Genes

14 pages, 4511 KiB

Open AccessArticle

The Metabolic Consequences of Pathogenic Variant in FXYD2 Gene Encoding the Gamma Subunit of Sodium/Potassium-Transporting ATPase in Two Siblings with Sodium-Dependent Defect of Fructose, Galactose and Glucose Renal Reabsorption

by Jan Zawadzki, Ryszard Grenda, Agnieszka Madej-Pilarczyk and Elżbieta Ciara

Genes 2025, 16(5), 535; https://doi.org/10.3390/genes16050535 (registering DOI) - 29 Apr 2025

Abstract

Background: Abnormal sodium-dependent hexose reabsorption in the proximal tubule, accompanied by a functional decrease in sodium and water reabsorption under conditions of increased volemia, may be attributed to a dysfunction of primary transporters related to a genetic defect in the Na,K-ATPase gamma subunit. [...] Read more.

Background: Abnormal sodium-dependent hexose reabsorption in the proximal tubule, accompanied by a functional decrease in sodium and water reabsorption under conditions of increased volemia, may be attributed to a dysfunction of primary transporters related to a genetic defect in the Na,K-ATPase gamma subunit. Methods: We examined two sisters, aged 6 and 8 years, who presented with hypercalciuria, glucosuria, fructosuria, galactosuria, and atypical proteinuria. Primary diabetes, galactosemia, and fructosemia were excluded, suggesting a defect in cellular hexose transport in the proximal tubule. We conducted tests on the family members to assess the impact of gradually increasing volemia, using a water-loading test, on tubular H+ transport and urinary excretion of calcium, citrate, endothelin-1 (ET-1), and atypical proteins. Whole-exome sequencing was performed in the affected patients to identify the genetic basis of this phenotype. Results: Extended investigations revealed a complex defect in tubular H⁺ transport, calcium and citrate handling, and atypical proteinuria, resulting from water load-driven overproduction of endothelin-1 (ET-1). Genetic analysis identified a heterozygous pathogenic variant, c.80G>A, p.(Arg27His), in the FXYD2 gene, which encodes the gamma subunit of sodium/potassium-transporting ATPase. Conclusions: Our findings provide evidence that a defect in FXYD2 (splice form a) leads to functional impairment of proximal tubular hexose reabsorption. This is the first report on the metabolic consequences of a pathogenic FXYD2 variant affecting the gamma subunit of sodium/potassium-transporting ATPase in humans. The genotype–phenotype correlation in two siblings with a sodium-dependent defect in fructose, galactose, and glucose renal reabsorption allowed us to characterize a disease with a distinct clinical course and biochemical profile, not previously reported in the medical literature or genetic databases. Analysis of this condition was crucial for the early introduction of reno-protective treatment aimed at slowing the progression of nephropathy and for risk assessment in family members, which was essential for genetic counseling. Full article

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

20 pages, 885 KiB

Open AccessReview

Genetic Contributions to Aggressive Behaviour in Pigs: A Comprehensive Review

by Anastasiya Kazantseva, Airat Bilyalov, Nikita Filatov, Stepan Perepechenov and Oleg Gusev

Genes 2025, 16(5), 534; https://doi.org/10.3390/genes16050534 (registering DOI) - 29 Apr 2025

Abstract

Aggressive behaviour in pigs poses significant challenges to animal welfare, production efficiency, and economic performance in the pork industry. This review explores the multifaceted causes of pig aggression, focusing on genetic, environmental, and physiological factors. Aggression in pigs is categorized into social, maternal, [...] Read more.

Aggressive behaviour in pigs poses significant challenges to animal welfare, production efficiency, and economic performance in the pork industry. This review explores the multifaceted causes of pig aggression, focusing on genetic, environmental, and physiological factors. Aggression in pigs is categorized into social, maternal, fear-induced, play, and redirected aggression, with early-life hierarchies and environmental stressors playing critical roles. Physiological markers, such as elevated cortisol and reduced serotonin levels, are closely linked to aggressive behaviour, while dietary interventions, including tryptophan supplementation, have shown promise in mitigating aggression. Environmental factors, such as overcrowding, noise, and heat stress, exacerbate aggressive tendencies, whereas enrichment strategies, like music and improved housing conditions, can reduce stress and aggression. Genome-wide analyses have pinpointed specific polymorphisms in neurotransmitter genes (DRD2, SLC6A4, MAOA) and stress-response loci (RYR1) as significant predictors of porcine aggression. Advances in genomic technologies, including genome-wide association studies (GWASs) and transcriptomic analyses, have further elucidated the genetic and epigenetic underpinnings of aggressive behaviour. Practical application in breeding programmes remains challenging due to aggression polygenic nature and industry hesitancy toward genomic approaches. Future research should focus on integrating genetic markers into breeding programmes, developing multitrait selection indices, and exploring epigenetic modifications to improve animal welfare and production efficiency. By addressing these challenges, the pork industry can enhance both the well-being of pigs and the sustainability of production systems. Full article

(This article belongs to the Special Issue Advances in Pig Genetic and Genomic Breeding)

► Show Figures

Figure 1

8 pages, 270 KiB

Open AccessReview

The Need for a Concert of Cytogenomic Methods in Chromosomic Research and Diagnostics

by Yiping Wang and Thomas Liehr

Genes 2025, 16(5), 533; https://doi.org/10.3390/genes16050533 (registering DOI) - 29 Apr 2025

Abstract

This review focuses on the experimental methods and technologies of cytogenomics and how they can be combined in the process of chromosomic diagnostics and research. It is stressed that no cytogenomic methods can be comprehensive on their own. The strengths and weaknesses of [...] Read more.

