. The Toll-like receptor 4/myeloid differentiation factor 2/cluster of differentiation 14 (TLR4/MD-2/CD14) complex in mammals detects lipopolysaccharide [...] Read more.

Due to their evolutionary divergence from mammals, zebrafish (Zf, Danio rerio), which are frequently employed in biomedical research, provide a distinctive viewpoint on innate immune systems. The Toll-like receptor 4/myeloid differentiation factor 2/cluster of differentiation 14 (TLR4/MD-2/CD14) complex in mammals detects lipopolysaccharide (LPS), a crucial component of Gram-negative bacteria, and it causes potent inflammatory reactions through a Toll/interleukin-1 receptor domain-containing adapter-inducing interferon-β (TRIF)-dependent and myeloid differentiation primary response 88 (MyD88)-dependent pathways. However, key components of this system, such as a responsive TLR4 axis and a functional CD14 ortholog, are absent in Zf. The Zf species nevertheless reacts to LPS, which leads to research into other recognition systems. This review looks at a number of TLR4-independent processes in Zf, such as scavenger receptors (SRs) including scavenger receptor class B type 1 (SR-BI) and cluster of differentiation 36 (CD36), nucleotide-binding oligomerization domain-containing protein 1 (NOD1)-dependent cytosolic sensing, peptidoglycan recognition proteins (PGRPs), Complement Component 3 (C3), and caspase-1-like protein 2 (Caspy2)-mediated inflammasome activation. An alternative and flexible immune system that makes up for the lack of canonical TLR4 signaling is revealed by these mechanisms. Additionally, the discovery of lymphocyte antigen 96 (ly96), an ortholog of MD-2 found in Zf, suggests evolutionary similarity; however, as it is only functional in artificial systems, it demonstrates minimal overlap with mammalian MD-2 activity. Knowing these pathways provides important information for studying inflammation, infection, and immunological modulation in vertebrates using Zf as a model. It also clarifies the evolutionary flexibility of innate immune recognition. Full article

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

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19 pages, 10808 KB

Open AccessArticle

Expression Pattern of Dab1, Reelin, PGP9.5 and Sox2 in the Stomach of Yotari (Dab1^−/−) Mice

by Petar Todorović, Nela Kelam, Anita Racetin, Natalija Filipović, Yu Katsuyama, Mirna Saraga-Babić and Katarina Vukojević

Genes 2025, 16(9), 1013; https://doi.org/10.3390/genes16091013 - 27 Aug 2025

Abstract

Background/Objectives: The Reelin–Dab1 signaling pathway, known for its crucial role in neurodevelopment, particularly in neuronal migration and the formation of cortical layers, has been a subject of extensive research. However, its involvement in gastrointestinal organogenesis is a relatively unexplored area. Our study [...] Read more.

Background/Objectives: The Reelin–Dab1 signaling pathway, known for its crucial role in neurodevelopment, particularly in neuronal migration and the formation of cortical layers, has been a subject of extensive research. However, its involvement in gastrointestinal organogenesis is a relatively unexplored area. Our study investigates the expression patterns of Dab1, Reelin, PGP9.5, and Sox2 during stomach development in yotari (Dab1^−/−) mice and aims to shed light on how Dab1 inactivation affects epithelial–mesenchymal signaling dynamics, thereby contributing to a deeper understanding of this pathway’s non-neural functions. Methods: Embryonic stomach tissues from yotari and wild-type mice, collected at developmental stages E13.5 and E15.5, were examined by immunofluorescenceto evaluate the difference in expression of Dab1, Reelin, PGP9.5, and Sox2. Semi-quantitative scoring and quantitative image analysis were used to assess protein localization and intensity within epithelial and mesenchymal compartments. Results: Dab1 expression was significantly increased in both the epithelium and mesenchyme of yotari mice at E13.5 and E15.5. Reelin expression in the epithelium showed a visible but statistically non-significant decrease in yotari at E15.5, while mesenchymal expression remained low and significantly lower than controls. PGP9.5 expression was significantly reduced in yotari epithelium at E13.5, then strongly upregulated at E15.5. Mesenchymal PGP9.5 remained consistently high. Sox2 showed no statistically significant changes but increased semi-quantitatively in yotari epithelium and mesenchyme at E15.5. These findings highlight compartment-specific disruptions and potential compensatory mechanisms following Dab1 inactivation. Conclusions: Our findings indicate that Dab1 deficiency leads to distinct molecular changes in epithelial and mesenchymal compartments of the developing stomach. The Reelin–Dab1 axis appears critical for epithelial–mesenchymal coordination, while PGP9.5 and Sox2 upregulation in yotari mice may represent potential compensatory responses that could support epithelial integrity, although this remains speculative without functional validation. Full article

