Search Results (110)

Background/Objectives: Cantú syndrome is a rare autosomal dominant genetic disorder caused by gain-of-function variants in the ABCC9 or KCNJ8 genes. Although its phenotypic expression is variable and can go unnoticed postnatally, certain ultrasound findings may raise suspicion during pregnancy. This article presents a case of prenatal diagnosis through exome sequencing, which also enabled retrospective diagnosis in the mother and a previously undiagnosed child, highlighting the clinical and emotional value of diagnostic certainty in fetal medicine. Methods: We conducted a descriptive observational study based on a case identified at the Fetal Medicine Unit of the Regional University Hospital of Málaga. The patient underwent high-resolution ultrasound and trio-based exome sequencing (fetus and both parents). Results: Prenatal exome sequencing revealed a heterozygous pathogenic variant in ABCC9, consistent with Cantú syndrome, identified simultaneously in the fetus and the mother as part of a trio-based analysis, confirming maternal inheritance. The same variant was later detected in the patient’s older daughter, who had been under pediatric evaluation for a suggestive phenotype but had not received a genetic diagnosis until this study. The prenatal diagnosis allowed for obstetric and neonatal planning, genetic counselling, and a reinterpretation of the clinical and emotional meaning of previous pregnancies. Conclusions: Prenatal diagnosis of Cantú syndrome enables anticipation of perinatal complications, planned clinical interventions, and also provides emotional relief and a coherent narrative for families. In scenarios of variable phenotypic expressivity, fetal medicine may represent a gateway to family diagnosis, with significant clinical and psychosocial implications. Full article

Attraction of glioblastoma cells to potassium was suspected when glioblastoma cells clustered around dying cells and migrated towards serum (high [K⁺]) and increased potassium. Potassium channel proteins (KCN family, 90 members) mediating alterations in the transmembrane flux may provide K⁺ that releases H⁺ bound to inner membranes in cancer cells for cytosolic proton transfer, possibly conformational in water (Grotthuss), to extrusion sites. Cell settling and migration assay results led to collecting 70 studies, unbiased by the authors for inclusion of KCN genes, that detected KCN differentially expressed genes (DEGs). Of 53 KCN DEGs found among 29 malignancies, 62.3% encoded H⁺-sensitive proteins. KCN DEGs encoding H⁺-sensitive proteins were more prevalent in 50 studies involving one or more categories (seven oncogenes and histone/DNA modifiers) versus those with none; p = 0.0325. Pertinent genes for lactate outflow, etc., had relatively normal levels of expression. Brain tumors in REMBRANDT (database) showed altered expression of KCN genes encoding H⁺-sensitive proteins in glioblastomas versus less invasive oligodendrogliomas of patients on anti-seizure medications, with less KCNJ16/Kir5.1; p = 5.32 × 10⁻⁸ in glioblastomas. Altered H⁺-sensitive potassium flux via the KCN family, downstream of oncogenes and histone/DNA modifiers, putatively incites proton transfers for H⁺ release during pH reversal (pHi > pHe) in cancer. Full article

Background/Objectives: Gliomas are complex and heterogeneous brain tumors characterized by an unfavorable clinical course and a fatal prognosis, which can be improved by an early determination of tumor kind. Here, we developed explainable machine learning (ML) models for classifying three major glioma subtypes (astrocytoma, oligodendroglioma, and glioblastoma) and predicting survival rates based on RNA-seq data. Methods: We analyzed publicly available datasets and applied feature selection techniques to identify key biomarkers. Using various ML models, we performed classification and survival analysis to develop robust predictive models. The best-performing models were then interpreted using Shapley additive explanations (SHAP). Results: Thirteen key genes (TERT, NOX4, MMP9, TRIM67, ZDHHC18, HDAC1, TUBB6, ADM, NOG, CHEK2, KCNJ11, KCNIP2, and VEGFA) proved to be closely associated with glioma subtypes as well as survival. Support Vector Machine (SVM) turned out to be the optimal classification model with the balanced accuracy of 0.816 and the area under the receiver operating characteristic curve (AUC) of 0.896 for the test datasets. The Case-Control Cox regression model (CoxCC) proved best for predicting survival with the Harrell’s C-index of 0.809 and 0.8 for the test datasets. Using SHAP we revealed the gene expression influence on the outputs of both models, thus enhancing the transparency of the prediction generation process. Conclusions: The results indicated that the developed models could serve as a valuable practical tool for clinicians, assisting them in diagnosing and determining optimal treatment strategies for patients with glioma. Full article