This review focuses on the experimental methods and technologies of cytogenomics and how they can be combined in the process of chromosomic diagnostics and research. It is stressed that no cytogenomic methods can be comprehensive on their own. The strengths and weaknesses of each method have to be considered. This is especially important in a time where the main stream of human genetics diagnostics is actively proclaiming that high throughput methods are able to replace all other established tests. Full article

(This article belongs to the Special Issue Clinical Cytogenetics: Current Advances and Future Perspectives)

14 pages, 1626 KiB

Open AccessArticle

Enhancing the Potential of Microhaplotypes for Forensic Applications: Insights from Afghan and Somali Populations

by Pedro Rodrigues, Nádia Pinto, Tess Otterlund, Carina G. Jønck, Maria João Prata, Claus Børsting and Vania Pereira

Genes 2025, 16(5), 532; https://doi.org/10.3390/genes16050532 (registering DOI) - 29 Apr 2025

Abstract

Microhaplotypes (MHs) are a novel class of genetic markers, exhibiting features that position them as an alternative to STRs and SNPs in addressing challenges commonly encountered in forensic investigations. Additionally, MHs can also offer valuable insights for ancestry inference. However, due to the [...] Read more.

Microhaplotypes (MHs) are a novel class of genetic markers, exhibiting features that position them as an alternative to STRs and SNPs in addressing challenges commonly encountered in forensic investigations. Additionally, MHs can also offer valuable insights for ancestry inference. However, due to the novelty of MHs, extensive research in different global populations is required before implementation in forensic casework and general research. In this study, individuals from Afghanistan and Somalia were characterized with the Ion AmpliSeq™ MH-74 Plex Research Panel previously developed for forensic genetic purposes. A total of 84 Afghan and 89 Somalian samples were sequenced on the Ion GeneStudio™ S5 System. This led to the identification of 32 and 42 single nucleotide variants in the Afghan and Somalian populations, respectively, that were not included in the former MH definitions. Most of the observed variants were considered to be rare occurrences, being observed one or two times in the dataset. The average values of the effective number of alleles (A_e) were 3.7 for Somalia and 3.6 for Afghanistan—pointing to elevated intrapopulation diversities compared to Europeans. Other parameters (H_o, H_e, PIC, PD, and PE) consistently showed higher average values in the Afghans and Somalis compared to the previously studied populations. PCA and STRUCTURE analyses with 1000 Genomes samples assigned the Somalis to a different cluster than the other sub-Saharan African populations. The analyses also showed higher European and East Asian co-ancestry in the Afghans than in the remaining South Asian populations. The capability of the MH-74 plex to address common kinship problems was evaluated through computational simulations, considering generic thresholds differing by one order of magnitude to assess the FDRs. The median LR > 10¹³ for true siblings when the hypotheses ‘full siblings’ and ‘unrelated individuals’ were compared. As expected, the median LRs were much lower for simulated half-siblings and cousins. This work evaluated the forensic potential of MHs in understudied populations. Overall, the studied panel was versatile and capable of being applied in different forensic applications. Full article

(This article belongs to the Section Population and Evolutionary Genetics and Genomics)

► Show Figures

Figure 1

16 pages, 3909 KiB

Open AccessArticle

Comparative Mitogenomics of Wonder Geckos (Sphaerodactylidae: Teratoscincus Strauch, 1863): Uncovering Evolutionary Insights into Protein-Coding Genes

by Dongqing Zheng, Rongrong Ma, Xianguang Guo and Jun Li

Genes 2025, 16(5), 531; https://doi.org/10.3390/genes16050531 (registering DOI) - 29 Apr 2025

Abstract

Background: Comparative studies of selection pressures on mitochondrial genomes and protein-coding genes (PCGs) are scarce in the genus Teratoscincus (Strauch, 1863), particularly within Sphaerodactylidae. Given their close evolutionary relationship, Teratoscincus przewalskii (Strauch, 1887) and Teratoscincus roborowskii (Bedriaga, 1906) serve as ideal models for [...] Read more.

Background: Comparative studies of selection pressures on mitochondrial genomes and protein-coding genes (PCGs) are scarce in the genus Teratoscincus (Strauch, 1863), particularly within Sphaerodactylidae. Given their close evolutionary relationship, Teratoscincus przewalskii (Strauch, 1887) and Teratoscincus roborowskii (Bedriaga, 1906) serve as ideal models for the characterization of mitochondrial genome sand analysis of selective pressure in this genus. Methods: In this study, we employed Sanger sequencing to sequence the mitochondrial genome of T. roborowskii (Bedriaga, 1906), and utilized sliding window analysis, selection pressure analysis etc. to compared it with that of its close relative, T. przewalskii (Strauch, 1887). Results: The results contain the genome composition, Ka/Ks values, AT/GC-skew, etc. Selection pressure analysis of PCGs across Teratoscincus (Strauch, 1863) species (including those in GenBank) revealed that most genes evolve slowly, with the exception of ATP8 and ND6, which exhibited faster evolutionary rates. Notably, the ND6 of T. roborowskii (Bedriaga, 1906) demonstrated rapid non-synonymous substitution rates which may contribute to the survival and reproductive success of the species by favoring advantageous mutations. Phylogenetic analysis for the mitochondrial genomes of Sphaerodactylidae, Phyllodactylidae, and Gekkonidae confirmed the distinctiveness of Sphaerodactylidae and the two Teratoscincus (Strauch, 1863) species. Conclusions: This study has advanced the understanding of adaptive evolution in Teratoscincus (Strauch, 1863) mitochondrial genomes, expanded the mitochondrial database of Sphaerodactylidae, and provided insights into the phylogenetic relationships of the genus. Full article

(This article belongs to the Special Issue Molecular Evolution, Mitochondrial Genomics and Mitochondrial Genome Expression in Animals: 2024–2025)

► Show Figures

Figure 1

11 pages, 395 KiB

Open AccessArticle

Hypermobile Ehlers–Danlos Syndrome: Diagnostic Challenges and the Role of Genetic Testing

by Irman Forghani, Julia See and William C. McGonigle

Genes 2025, 16(5), 530; https://doi.org/10.3390/genes16050530 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Hypermobile Ehlers–Danlos syndrome (hEDS) is the most common subtype of Ehlers–Danlos syndromes (EDS), a heterogeneous group of hereditary connective tissue disorders. The hallmark features of hEDS include generalized joint hypermobility (GJH), soft or velvety skin, and persistent joint pain. The molecular [...] Read more.