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

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17 pages, 4201 KB

Open AccessArticle

Genetic Characterization of Primordial Germ Cells in Spotted Sea Bass (Lateolabrax maculatus)

by Jieyun Guo, Lulu Yan, Chao Zhao, Bo Zhang, Bo Zhang and Lihua Qiu

Genes 2025, 16(9), 1012; https://doi.org/10.3390/genes16091012 - 27 Aug 2025

Abstract

Background: Primordial germ cells (PGC) are the progenitor cells of sperm and eggs during the embryonic stage. The maternal gene vasa has been widely studied for its role in PGC origin, and other genes like dead end (dnd) have also been identified. Objectives: [...] Read more.

Background: Primordial germ cells (PGC) are the progenitor cells of sperm and eggs during the embryonic stage. The maternal gene vasa has been widely studied for its role in PGC origin, and other genes like dead end (dnd) have also been identified. Objectives: Spotted sea bass is an important economic marine fish, and the study of its germ cell characteristics provides important basic data for future population breeding and protection. Methods: In this study, we cloned the full-length sequences of Lmvasa (2384 bp, encoding 1905 aa) and Lmdnd (1523 bp, encoding 386 aa) using RACE. Temporal and spatial expression patterns of Lmvasa and Lmdnd in embryos and gonads were analyzed by PCR, immunohistochemistry, and in situ hybridization. We also used microinjections of chimeric RNA containing GFP and Lmvasa 3′ UTR to visualize PGCs. Results: Our results showed that Lmvasa and Lmdnd are expressed primarily in early embryonic development (pre-blastula stage) and were expressed only in the gonads. Immunohistochemistry revealed abundant expression of Lmvasa and Lmdnd proteins in spermatogonia, weak expression in spermatocytes, and no expression in spermatozoa. In ovaries, both genes were expressed throughout oogenesis. Furthermore, PGCs in spotted sea bass belonged to an early localization pattern. Microinjection experiments demonstrated that Lmvasa 3′ UTR effectively labeled PGCs in embryos of spotted sea bass, zebrafish, and medaka. Conclusions: These findings may contribute to understanding PGC development in spotted sea bass and other Percidae. Full article

(This article belongs to the Special Issue Molecular Genetics Applied to Aquaculture: From Breeding Stock Selection to Biotechnological Innovations)

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20 pages, 364 KB

Open AccessReview

CSN1S1 and CSN1S2: Two Remarkable Examples of Genetically Modulated Alternative Splicing via Identification of Allele-Specific Splicing Events

by Gianfranco Cosenza, Andrea Fulgione, Emanuele D’Anza, Sara Albarella, Francesca Ciotola and Alfredo Pauciullo

Genes 2025, 16(9), 1011; https://doi.org/10.3390/genes16091011 - 27 Aug 2025

Abstract

Splicing regulatory sequences are cornerstones for exon recognition. Mutations that modify them can severely compromise mRNA maturation and protein production. A wide range of mutations, including SNPs and InDels, can influence splicing regulatory signals either directly (e.g., altering canonical donor and acceptor dinucleotides) [...] Read more.