Background/Objectives: Heart failure with reduced ejection fraction (HFrEF) is associated with significant renal complications, affecting disease progression and patient outcomes. Sodium-glucose co-transporter-2 (SGLT2) inhibitors have emerged as a key therapeutic strategy, offering cardiovascular and renal benefits in these patients. However, interindividual variability in response to dapagliflozin underscores the role of pharmacogenetics in optimizing treatment efficacy. This study investigates the influence of genetic polymorphisms on renal outcomes in HFrEF patients treated with dapagliflozin, focusing on variations in genes such as SLC5A2, UMOD, KCNJ11, and ACE. Methods: This prospective, observational cohort study was conducted at the National Heart Institute, Cairo, Egypt, enrolling 200 patients with HFrEF. Genotyping of selected single nucleotide polymorphisms (SNPs) was performed using TaqMan™ assays. Renal function, including estimated glomerular filtration rate (eGFR), Kidney Injury Molecule-1 (KIM-1), and Neutrophil Gelatinase-Associated Lipocalin (NGAL) levels, was assessed at baseline and after six months of dapagliflozin therapy. Results: Significant associations were found between genetic variants and renal outcomes. Patients with AA genotype of rs3813008 (SLC5A2) exhibited the greatest improvement in eGFR (+7.2 mL ± 6.5, p = 0.004) and reductions in KIM-1 (−0.13 pg/mL ± 0.49, p < 0.0001) and NGAL (−6.1 pg/mL ± 15.4, p < 0.0001). Similarly, rs12917707 (UMOD) TT genotypes showed improved renal function. However, rs5219 (KCNJ11) showed no significant impact on renal outcomes. Conclusions: Pharmacogenetic variations influenced renal response to dapagliflozin in HFrEF patients, particularly in SLC5A2 and UMOD genes. These findings highlighted the potential of personalized medicine in optimizing therapy for HFrEF patients with renal complications. Full article

Growth traits are the most important economic traits in red tilapia (Oreochromis spp.) production, and are the main targets for its genetic improvement. Increasing salinity levels in the environment are affecting the growth, development, and molecular processes of aquatic animals. Red tilapia tolerates saline water to some degree. However, few credible genetic markers or potential genes are available for choosing fast-growth traits in salt-tolerant red tilapia. This work used genome-wide association study (GWAS) and RNA-sequencing (RNA-seq) to discover genes related to four growth traits in red tilapia cultured in saline water. Through genotyping, it was determined that 22 chromosomes have 12,776,921 high-quality single-nucleotide polymorphisms (SNPs). One significant SNP and eight suggestive SNPs were obtained, explaining 0.0019% to 0.3873% of phenotypic variance. A significant SNP peak associated with red tilapia growth traits was located on chr7 (chr7-47464467), and plxnb2 was identified as the candidate gene in this region. A total of 501 differentially expressed genes (DEGs) were found in the muscle of fast-growing individuals compared to those of slow-growing ones, according to a transcriptome analysis. Combining the findings of the GWAS and RNA-seq analysis, 11 candidate genes were identified, namely galnt9, esrrg, map7, mtfr2, kcnj8, fhit, dnm1, cald1, plxnb2, nuak1, and bpgm. These genes were involved in ‘other types of O-glycan biosynthesis’, ‘glycine, serine and threonine metabolism’, ‘glycolysis/gluconeogenesis’, ‘mucin-type O-glycan biosynthesis’ and ‘purine metabolism signaling’ pathways. We have developed molecular markers to genetically breed red tilapia that grow quickly in salty water. Our study lays the foundation for the future marker-assisted selection of growth traits in salt-tolerant red tilapia. Full article