Background/Objectives: Hypermobile Ehlers–Danlos syndrome (hEDS) is the most common subtype of Ehlers–Danlos syndromes (EDS), a heterogeneous group of hereditary connective tissue disorders. The hallmark features of hEDS include generalized joint hypermobility (GJH), soft or velvety skin, and persistent joint pain. The molecular etiology of hEDS remains unknown, and diagnosis is primarily clinical. The updated diagnostic criteria for hEDS requires the fulfillment of three criteria: (1) GJH, (2) a combination of musculoskeletal and systemic manifestations consistent with a connective tissue disorder, and (3) the exclusion of alternative diagnoses. However, the exclusion process and the role of genetic testing have not yet been fully refined. Methods: This retrospective review utilized data from the Hereditary Connective Tissue Disorders (HCTD) patient registry at the University of Miami, which includes individuals evaluated at the HCTD Clinic using a standardized internal clinical and genetic protocol. We analyzed data from 907 patients referred for hEDS evaluation between June 2019 and December 2022. Results: Among these patients, 178 met the 2017 diagnostic criteria for hEDS. Genetic testing identified an alternative or additional diagnosis in 47 of these individuals (26.4%), with clinical implications requiring distinct management strategies. Conclusions: These findings underscore the importance of criterion three—exclusion of alternative diagnoses—and highlight the critical yet underutilized role of genetic testing in the assessment of joint hypermobility. Furthermore, the results suggest that hypermobility may present a shared phenotype across a spectrum of disorders, including inflammatory diseases, monogenic syndromes, and chromosomal abnormalities. Full article

(This article belongs to the Special Issue The Genetic Landscape of Connective Tissue Disorders)

► Show Figures

Figure 1

19 pages, 5383 KiB

Open AccessArticle

Development and Application of a TaqMan-Based qPCR Assay for Detecting ENTV-2 in Goats

by Pengfei Li, Haike Yin, Xiaoan Cao, Xi Lan, Jinyan Wu, Jijun He, Ligang Yuan and Youjun Shang

Genes 2025, 16(5), 529; https://doi.org/10.3390/genes16050529 (registering DOI) - 29 Apr 2025

Abstract

Background: In recent years, enzootic nasal tumor virus 2 (ENTV-2) has become prevalent in China, resulting in substantial economic losses for the goat industry. In order to enrich the availability of detection methods for ENTV-2, this study developed an expedited and accurate reverse-transcription [...] Read more.

Background: In recent years, enzootic nasal tumor virus 2 (ENTV-2) has become prevalent in China, resulting in substantial economic losses for the goat industry. In order to enrich the availability of detection methods for ENTV-2, this study developed an expedited and accurate reverse-transcription quantitative real-time polymerase chain reaction (RT-qPCR) assay to facilitate the detection and quantification of ENTV-2. Methods: Specifically, a pair of primers and a TaqMan probe targeting conserved regions of the pro gene were designed to allow the specific amplification and detection of viral RNA in clinical samples. Moreover, modifying the method for use in a quantitative real-time PCR (qPCR) assay enables the detection of proviral DNA in tumor specimens. Results: Both methods exhibited a detection limit for the ENTV-2 standard plasmid at 10⁰ copies/µL. The detection methods we established exhibited high specificity and sensitivity to ENTV-2, without cross-reactivity with other pathogens causing respiratory diseases or endogenous retroviruses (EBRVs). We performed an ENTV-2 analysis of clinical samples in goats via RT-qPCR using nasal swab samples (n = 558) collected from three geographically distinct flocks in Lingyou County, Baoji City, Shaanxi Province, China, and 58 positive samples were detected for a positivity rate of 10.4%. After euthanasia, the autopsy report showed nasal cavity masses. Histopathological analysis demonstrated an epithelial neoplasm, in compliance with the features of enzootic nasal adenocarcinoma (ENA). Three full-length genomes were sequenced to assess genomic sequence conservation and variation. Multiple-sequence alignment demonstrated the existence of sequence variations among strains. Phylogenetic analysis of the nucleotide sequences revealed that the ENTV-2 SX1~3 isolates were phylogenetically related to the Chinese ENTV-2 isolates, especially the JY strain. Furthermore, recombination analysis suggested that both ENTV-2 SX1 and ENTV-2 SX2 might be recombinant variants. Conclusions: In conclusion, both methods are highly specific for the pro gene of ENTV-2, and the development of this assay has been deemed crucial to the early identification and subsequent control of this viral infection. Our results provide valuable information for further research on the genetic variation and evolution of ENTV-2 in China. Full article

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

26 pages, 6240 KiB

Open AccessArticle

Dysregulation of Locus-Specific Repetitive Elements in TCGA Pan-Cancers

by Chao Wang and Chun Liang

Genes 2025, 16(5), 528; https://doi.org/10.3390/genes16050528 (registering DOI) - 29 Apr 2025

Abstract

Background: Understanding the role of repetitive elements (REs) in cancer development is crucial for identifying novel biomarkers and therapeutic targets. Methods: This study investigated the locus-specific dysregulation of REs, including the differential expression and methylation of REs, across 12 TCGA cancer types stratified [...] Read more.