Splicing regulatory sequences are cornerstones for exon recognition. Mutations that modify them can severely compromise mRNA maturation and protein production. A wide range of mutations, including SNPs and InDels, can influence splicing regulatory signals either directly (e.g., altering canonical donor and acceptor dinucleotides) or indirectly (e.g., creating cryptic splice sites). CSN1S1 and CSN1S2 genes encode for the two main milk proteins, αs1 and αs2 caseins, respectively. They represent a remarkable and unique example of the possibilities for alternative splicing of individual genes, both due to the high number of alternative splices identified to date and for recognized allele-specific splicing events. To date, at least 13 alleles of CSN1S1 originating from mutations that affect canonical splice sites have been described in Bos taurus (CSN1S1 A, A1, and H), Ovis aries (E, H, and I), Capra hircus (D and G), Bubalus bubalis (E, F) and Camelidae (A, C, and D). Similarly, allele-specific splicing events have been described at the CSN1S2 locus in B. taurus. (CSN1S2 D), C. hircus (CSN1S2 D), B. bubalis (CSN1S2 B, B1, and B2), Equus asinus (CSN1S2 I B), and Camelidae. This review highlights that mutations affecting canonical splice sites, particularly donor sites, are significant sources of genetic variation impacting the casein production of the main dairy livestock species. Currently, a key limitation on this topic is the lack of detailed functional and proteomic studies. Future research should leverage advanced omics technologies like long-read transcriptomics and allele-resolved RNA sequencing to characterize these splicing mechanisms, guiding precision breeding strategies. Full article

(This article belongs to the Special Issue The 15th Anniversary of Genes: Feature Papers in the "Animal Genetics and Genomics" Section)

16 pages, 272 KB

Open AccessReview

Pharmacogenetics Approach for Personalized Tacrolimus Dosing in Heart Transplantation: A Case Report and Literature Review

by Nives Nikpalj, Jure Samardžić, Nada Božina, Livija Šimičević, Lana Ganoci and Tamara Božina

Genes 2025, 16(9), 1010; https://doi.org/10.3390/genes16091010 - 26 Aug 2025

Abstract

Background: Tacrolimus is a cornerstone of immunosuppressive therapy following heart transplantation. Despite routine therapeutic drug monitoring (TDM), substantial interindividual variability in tacrolimus pharmacokinetics presents a persistent challenge. Pharmacogenetic profiling—particularly of CYP3A5 and CYP3A4 polymorphisms—offers a promising approach to individualize tacrolimus dosing and improve [...] Read more.

Background: Tacrolimus is a cornerstone of immunosuppressive therapy following heart transplantation. Despite routine therapeutic drug monitoring (TDM), substantial interindividual variability in tacrolimus pharmacokinetics presents a persistent challenge. Pharmacogenetic profiling—particularly of CYP3A5 and CYP3A4 polymorphisms—offers a promising approach to individualize tacrolimus dosing and improve clinical outcomes. Case Presentation: We describe a 54-year-old male heart transplant recipient with persistently subtherapeutic tacrolimus trough concentrations despite escalating standard doses. Tacrolimus dosing initially started at 3.5 mg twice daily, escalated to 7.0 mg twice daily, with final maintenance dosing at 6.5 mg twice daily. TDM values were persistently subtherapeutic at 3–5 ng/mL for over a month before achieving therapeutic targets >10 ng/mL. Pharmacogenetic testing revealed a CYP3A5 expresser genotype (*1/*3) and normal CYP3A4 activity (*1/*1), suggesting enhanced metabolic clearance. In accordance with CPIC guidelines, tacrolimus dosing was intensified and supported by co-administration of diltiazem (60 mg twice daily, later adjusted to 90 mg twice daily), a CYP3A4 inhibitor. Subsequent TDM confirmed achievement of therapeutic levels. At nine months post-transplant, the patient exhibited stable graft function and excellent clinical status. Discussion: This case underscores the value of genotype-informed tacrolimus dosing in clinical scenarios where standard TDM is insufficient. Pharmacogenetic variation—particularly involving CYP3A5 expression—has been consistently associated with altered tacrolimus exposure and dose requirements. The literature supports routine genotyping in solid organ transplant recipients, although implementation remains limited. Additional considerations include drug–drug interactions, notably with CYP3A-modulating agents such as diltiazem and antifungals, which may further influence tacrolimus pharmacokinetics. Current evidence suggests that the utility of CYP3A4 genotyping may be phase-dependent, being more impactful during early post-transplant periods. Conclusions: Incorporating pharmacogenetic data alongside TDM facilitates more precise and individualized tacrolimus therapy, optimizing immunosuppressive efficacy and minimizing risk. This case, supported by literature review, advocates for broader integration of genotype-guided strategies in transplant pharmacotherapy. Full article