Background: Molecular analysis in patients with nephrolithiasis (NL) and/or nephrocalcinosis (NC) enables more accurate evaluation of underlying etiologies. The existing clinical evidence regarding genetic testing in adults with NL comprises only a few cohort studies. Materials and Methods: We retrospectively analyzed 49 adult patients diagnosed with NL and/or NC from a single center, on whom we performed a genetic test using a nephrolithiasis panel. We reviewed the phenotype of the patients and compared the cases with positive and negative molecular diagnosis. Results: In total, 49 adult patients with NL and/or NC underwent genetic testing. Of the tested patients, 29 (59.2%) patients had 24 abnormal variants in 14 genes. Mendelian diseases were diagnosed in 14 (28.6%) cases: cystinuria (SLC3A1, SLC7A9; n = 4), hereditary distal renal tubular acidosis (SLC4A1; n = 3), Dent disease (CLCN5; n = 2), familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (CLDN16; n = 1), infantile hypercalcemia type 1 (CYP24A1; n = 1), primary hyperoxaluria type 1 (AGXT; n = 1), Bartter syndrome type 2 (KCNJ1; n = 1), and autosomal dominant tubulointerstitial kidney disease (UMOD; n = 1). Eight (16.3%) patients had pathogenic or likely pathogenic monoallelic variants as predisposing factors for NL and/or NC, and seven (14.3%) had biallelic or monoallelic variants of uncertain significance. Patients with positive genetic tests had a lower estimated glomerular filtration rate (p = 0.03) and more frequent NL associated with NC (p = 0.007) and were unlikely to have arterial hypertension (p = 0.03) when compared with patients with negative tests. Conclusions: Our study shows an increased effectiveness of molecular diagnosis and highlights the benefits of genetic testing. NL associated with NC and the presence of chronic kidney disease are the characteristics that should prompt the clinician to suspect an inherited form of NL and/or NC. Full article

Background: Pekin ducks are well-known meat-type ducks, whereas Shaoxing ducks are bred for their egg-laying abilities. Growth and development of poultry species is well studied; however, very little is known regarding differences in intestinal gene expression between Pekin and Shaoxing ducks. Methods: To investigate intestinal differences between Pekin and Shaoxing ducks, we conducted transcriptome analysis on ileal and cecal tissues from five 42-day-old ducks per breed, raised under identical housing and feeding conditions to minimize environmental influences. Results: The results showed that a total of 379 differentially expressed genes (DEGs) with p < 0.05 and |log₂FoldChange| > 1 were identified in the ileum when Pekin ducks were compared to Shaoxing ducks, among which 158 were upregulated and 221 were downregulated. Compared to Shaoxing ducks, a total of 367 DEGs with p < 0.05 and |log₂FoldChange| > 1 were identified in the ceca of Pekin ducks, among which 204 were upregulated and 163 were downregulated. Among these DEGs, nine genes were reported to be associated with growth and metabolism, namely, P2RX6, KCNJ6, CASQ2, EHHADH, ACSBG1, ELOVL4, AIF1L, VILL, and FABP1. Functional enrichment analyses using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases indicated that the DEGs were significantly involved in pathways such as calcium signaling, unsaturated fatty acid biosynthesis, fatty acid degradation, and tryptophan metabolism. Conclusions: In conclusion, our study identified transcriptome differences in the intestines of meat-type and laying-type ducks, offering insights into the genetic basis of their growth and metabolic differences. Future studies should validate key genes and explore environmental influences on gene expression. Full article