Background: Understanding the role of repetitive elements (REs) in cancer development is crucial for identifying novel biomarkers and therapeutic targets. Methods: This study investigated the locus-specific dysregulation of REs, including the differential expression and methylation of REs, across 12 TCGA cancer types stratified by their genomic context (i.e., genic and intergenic REs). Results: We found uniquely dysregulated genic REs co-regulated with their corresponding transcripts and associated with distinct biological functions in different cancer types. Uniquely dysregulated intergenic REs were identified in each cancer type and used to cluster different sample types. Recurrently dysregulated REs were identified in several cancer types, with genes associated with up-regulated genic REs involved in cell cycle processes and those associated with down-regulated REs involved in the extracellular matrix. Interestingly, four out of five REs consistently down-regulated in all 12 cancer types were located in the intronic region of the TMEM252, a recently discovered tumor suppressor gene. TMEM252 expression was also down-regulated in 10 of 12 cancer types, suggesting its potential importance across a wide range of cancer types. With the corresponding DNA methylation array data, we found a higher prevalence of hypo-methylated REs in most cancer types (10 out of 12). Despite the slight overlaps between differentially expressed REs and differentially methylated REs, we showed that the methylation of locus-specific REs negatively correlates with their expression in some of these 12 cancer types. Conclusions: Our findings highlight the cancer-specific and recurrent deregulation of REs, their functional associations, and the potential role of TMEM252 as a pan-cancer tumor suppressor, providing new insights into biomarker discovery and therapeutic development. Full article

(This article belongs to the Section Bioinformatics)

► Show Figures

Figure 1

17 pages, 3624 KiB

Open AccessArticle

Competitive Endogenous RNA Network Involving Immune Subgroups, Infiltration, and lncRNAs in Prostate Cancer

by Wenkang Niu, Tingting Zhang and Lei Ma

Genes 2025, 16(5), 527; https://doi.org/10.3390/genes16050527 (registering DOI) - 29 Apr 2025

Abstract

Prostate cancer (PCa) is the most frequently diagnosed malignancy in the male genitourinary tract. However, the regulatory mechanism of competitive endogenous RNAs (ceRNAs) in PCa remains unclear. In this study, we first performed immune scores of mRNA data from 481 PCa samples using [...] Read more.

Prostate cancer (PCa) is the most frequently diagnosed malignancy in the male genitourinary tract. However, the regulatory mechanism of competitive endogenous RNAs (ceRNAs) in PCa remains unclear. In this study, we first performed immune scores of mRNA data from 481 PCa samples using single-sample Gene Set Enrichment Analysis (ssGSEA). Based on the immune scores, we then evaluated the tumor immune microenvironment and analyzed 28 types of immune cells in PCa, we constructed a comprehensive network with four lncRNAs (MEG3, PCAT1, SNHG19, TRG-AS1), three miRNAs (hsa-miR-488-3p, hsa-miR-210-5p, hsa-miR-137), and twenty-seven mRNAs (including H2AFJ, THBS1, HPGD). Among the 28 immune cell types, seven immune cell types were found to be significantly associated with clinical characteristics. These network nodes have prognostic significance in multiple cancers and play critical roles in malignancy development, indicating the network’s predictive capability. We also observed a strong correlation (r = 0.6) between T-helper type 1 (Th1) cells and lncRNA network modules. The network connectivity highlights the association between immune therapy biomarkers for PCa, particularly those related to H2AFJ, THBS1, and HPGD. These findings provide valuable insights into the ceRNA regulatory network and its implications for immune-based therapies in PCa. Full article

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

► Show Figures

Figure 1

15 pages, 4253 KiB

Open AccessArticle

Whole-Genome DNA Methylation Analysis in Age-Related Hearing Loss

by Marie Valerie Roche, Denise Yan, Yan Guo, Naser Hamad, Juan I. Young, Susan H. Blanton, Feng Gong and Xue Zhong Liu

Genes 2025, 16(5), 526; https://doi.org/10.3390/genes16050526 (registering DOI) - 29 Apr 2025

Abstract

Background: Presbycusis, also known as age-related hearing loss (ARHL), is the most frequent sensory disability affecting elderly adults worldwide. ARHL is characterized by bilateral, progressive, sensorineural hearing loss that is more pronounced at a high frequency. Conventional factors associated with ARHL include diabetes, [...] Read more.

Background: Presbycusis, also known as age-related hearing loss (ARHL), is the most frequent sensory disability affecting elderly adults worldwide. ARHL is characterized by bilateral, progressive, sensorineural hearing loss that is more pronounced at a high frequency. Conventional factors associated with ARHL include diabetes, hypertension, and a family history of hearing loss. The severity of hearing impairment varies between individuals. The defined causative molecular pathogenesis for ARHL is unknown, thus the identification of underlying pathogenic mechanisms involved in ARHL is imperative for the development of effective therapeutic approaches. Epigenetics is the study of phenotypic changes caused by the modification of gene expression rather than the alteration of a DNA sequence. While it is hypothesized that ARHL could result from undiscovered epigenetic susceptibility, there is a shortage of information on the role that epigenetic modification plays in ARHL. Here we present an investigation on the involvement of DNA methylation in ARHL. Results: Clinical, audiometric and DNA testing, and high-throughput methylation pattern screening were undertaken for ARHL patients and matched control subjects. Our results demonstrate a strong correlation between patients’ hearing measurements and methylation at CpG sites cg1140494 (ESPN) and cg27224823 (TNFRSF25). We identified 136 differentially methylated CpGs that were shared between a high and low audiometric frequency in the patient’s cohort. CpG cites in hearing loss candidate genes, KCNQ1, TMEM43, GSTM1, TCF25, and GSR, were found to be highly methylated in presbycusis patients as compared to the controls. A methylation polymerase chain reaction (PCR) assay was used to confirm methylation levels at a specific gene locus in ARHL patients and controls. Conclusions: Altered DNA methylation and its impact on gene expression has been implicated in many biological processes. By interrogating the methylation status across the genome of both hearing loss patients and those with normal hearing, our study can help to establish an association between the audiometric patterns and methylation status in ARHL, yielding new avenues for the identification of potential candidate genes for hearing loss. Full article