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

12 pages, 721 KB

Open AccessCase Report

Variants in GSTZ1 Gene Underlying Maleylacetoacetate Isomerase Deficiency: Characterization of Two New Individuals and Literature Review

by Ferdinando Barretta, Fabiana Uomo, Alessandra Verde, Mariagrazia Fisco, Giovanna Gallo, Lucia Albano, Daniela Crisci, Cristina Mazzaccara, Pietro Strisciuglio, Margherita Ruoppolo, Simona Fecarotta, Giancarlo Parenti, Giulia Frisso and Alessandro Rossi

Genes 2025, 16(9), 1009; https://doi.org/10.3390/genes16091009 - 26 Aug 2025

Abstract

Introduction: Elevated succinylacetone (SA) is the hallmark of tyrosinemia type 1, which requires immediate treatment. Mild SA elevation has also been recently reported in maleylacetoacetate isomerase deficiency (MAAID). Methods: We report on two cases of MAAID, review clinical features of MAAID and discuss [...] Read more.

Introduction: Elevated succinylacetone (SA) is the hallmark of tyrosinemia type 1, which requires immediate treatment. Mild SA elevation has also been recently reported in maleylacetoacetate isomerase deficiency (MAAID). Methods: We report on two cases of MAAID, review clinical features of MAAID and discuss its management. Results: Both cases displayed elevated SA and normal Tyrosine levels at newborn screening. Case 1 showed intermittent SA elevation; Nitisinone and dietary treatment were started, then discontinued after the identification of two variants in the GSTZ1 gene and the definitive diagnosis of MAAID. Case 2, showing no SA elevation at the confirmatory tests and two variants in the GSTZ1 gene, did not start treatment. mRNA analysis confirmed the pathogenicity of the c.68-12 G>A variant, found in both patients. Discussion: MAAID should be considered in newborns showing elevated SA and no variants in the FAH gene. Our study reports for the first time the course of SA in a patient affected by MAAID. Furthermore, it expands the molecular epidemiology of this rare disease, also investigating the pathogenicity of a novel splicing mutation. Although our data argue against medical treatment in MAAID, longer follow-up data are warranted. Full article

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

13 pages, 1344 KB

Open AccessArticle

Focus on Clinical and Genetic Aspects of PKAN Through the Description of New Patients

by Marika Giuliano, Eugenia Borgione, Mariangela Lo Giudice, Francesco Domenico Di Blasi, Sandro Santa Paola, Girolamo Aurelio Vitello, Maurizio Elia, Roberto Russo, Corrado Romano and Carmela Scuderi

Genes 2025, 16(9), 1008; https://doi.org/10.3390/genes16091008 - 26 Aug 2025

Abstract

Background/Objectives: The most prevalent form of neurodegeneration with brain iron accumulation (NBIA) is pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the PANK2 gene. The hallmark of PKAN is the “eye-of-the-tiger” sign, which is characterized by a bilateral region of central hyperintense [...] Read more.