Background: Breast cancer (BC), one of the most common cancers, has increased in Mexico during the past decade, along with other chronic and metabolic diseases. Methods: Herein, we analyzed 121 SNPs (85 SNPs related to BC and/or glucose-associated metabolic pathways and 36 SNP classified as ancestry markers) in 92 confirmed BC cases and 126 unaffected BC women from Northeastern Mexico. The relationship of these 121 SNPs with BC, considering BMI, menopause status, and age as cofactors, was explored using a gene–environment (G × E) interaction multi-locus model. Results: Twelve gene variants were significantly associated with BC: three located in exome (rs3856806 PPARG, rs12792229 MMP8, and rs5218 KCNJ11-ABCC8), and nine in non-coding regions, which are involved in accelerated decay of the mRNA transcripts, regulatory regions, and flanking regions (rs3917542 PON1; rs3750804 and rs3750805 TCF7L2; rs1121980 and rs3751812 FTO; rs12946618 RPTOR; rs2833483 SCAF4; rs11652805 AMZ2P1-GNA13; and rs1800955 SCT-DEAF1-DRD4). Conclusions: This study identified an association between BC and menopause, age (above 45), obesity, and overweight status with gene variants implicated in diabetes mellitus, obesity, insulin resistance, inflammation, and remodeling of the extracellular matrix. Full article

Background: Short QT syndrome (SQTS) is a rare inheritable channelopathy characterized by a shortened corrected QT interval on an electrocardiogram and a significant risk of atrial and ventricular arrhythmias, potentially leading to sudden cardiac death. Despite advancements in our understanding of SQTS, knowledge gaps persist due to its extreme rarity. This scoping review aims to summarize the available knowledge on its clinical presentations, genetic mutations, and management strategies, while identifying areas for further investigation. Methods: This scoping review was conducted across the PubMed, Scopus, and Cochrane databases and identified relevant case reports, case series, and available studies on SQTS. We focused on articles that reported clinical outcomes, genetic mutations, diagnostic criteria, and management strategies, while excluding studies on the secondary causes of short QT intervals. Results: SQTS is present across a wide age range, from asymptomatic individuals to those experiencing syncope, palpitations, or sudden cardiac arrest. Common genetic mutations include KCNQ1, KCNH2, and KCNJ2. Management strategies vary, with some patients receiving implantable cardioverter defibrillators for secondary prevention and others treated pharmacologically, primarily with hydroquinidine. Our findings highlight the rarity and clinical variability of SQTS, underscoring the need for optimized diagnostic criteria and individualized management strategies. Conclusions: This review emphasizes the need for continued research to better understand the genetic basis of SQTS, optimize diagnostic tools, and improve treatment approaches. Large-scale studies and the integration of genetic and clinical data are critical to addressing the gaps in SQTS management and improving outcomes for patients with this potentially life-threatening arrhythmic disorder. Full article

Background and Objectives: Epilepsy, known as an unprovoked seizure, arises from the human brain. Genetics plays a fundamental role in the development and progression of the disorder. This study aimed to investigate the influence of voltage-gated K⁺ channels on the risk of epilepsy. Materials and Methods: Several genetic variants were examined using PCR sequencing. This case–control study was conducted on 296 individuals who were diagnosed with epilepsy, in addition to 293 healthy participants. Results: This study revealed that within KCNAB1, both rs3755631 and rs4679773 are correlated with epilepsy, and the p-values = 0.04 for both allelic associations. In addition, regarding the KCNJ10 gene, we found that rs2820585, rs946420, rs1186679, rs61822012, and rs1186685 were significantly correlated with epilepsy risk (p-values = 0.034, 0.045, 0.021, 0.048, and 0.018), respectively. Conclusions: From the current study, we conclude that voltage-gated potassium channels can impact epilepsy risk and can also interfere with the prognosis of epilepsy. Full article