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

► Show Figures

Figure 1

36 pages, 1680 KiB

Open AccessReview

Genotoxicity in Unconventional Mammalian Models of Wild, Urban, and Agricultural Ecosystems: A Systematic Review Under the One Health Approach

by Nora Bibiana M. Gorla, Mariela Nieves and Daniela Marisol Ferré

Genes 2025, 16(5), 525; https://doi.org/10.3390/genes16050525 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: This systematic review evaluates unconventional mammalian models from wild, agricultural, and urban/domestic ecosystems for genotoxicity assessment under the One Health framework. Non-human primates (NHPs), cattle, and domestic dogs are analyzed as sentinel species due to their distinct environmental niches, unique human interactions, [...] Read more.

Background/Objectives: This systematic review evaluates unconventional mammalian models from wild, agricultural, and urban/domestic ecosystems for genotoxicity assessment under the One Health framework. Non-human primates (NHPs), cattle, and domestic dogs are analyzed as sentinel species due to their distinct environmental niches, unique human interactions, and species-specific traits. In conjunction with this, evidence is presented about the in vitro use of cells of these mammals for the genotoxicological evaluation of different chemical substances, such as veterinary drugs, environmental pollutants, and pesticides. The synthesis focuses on standardized genetic toxicology assays (e.g., chromosomal aberrations, micronucleus, comet assay) aligned with Organization for Economic Cooperation and Development (OECD) guidelines. Methods: A structured search of international literature identified studies employing OECD-compliant genotoxicity assays in NHPs, cattle, dogs, and others not listed in OECD. Data was categorized by species, assay type, chemical class evaluated, environmental context (wild, agricultural, urban), and merits of the papers. Results: NHPs, despite their phylogenetic proximity to humans, show limited genotoxicity data in contrast to biomedical research, which has been constrained by ethical concerns and fieldwork logistics. Cattle emerge as robust models in agricultural settings due to the abundance of studies on the genotoxic capacity of pesticides, veterinary drug, and environmental biomonitoring, with direct implications for food safety. Domestic dogs are recognized as powerful sentinels for human health due to shared exposomes, physiological similarities (e.g., shorter cancer latency), and reduced lifestyle confounders; however, genotoxicity studies in dogs remain sparse compared to chemical exposure monitoring or cancer research. Conclusions: This review advocates for expanded, integrated use of these models to address genotoxic threats across ecosystems, which would benefit both animal and human health. In the application of biomonitoring studies with sentinel animals, a critical gap persists: the frequent lack of integration between xenobiotic quantification in environmental and biological samples, along with genotoxicity biomarkers evaluation in sentinel populations, which hinders comprehensive environmental risk assessment. Full article

(This article belongs to the Collection Feature Papers in ‘Animal Genetics and Genomics’)

► Show Figures

Graphical abstract

7 pages, 520 KiB

Open AccessReview

Phenotypic Spectrum of KATNIP-Associated Joubert Syndrome: Possible Association with Esophageal Atresia and Review of the Literature

by Maria Giovanna Tedesco, Ilaria Donati, Chiara Romeo, Sara Dal Bo, Chiara Nardini, Anna Maria Innoceta, Giulia Parmeggiani, Anna Patanè and Claudio Graziano

Genes 2025, 16(5), 524; https://doi.org/10.3390/genes16050524 (registering DOI) - 29 Apr 2025

Abstract

Background: Joubert syndrome (JS) is a multi-systemic ciliopathy, characterized by intellectual disability and congenital anomalies involving the brain, kidney, heart, and eye. Even if clinical presentation is variable, most authors consider a brain abnormality known as the molar tooth sign (MTS) as mandatory [...] Read more.

Background: Joubert syndrome (JS) is a multi-systemic ciliopathy, characterized by intellectual disability and congenital anomalies involving the brain, kidney, heart, and eye. Even if clinical presentation is variable, most authors consider a brain abnormality known as the molar tooth sign (MTS) as mandatory for diagnosis. About 40 genes were identified to be associated with JS, usually with an autosomal recessive pattern. KATNIP variants represent a rare cause of JS; only six families were previously reported. Methods: We performed exome sequencing in a child with a syndromic phenotype, described the clinical features and molecular findings, and performed a review of the literature to identify known individuals with pathogenic variants in KATNIP, highlighting clinical characteristics and gene-phenotype correlations. Results: Using exome sequencing, we identified a homozygous novel frameshift variant c.808del, p.Ser270ValfsTer28 in KATNIP in a 5-year-old male from a consanguineous family of Roma ethnic background. Notable clinical features of the proband include severe developmental delay, hypotonia, and post-axial polydactyly. He did not have MTS, but showed severe anemia and esophageal atresia, which was already reported in association with a KATNIP variant. We collected the phenotypes of all reported patients and discussed common and distinct features with respect to typical JS. Affected individuals shared JS clinical features, although the typical MTS was not always present, polydactyly and renal abnormalities were absent, while pituitary abnormalities were common. Conclusions: Our report provides new data for KATNIP-related JS, expanding the clinical phenotypic spectrum and suggesting a possible role of KATNIP defects in the development of esophageal atresia. Full article

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

► Show Figures

Figure 1

13 pages, 2291 KiB

Open AccessArticle

Genetic Analysis Reveals a Protective Effect of Sphingomyelin on Cholelithiasis

by Kun Mao, Ang Li, Haochen Liu, Yuntong Gao, Ziyan Wang, Xisu Wang, Shixuan Liu, Ziyuan Gao, Jiaqi Quan, Moyan Shao, Yunxi Liu, Liang Shi, Bo Zhang and Tianxiao Zhang

Genes 2025, 16(5), 523; https://doi.org/10.3390/genes16050523 (registering DOI) - 29 Apr 2025

Abstract

Background: Cholelithiasis is the most common disorder affecting the biliary system. Choline is an essential nutrient in the human diet and is crucial for the synthesis of neurotransmitters. Previous studies have suggested an association between choline metabolites and cholelithiasis. However, the underlying mechanisms [...] Read more.