Background/Objectives: The most prevalent form of neurodegeneration with brain iron accumulation (NBIA) is pantothenate kinase-associated neurodegeneration (PKAN), caused by mutations in the PANK2 gene. The hallmark of PKAN is the “eye-of-the-tiger” sign, which is characterized by a bilateral region of central hyperintense signal surrounded by a hypointense signal in the medial globus pallidus on T2-weighted brain magnetic resonance imaging (MRI). Methods: Whole-exome sequencing (WES) was performed in four patients who presented with dystonia, cognitive impairment and abnormalities of the globus pallidus. All patients underwent comprehensive clinical and instrumental evaluations. Results: Molecular analysis using WES revealed PANK2 variants in all four cases. Two patients were homozygous for the known pathogenic variant c.1169A > T (p.N390I). The remaining two patients displayed compound heterozygotes, each carrying the novel splicing variant c.906-1G > A on one allele, combined with a different second variant on the other allele: the new missense variant c.617G > A (p.G206D) in one case and the known pathogenic variant c.1231G > A (p.G411R) in the other. In one case, brain imaging documented the transition from initial hyperintensity of the globus pallidus to the development of the “eye-of-the-tiger” sign. In two cases, MRI findings clearly demonstrated the characteristic “eye-of-the-tiger” appearance. Ultimately, in one case, the imaging likely captured a later disease stage, in which the “eye-of-the-tiger” sign was no longer visible, and only the residual hypointensity remained. Conclusions: This study describes two novel likely pathogenic variants and documents the full MRI progression of globus pallidus involvement in PKAN. The sequence starts with early T2 hyperintensity, followed by the emergence of the typical “eye-of-the-tiger” sign, and culminates in marked hypointensity in advanced stages. Since the initial clinical presentation may mimic mitochondrial disorders or other neurometabolic conditions, these imaging features are crucial for guiding differential diagnosis and enabling accurate disease identification. Full article

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

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15 pages, 1231 KB

Open AccessArticle

Association Study of SPARCL1 Gene Polymorphisms in Ischemic Stroke

by Seong Shin Kwak, Ki Ook Lee, Chang Soo Ryu, Eun Ju Ko, Hyeon Woo Park, Jae Hyun Lee, Ok Joon Kim and Nam Keun Kim

Genes 2025, 16(9), 1007; https://doi.org/10.3390/genes16091007 - 26 Aug 2025

Abstract

Background/Objectives: Stroke is a cerebrovascular disorder characterized by vessel occlusion or rupture, resulting in brain damage and subsequent physical impairment. Recent studies have implicated hevin–calcyon protein binding in the repair of brain injury. Secreted protein acidic and rich in cysteine–like 1 (SPARCL1 [...] Read more.

Background/Objectives: Stroke is a cerebrovascular disorder characterized by vessel occlusion or rupture, resulting in brain damage and subsequent physical impairment. Recent studies have implicated hevin–calcyon protein binding in the repair of brain injury. Secreted protein acidic and rich in cysteine–like 1 (SPARCL1) encodes hevin. This study investigated SPARCL1 gene polymorphisms in ischemic stroke to identify potential biomarkers for brain injury treatment. Methods: we examined the associations of SPARCL1 polymorphisms (rs1049544, rs1130643, rs7695558, rs1049539) with ischemic stroke. This case–control study involved 387 controls and 509 patients with ischemic stroke. Genotyping was performed via real-time polymerase chain reaction with the TaqMan™ SNP Genotyping Kit. Results: The rs1049544 polymorphism was significantly associated with ischemic stroke prevalence (GG vs. CC: adjusted odds ratio [AOR] = 0.642, p = 0.043; GG + GC vs. CC: AOR = 0.671, p = 0.045). Additionally, rs1049544 was significantly associated with large-artery disease prevalence (GG vs. CC: AOR = 0.489, p = 0.028; GG + GC vs. CC: AOR = 0.527, p = 0.033), and rs1130643 (TT vs. TC: AOR = 0.362, p = 0.039) was associated with cardioembolism prevalence in ischemic stroke subtype analysis. In haplotype analysis, G-G (rs1049544/rs7695558; odds ratio = 4.942, p = 0.001) and C-T (rs1049544/rs1049539; odds ratio = 0.776, p = 0.043) haplotypes were associated with ischemic stroke prevalence. Although some genotypes were not individually associated with ischemic stroke, the presence of the rs1049544 C allele appeared to enhance risk. Conclusions: These findings suggest that SPARCL1 polymorphisms are associated with ischemic stroke and may be considered potential biomarkers for risk assessment. Full article

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

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7 pages, 183 KB

Open AccessEditorial

Editorial: Special Issue “Genetic Newborn Screening”

by Hisahide Nishio and Hiroyuki Awano

Genes 2025, 16(9), 1006; https://doi.org/10.3390/genes16091006 - 26 Aug 2025

Abstract

Traditional newborn screening (NBS) is performed by measuring disease-specific biomarkers using the latest state-of-the-art technologies [...] Full article

(This article belongs to the Special Issue Genetic Newborn Screening)

17 pages, 3233 KB

Open AccessArticle

Diagnosis of Periodontitis via Neutrophil Degranulation Signatures Identified by Integrated scRNA-Seq and Deep Learning

by Huijian Wu, Linqing Huang, Shuting Cai, Xiaoming Xiong and Yan He

Genes 2025, 16(9), 1005; https://doi.org/10.3390/genes16091005 - 26 Aug 2025

Abstract

Background and objective: Periodontitis, a chronic inflammatory disease driven by host immune dysregulation, leads to progressive destruction of periodontal tissues. This study employed an integrative approach combining single-cell transcriptomics, hierarchical weighted gene co-expression network analysis (hdWGCNA), and deep learning algorithms to identify [...] Read more.

Background and objective: Periodontitis, a chronic inflammatory disease driven by host immune dysregulation, leads to progressive destruction of periodontal tissues. This study employed an integrative approach combining single-cell transcriptomics, hierarchical weighted gene co-expression network analysis (hdWGCNA), and deep learning algorithms to identify key biomarkers associated with neutrophil degranulation in periodontitis, aiming to establish diagnostic models for early detection and precision interventions. Methods: We integrated single-cell RNA sequencing (scRNA-seq) data from human gingival tissues with bulk transcriptomic datasets. Pathogenic neutrophil subsets were characterized via pseudotime trajectory and cell–cell communication analyses. Hierarchical weighted gene co-expression network analysis (hdWGCNA) identified functional modules linked to degranulation. Machine learning and a convolutional neural network (CNN) model combining gene expression and immune cell profiles were developed for diagnosis. Results: scRNA-seq revealed a neutrophil subpopulation significantly increased infiltration in periodontitis, with cell–cell communication and pseudotime trajectory analyses demonstrating amplified inflammatory crosstalk. hdWGCNA identified the turquoise module enriched in PD-KEY-Neutrophils, containing hub genes linked to neutrophil degranulation and complement activation. Immune infiltration and non-negative matrix factorization linked high-degranulation neutrophil signatures to the periodontal immunity microenvironment. Machine learning demonstrated that the neutrophil degranulation-associated genes effectively distinguish diseased gingival tissue, suggesting their potential to predict periodontitis. Finally, integrating transcriptomic and immunological data, we developed a gene-immune CNN deep learning model accurately diagnosed periodontitis in diverse cohorts (AUC = 0.922). Conclusions: Our study identified a pathogenic neutrophil subpopulation driving periodontitis through degranulation and inflammation. The neutrophil degranulation genes serve as critical biomarkers, offering new insights for clinical diagnosis and treatment of periodontitis. Full article

(This article belongs to the Section Bioinformatics)

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19 pages, 3940 KB

Open AccessArticle

Extinction of Contextual Fear Memory and Passive Avoidance Memory and Subsequent Anxiety-like and Depressive-like Behavior of A53T and A53T-L444P Mice

by Emily Bunnell, Elizabeth Saltonstall, Alexandra Pederson, Charlie Baxter, Elia Ramicciotti, Naomi Robinson, Phoebe Sandholm, Abigail O′Niel and Jacob Raber

Genes 2025, 16(9), 1004; https://doi.org/10.3390/genes16091004 - 26 Aug 2025

Abstract

Background: Genetic factors pertinent to Parkinson’s disease (PD) might predispose an individual to post-traumatic stress disorder (PTSD). Humans who are heterozygous for the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased PD risk and elevated levels of alpha synuclein (aSyn). Mice that [...] Read more.