Background: Cholelithiasis is the most common disorder affecting the biliary system. Choline is an essential nutrient in the human diet and is crucial for the synthesis of neurotransmitters. Previous studies have suggested an association between choline metabolites and cholelithiasis. However, the underlying mechanisms remain unclear. This research aims to fill the knowledge gap regarding the role of choline metabolites in cholelithiasis. Methods: Genetic data related to choline metabolites and other covariates were retrieved from the U.K. Biobank and IEU OpenGWAS database. Two-sample (TSMR) and multivariate Mendelian randomization (MVMR) analyses, mediation analysis, linkage disequilibrium score regression (LDSC), colocalization analysis, and enrichment analysis were performed. Results: A significant causal relationship was identified between serum level of sphingomyelin and cholelithiasis (p-value = 0.0002). A protective causal effect was identified in MVMR analysis. The following mediated MR analysis indicated that only LDL mediated a large part of the causal relationship (59.18%). Seven genes, including GCKR, SNX17, ABCG8, MARCH8, FUT2, APOH, and HNF1A, were revealed to be colocalized with the causal signal between sphingomyelin and cholelithiasis. Conclusion: The present study has identified a protective effect between sphingomyelin and cholelithiasis. This effect is largely mediated by LDL. The findings of this study offer valuable information for further exploration of the molecular mechanisms of cholelithiasis. Full article

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

► Show Figures

Figure 1

13 pages, 242 KiB

Open AccessArticle

A Series of Patients with Genodermatoses in a Reference Service for Rare Diseases: Results from the Brazilian Rare Genomes Project

by Carlos Eduardo Steiner, Maria Beatriz Puzzi, Antonia Paula Marques-de-Faria, Ruy Pires de Oliveira Sobrinho, Vera Lúcia Gil-da-Silva-Lopes, Carolina Araújo Moreno and The Rare Genomes Project Consortium

Genes 2025, 16(5), 522; https://doi.org/10.3390/genes16050522 (registering DOI) - 29 Apr 2025

Abstract

Background/Objectives: Genodermatoses are genetic conditions with clinical symptoms manifesting in the skin and adjoining tissues, individually rare but comprising a large and heterogeneous group of disorders that represents 15% of genetic diseases. This article discusses the results of individuals with genodermatoses from a [...] Read more.

Background/Objectives: Genodermatoses are genetic conditions with clinical symptoms manifesting in the skin and adjoining tissues, individually rare but comprising a large and heterogeneous group of disorders that represents 15% of genetic diseases. This article discusses the results of individuals with genodermatoses from a reference center for rare diseases studied through whole genome sequencing conducted by the Brazilian Rare Genomes Project between 2021 and 2023. Methods: A retrospective case series with data comprising sex, age at first assessment in the hospital, family history, clinical findings, and molecular results. Results: Excluding neurofibromatosis type 1, Ehlers–Danlos syndrome and RASopathies are discussed elsewhere. Diagnoses in this work comprised ectodermal dysplasias (n = 6), ichthyosis (n = 4), albinism (n = 4), tuberous sclerosis complex (n = 4), and incontinentia pigmenti (n = 3), in addition to 11 others with individual rare conditions. The sex ratio was 17:16 (M:F), consanguinity was present in 6/33 (18%), and the age at the first evaluation ranged from neonatal to 26 years (median 13.65 years). Negative results were 3/33 (9%), novel variants were 17/41 (41.4%), and 7/30 (23%) presented initially with a double molecular diagnosis, three confirming composed phenotypes. Conclusions: Besides reporting 17 novel variants in 14 genes (BLM, CACNA1B, EDA, ELN, ENG, ERC6, EVC2, PNPLA1, PITCH1, PORCN, SIN3A, TP63, TYR, and WNT10B), the study also identified three atypical clinical presentations due to dual diagnoses, and the c.454C>T variant in the SDR9C7 gene, previously reported only in dogs, was, for the first time, confirmed as causative for ichthyosis in humans. Full article

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

9 pages, 1023 KiB

Open AccessReview

A Novel Frameshift Variant and a Partial EHMT1 Microdeletion in Kleefstra Syndrome 1 Patients Resulting in Variable Phenotypic Severity and Literature Review

by Maria Tzetis, Anastasios Mitrakos, Ioanna Papathanasiou, Vasiliki Koute, Konstantina Kosma, Roser Pons, Aspasia Michoula, Ioanna Grivea and Aspasia Tsezou

Genes 2025, 16(5), 521; https://doi.org/10.3390/genes16050521 (registering DOI) - 29 Apr 2025

Abstract

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical [...] Read more.