Background: Genetic factors pertinent to Parkinson’s disease (PD) might predispose an individual to post-traumatic stress disorder (PTSD). Humans who are heterozygous for the glucocerebrosidase 1 (GBA) L444P Gaucher mutation have an increased PD risk and elevated levels of alpha synuclein (aSyn). Mice that are heterozygous for the GBA mutation and express aSyn with the A53T mutation show elevated anxiety levels at 20 months of age compared to those expressing only A53T. Objective: This study aims to assess whether A53T and A53T-L444P affect the risk of developing PTSD phenotypes and whether sex and age modulate this risk. Methods: Young (5.1 ± 0.2 months) and older (11.3 ± 0.2 months) A53T and GBA L444P female and male mice were tested for fear learning and memory extinction in the contextual fear conditioning and passive avoidance paradigms. Subsequently, the mice were tested for measures of activity and anxiety in the open field and for depressive-like behavior in the forced swim test. Results: In the contextual fear memory extinction paradigm, only young A53T female mice showed contextual fear memory extinction, while older A53T female mice showed increased activity levels over subsequent days. In the passive avoidance memory paradigm, no mice showed extinction of passive avoidance memory. When the frequency of entering the more anxiety-provoking center of the open field was analyzed, a test history x sex x age interaction was observed. In the forced swim test, test history affected the depressive-like behavior in mice trained; there was more depressive-like behavior in mice trained in the contextual fear memory extinction paradigm than in mice trained in the passive avoidance memory extinction paradigm. Moreover, there was an effect of age with more depressive-like behavior in older than in younger mice, and an effect of genotype with more depressive-like behavior in A53T-L444P compared to A53T mice. When cortical phosphorylated tau (pS 199) levels were analyzed, there was an effects of genotype, a sex x age interaction, and ant age x test history interaction. Conclusions: A53T and A53T-L444P affect the risk of developing PTSD phenotypes. Fear extinction test history, genotype, and age affect depressive-like behavior and tau pathology. Full article

(This article belongs to the Section Neurogenomics)

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11 pages, 1702 KB

Open AccessArticle

Phenotypic and Genetic Stability of the Aldrovanda vesiculosa L. Plants Regenerated in Tissue Culture

by Marzena Parzymies, Katarzyna Głębocka, Magdalena Pogorzelec, Barbara Banach-Albińska, Alicja Świstowska and Michał Arciszewski

Genes 2025, 16(9), 1003; https://doi.org/10.3390/genes16091003 - 25 Aug 2025

Abstract

Background: Tissue culture might be a method supplementing traditional plant propagation in various fields, like agriculture, medicine, industry, and the active conservation of plant species. For the purpose of plant restoration, it is important that the obtained progenies are identical with the mother [...] Read more.

Background: Tissue culture might be a method supplementing traditional plant propagation in various fields, like agriculture, medicine, industry, and the active conservation of plant species. For the purpose of plant restoration, it is important that the obtained progenies are identical with the mother plants to ensure the true-to-typeness of the future population. Methods: In the present study, the stability of Aldrovanda vesiculosa regenerants obtained in vitro through phenotypic and genetic analysis was estimated. Clones of aldrovanda plants were cultivated in tissue culture in the 1/10 MS liquid medium under the same conditions for over a year, with five weeks of subculturing. Results: It was observed that two clones formed plants that displayed atypical growth structures, the shoots were shorter with many lateral shoots, and they had a lower fresh weight. They also formed fewer and smaller snap-traps, which, in the case of carnivorous plants, determines the capability of catching prey. The 35 in vitro regenerated plants and 5 specimens obtained from the natural habitat were subjected to genetic analyses with two molecular markers: start codon targeted (SCoT) polymorphism and sequence-related amplified polymorphism (SRAP). Despite the visible morphological variants, the genetic stability of all the regenerants with the individuals from natural stands was confirmed. All of them were monomorphic except three bands that were obtained for reference, where individuals were amplified with SCoT28 and me12-em13 SRAP primers. Conclusions: As shown in the presented research, it might be recommended to use different methods to evaluate the stability of in vitro cultivated plants. Full article

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

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13 pages, 526 KB

Open AccessReview

MODY5 and 17q12 Microdeletion Syndrome: Phenotype Variability, Prenatal and Postnatal Counseling

by Paolo Fontana, Claudia Costabile, Mariateresa Falco, Maria Rosaria Barillari and Fortunato Lonardo

Genes 2025, 16(9), 1002; https://doi.org/10.3390/genes16091002 - 25 Aug 2025

Abstract

Maturity-Onset Diabetes of the Young Type 5 (MODY5) is caused by heterozygous pathogenic variants in the HNF1B gene, encoding the transcription factor hepatocyte nuclear factor-1β. HNF1B haploinsufficiency typically leads to young-onset non-immune diabetes and highly variable renal involvement, whose more frequent features are [...] Read more.

Maturity-Onset Diabetes of the Young Type 5 (MODY5) is caused by heterozygous pathogenic variants in the HNF1B gene, encoding the transcription factor hepatocyte nuclear factor-1β. HNF1B haploinsufficiency typically leads to young-onset non-immune diabetes and highly variable renal involvement, whose more frequent features are bilateral kidney cysts and renal hypodysplasia. Kidney cysts or echogenic kidneys can be identified by ultrasonography in the prenatal period, but the renal involvement can also start in childhood or later. Notably, a recurrent microdeletion syndrome at 17q12 (deleting HNF1B plus ~15 neighboring genes) accounts for ~40–50% of cases. The 17q12 deletion is a contiguous gene syndrome and affected individuals present with a complex phenotype, including neurodevelopmental disorders, liver and pancreas abnormalities, and other congenital defects. When counseling the patient and the parents, the clinician must consider multiple factors, including the molecular defect and the age of onset of the symptoms, with particular attention to prenatal diagnosis. A multidisciplinary approach and an early diagnosis are essential for the management of these conditions. Full article

(This article belongs to the Section Genetic Diagnosis)

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26 pages, 1443 KB

Open AccessReview

Avian Cytogenomics: Small Chromosomes, Long Evolutionary History

by Darren K. Griffin, Rafael Kretschmer, Denis M. Larkin, Kornsorn Srikulnath, Worapong Singchat, Valeriy G. Narushin, Rebecca E. O’Connor and Michael N. Romanov

Genes 2025, 16(9), 1001; https://doi.org/10.3390/genes16091001 - 25 Aug 2025

Abstract

This review considers fundamental issues related to the genomics of birds (Aves), including the special organization and evolution of their chromosomes. In particular, we address the capabilities of molecular genetic/genomic approaches to clarify aspects of their evolutionary history, including how they have adapted [...] Read more.

This review considers fundamental issues related to the genomics of birds (Aves), including the special organization and evolution of their chromosomes. In particular, we address the capabilities of molecular genetic/genomic approaches to clarify aspects of their evolutionary history, including how they have adapted to multiple habitats. We contemplate general genomic organization, including the small size and typical number of micro/macrochromosomes. We discuss recent genome sequencing efforts and how this relates to cytogenomic studies. We consider the emergence of this unique organization ~245 million years ago, examining examples where the “norm” is not followed. We address the functional role of synteny disruptions, centromere repositioning, repetitive elements, evolutionary breakpoints, synteny blocks and the role of the unique ZW sex chromosome system. By analyzing the cytogenetic maps and chromosomal rearrangements of eight species, the possibility of successfully applying modern genomic methods/technologies to identify general and specific features of genomic organization and an in-depth understanding of the fundamental patterns of the evolution of avian genomes are demonstrated. An interpretation of the observed genomic “variadicity” and specific chromosomal rearrangements is subsequently proposed. We also present a mathematical assessment of cross-species bacterial artificial chromosome (BAC) hybridization during genomic mapping in the white-throated sparrow, a species considered a key model of avian behavior. Building on model species (e.g., chicken), avian cytogenomics now encompasses hundreds of genomes across nearly all families, revealing remarkable genomic conservation with many dynamic aspects. Combining classical cytogenetics, high-throughput sequencing and emerging technologies provides increasingly detailed insights into the structure, function and evolutionary organization of these remarkable genomes. Full article

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

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