Background: Kleefstra syndrome 1(KLEFS1, OMIM#610253) is a rare neurodevelopmental disorder (NDD) instigated by heterozygous variants or microdeletions occurring in the 9q34.4 genomic region of the euchromatic histone methyltransferase-1 (EHMT1) gene and is inherited in an autosomal dominant (AD) manner. The clinical phenotype of KLEFS1 includes moderate to severe intellectual disability (ID), hypotonia, and distinctive facial features and additionally involves other organ systems (heart, renal, genitourinary, sensory) albeit with phenotypic heterogeneity between patients. The purpose of this study is to expand the genotypic spectrum of KLEFS1 and compare phenotypic features of the syndrome of already published cases. Methods: Exome sequencing (ES), chromosomal microarray analysis (CMA), as well as sanger sequencing, for confirmation of the de novo status of the frameshift variant, were used. Results: Here we describe two more cases, both males with a similar age and carriers of novel variants; one with a frameshift variant involving exon 13: p.Val692Glyfs*64 and the other with the smallest so far described, 11 Kb (exons 19-25), 9q34.4 microdeletion: 9q34.3 (140703393-140714454). Both presented with an NDD disorder with one showing more severe ID with significant social disabilities, while the other with the microdeletion had mild ID and following a normal education curriculum. Neither of them were obese nor had any other significant organ system disorder. Conclusions: The observed phenotypic variability due to genotypic differences in the two children contributes to the expanding spectrum of KLEFS1 disease phenotypes. Full article

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

► Show Figures

Figure 1

19 pages, 48612 KiB

Open AccessArticle

Identification and Functional Validation of ACSL1 and FABP3 as Muscle-Related Genes Screened by Transcriptomics in Crossbred Duroc × Berkshire × Diannan Small-Eared Pigs

by Bohe Chen, Sui Liufu, Sheng Wen, Kaiming Wang, Wenwu Chen, Lanlin Xiao, Xiaolin Liu, Lei Yi, Jingwen Liu, Xin Xu, Caihong Liu, Wu Wen, Haiming Ma and Qiuchun Deng

Genes 2025, 16(5), 520; https://doi.org/10.3390/genes16050520 (registering DOI) - 29 Apr 2025

Abstract

Background: Crossbreeding strategies that combine the growth performance of Western pig breeds with the meat quality traits of Chinese indigenous breeds have garnered considerable interest. Duroc pigs are known for their high growth efficiency but have relatively low intramuscular fat (IMF) content. In [...] Read more.

Background: Crossbreeding strategies that combine the growth performance of Western pig breeds with the meat quality traits of Chinese indigenous breeds have garnered considerable interest. Duroc pigs are known for their high growth efficiency but have relatively low intramuscular fat (IMF) content. In contrast, native breeds like the Diannan Small-Eared pig exhibit superior pork quality with higher IMF levels. This study aimed to compare the muscle growth characteristics and molecular mechanisms between Duroc × Landrace × Yorkshire (DLY) and Duroc × Berkshire × Diannan Small-Eared (DBD) pigs. Methods: The longissimus dorsi tissue of 210-day-old DLY and DBD pigs was collected for analysis. HE staining assessed muscle fiber characteristics, IMF content was measured, and ELISA quantified muscle-derived growth and development-related factors. Transcriptome sequencing was conducted, followed by differential gene expression analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein–protein interaction (PPI) analyses. Functional validation of key genes was performed in C2C12 cells. Results: DBD pigs exhibited significantly larger muscle fiber diameter and higher IMF content compared to DLY pigs. IGF1 and GH levels were elevated in DBD pigs. Transcriptome analysis identified 185 upregulated and 102 downregulated genes, with enrichment in pathways including PI3K-Akt, MAPK, FoxO, and cGMP-PKG signaling. ACSL1 and FABP3 were functionally validated, showing promotion of differentiation and inhibition of proliferation in C2C12 cells. Conclusions: DBD pigs exhibit superior muscle growth traits and higher IMF content compared to DLY pigs. ACSL1 and FABP3 may serve as key regulators of muscle development in pigs. Full article

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

► Show Figures

Figure 1

7 pages, 860 KiB

Open AccessCase Report

Expanding the Mutational Spectrum of TSPEAR in Ectodermal Dysplasia Type 14: A Familial Case Study

by Roberto Sirica, Alessandro Ottaiano, Daniele De Brasi, Simone Marcella, Fabio Acquaviva, Monica Ianniello, Nadia Petrillo, Valentina De Angelis, Raffaella Ruggiero, Rossana D’Angelo, Eloisa Evangelista, Antonio Fico and Giovanni Savarese

Genes 2025, 16(5), 519; https://doi.org/10.3390/genes16050519 (registering DOI) - 29 Apr 2025

Abstract

Background: Ectodermal dysplasia (ED) encompasses a heterogeneous group of genetic disorders affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands. Among these, variants in TSPEAR (Thrombospondin-type laminin G domain and epilepsy-associated repeats) have been implicated in autosomal recessive ED type 14 [...] Read more.

Background: Ectodermal dysplasia (ED) encompasses a heterogeneous group of genetic disorders affecting ectoderm-derived structures such as hair, teeth, nails, and sweat glands. Among these, variants in TSPEAR (Thrombospondin-type laminin G domain and epilepsy-associated repeats) have been implicated in autosomal recessive ED type 14 (OMIM 618180), predominantly manifesting with dental anomalies and hair dysplasia. However, the mutational spectrum of TSPEAR remains incompletely characterized. Methods: Two female siblings (ID#1 and ID#4) were clinically evaluated for ED. Genetic analysis, including next-generation sequencing (NGS) and Sanger validation, was conducted to identify TSPEAR variants. A segregation study confirmed inheritance patterns within the family. Results: Both affected siblings exhibited hallmark features of TSPEAR-related ED14, including oligodontia with dysmorphic, pointed maxillary central incisors. Hair thinning and cutaneous angiomas were predominant in ID#4. Genetic analysis identified two compound heterozygous variants in TSPEAR: c.543-1G>A, a splice-site variant likely to disrupt mRNA processing, and NM_144991.2:c.1251G>C(p.Gln417His), a missense variant with predicted deleterious effects. Segregation analysis confirmed maternal and paternal inheritance of the respective variants. A third sibling, ID#5, was identified as a heterozygous carrier without clinical manifestations. Conclusions: This study contributes to the expanding understanding of TSPEAR-related ED14 by providing novel genotype–phenotype correlations. Full article

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

► Show Figures

Figure 1

13 pages, 508 KiB

Open AccessArticle

The rs1403543 Polymorphism of AGTR2, Which Encodes the Type-2 Angiotensin II Receptor, and Left Ventricular Mass in Polish Full-Term Newborns

by Iwona Gorący, Karol Miler, Klaudyna Lewandowska, Monika Rychel, Beata Łoniewska and Andrzej Ciechanowicz

Genes 2025, 16(5), 518; https://doi.org/10.3390/genes16050518 - 29 Apr 2025

Abstract

Background/Objectives: Left ventricular hypertrophy is a significant independent risk factor for increased cardiovascular morbidity and mortality. There are some reports indicating an association of rs1403543 (1675G>A) polymorphism in the AGTR2 gene, which encodes the type-2 angiotensin II receptor, with left ventricular hypertrophy or [...] Read more.

Background/Objectives: Left ventricular hypertrophy is a significant independent risk factor for increased cardiovascular morbidity and mortality. There are some reports indicating an association of rs1403543 (1675G>A) polymorphism in the AGTR2 gene, which encodes the type-2 angiotensin II receptor, with left ventricular hypertrophy or increased left ventricular mass (LVM) in adults. The aim of this study was to analyze the possible association of the AGTR2:rs1403543 polymorphism with LVM in full-term Polish healthy newborns. Methods: The study group comprised 207 consecutive, full-term, healthy newborns. LVM was assessed, on the 3rd day after birth, from the M-mode echocardiographic measurements of left ventricular dimensions using the Penn convention, with the Huwez et al.-modified equation mode. The AGTR2 polymorphism was identified by PCR-RFLP in genomic DNA extracted from cord blood leukocytes. Results: There were no significant differences in clinical and echocardiographic characteristics of male newborns in regard to the AGTR2:rs1403543 polymorphism. However, the LVM/body mass ratio in female newborns carrying at least one A allele (i.e., with genotype GA or AA) was significantly lower as compared to its value in reference (GG) homozygotes. In addition, in female newborns, the frequency of AGTR2 genotypes with at least one A allele was significantly higher in the lower tertile of LVM/body mass or LVM/body surface area (calculated using the Mosteller formula) ratios as compared with upper tertiles. Conclusions: Our results suggest that the AGTR2:rs1403543 polymorphism may be associated with the physiological variability of cardiac mass in female newborns. Full article

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

► Show Figures

Figure 1

16 pages, 3544 KiB

Open AccessArticle

Characterization of Extrachromosomal Circular DNA in Primary and Cisplatin-Resistant High-Grade Serous Ovarian Cancer

by Youya Wang, He Li, Qinglan Li, Yi Li, Hao Wu, Yan Ge, Xingnuo Zhu, Zhiguo Zheng and Zhongsheng Sun

Genes 2025, 16(5), 517; https://doi.org/10.3390/genes16050517 - 29 Apr 2025

Abstract

Background: Cisplatin resistance is a major cause of tumor recurrence and mortality in high-grade serous ovarian cancer (HGSOC). Extrachromosomal circular DNA (eccDNA) has emerged as a critical factor in tumor evolution and drug resistance. However, the specific contribution of eccDNA to cisplatin resistance [...] Read more.

Background: Cisplatin resistance is a major cause of tumor recurrence and mortality in high-grade serous ovarian cancer (HGSOC). Extrachromosomal circular DNA (eccDNA) has emerged as a critical factor in tumor evolution and drug resistance. However, the specific contribution of eccDNA to cisplatin resistance in HGSOC remains unclear. Methods: We performed whole-genome sequencing, Circle-Seq, and RNA-Seq in four pairs of primary and cisplatin-resistant (cisR) HGSOC cell lines to characterize genome-wide eccDNA distribution and features. Functional enrichment analyses were subsequently conducted on differentially expressed eccDNA-related genes. Results: In the SKOV3 cisR cell line, we identified a large extrachromosomal circular DNA (ecDNA) carrying the HIF1A gene, which regulates DNA repair, drug efflux, and epithelial–mesenchymal transition, contributing to cisplatin resistance. Using Circle-Seq, we detected a total of 161,062 eccDNAs, most of which were less than 1000 bp and distributed across all chromosomes. Notably, the number of eccDNAs on chromosome 21 differed significantly between the primary and cisR cell lines. Additionally, eccDNAs were predominantly located in non-coding repetitive elements. Functional analysis of eccDNA-related differentially expressed genes revealed that, compared to primary cell lines, cisR cell lines were associated with mitotic spindle assembly, regulation of vascular permeability, and cell differentiation. eccDNA-related genes involved in these pathways include MISP, WIPF1, RHOD, KRT80, and PLVAP. Conclusions: Our findings suggest that eccDNAs, particularly ecDNA amplifications like HIF1A, contribute significantly to cisplatin resistance mechanisms in HGSOC. These insights highlight eccDNA as a potential target for overcoming therapeutic resistance and improving treatment outcomes in ovarian cancer. Full article

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

► Show Figures

Figure 1

Journal Description

Genes

Latest Articles

Journal Menu

Journal Browser

Highly Accessed Articles

Latest Books

E-Mail Alert

News

Topics

Conferences

Special Issues

Topical Collections

Further Information

Guidelines

MDPI Initiatives

Follow MDPI