Background: Neonatal diabetes (NDM) is a rare genetic disorder diagnosed in infants under six months of age, characterized by persistent hyperglycemia resulting from insufficient or absent insulin production. Unlike the more common forms of diabetes, such as type 1 diabetes (T1D) and type 2 diabetes (T2D), NDM is predominantly caused by monogenic mutations affecting ATP-sensitive potassium (K-ATP) channels in pancreatic beta cells. The most common mutations involved in NDM are found in the KCNJ11 and ABCC8 genes, which encode the Kir6.2 and SUR1 subunits of the K-ATP channel, respectively. These mutations prevent normal insulin secretion by disrupting the function of the K-ATP channel. While genetic advances have identified about 40 genes implicated in NDM, the KCNJ11 and ABCC8 mutations are most commonly seen. Methods: This review provides a comprehensive exploration of the genetic basis, clinical presentation, and treatment strategies for NDM including the role of sulfonylureas, which have revolutionized the management of this condition. Furthermore, it presents a detailed case study of an infant diagnosed with an ABCC8 mutation, illustrating the pivotal role of genetic testing in guiding clinical decisions. Conclusions: Finally, the article discusses challenges in management, such as the persistence of neurological impairments, and outlines potential directions for future research including genetic therapies and prenatal diagnosis. Full article

The aim of the present study was to investigate the dietary effects of replacing corn with different proportions of fermented straw on the growth performance and intestinal health of finishing pigs. A total of 275 healthy commercial finishing pigs aged 126 days (average body weight, 82.96 ± 3.07 kg) were randomly allocated into three groups: the control (CTR, basal diet) group, the 5% fermented straw (FJJG5, replacing 5% of the corn) group, and the 10% fermented straw (FJJG10, replacing 10% of the corn) group. There were six replicates in each group and 14–16 pigs per replicate. On day 39 of the experiment, one animal from each replicate was slaughtered for sampling and for further analysis. The results showed that the finishing pigs in the FJJG10 group had a reduced average daily weight gain and an increased feed-to-gain ratio. The FJJG5 group had reduced total cholesterol, high-density lipoprotein, and low-density lipoprotein in their serum, while the FJJG5 and FJJG10 groups had reduced contents of lactate dehydrogenase. In addition, the FJJG5 group exhibited increased T-SOD activity and MDA content in the colon, while the FJJG10 group also showed increased T-AOC activity in their serum and increased contents of MDA in the colon. The FJJG5 group exhibited increased activities of jejunal disaccharidase and lipase, while the FJJG10 group exhibited decreased jejunal crypt depths. Moreover, the FJJG5 group presented an increased relative expression of APOA4, LPL, and MUC2 but decreased SLC7A7 and IL-10 in the jejunum and APOA4 in the colon. The FJJG10 group exhibited a decreased relative expression of SLC7A7 and IL-10 in the jejunum and decreased MMP13, KCNJ13, APOA4, SLC7A7, LPL, and IL-10 in the colon. Furthermore, the FJJG5 group exhibited an increased relative abundance of Lactobacillus in colon contents, while the FJJG10 group had a reduced relative abundance of streptococcus. In conclusion, 5% fermented straw can improve the lipid metabolism and colon microbiota structure of finishing pigs, while 10% fermented straw has adverse effects on the growth performance and intestinal health of finishing pigs. Full article

Inherited arrhythmia syndromes include several different diseases, as well as Brugada syndrome (BrS), long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS). They represent, together with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), an important cause of sudden cardiac death in the young. Most arrhythmia syndromes are inherited in an autosomal dominant manner, and genetic studies are suggested.: to report the spectrum of genetic variations and clinical phenotype in an Italian cohort with confirmed inherited arrhythmia syndromes and arrhythmogenic cardiomyopathy using whole-exome sequencing (WES). Patients with confirmed inherited arrhythmia syndromes and hereditary cardiomyopathy were recruited at the Cardiology Unit, University Polyclinic Hospital of Foggia, Italy and were included in this study. Genomic DNA samples were extracted from peripheral blood and conducted for WES. The variants were annotated using BaseSpace Variant Interpreter Annotation Engine 3.15.0.0 (Illumina). Reported variants were investigated using ClinVar, VarSome Franklin and a literature review. They were categorised agreeing to the criteria of the American College of Medical Genetics and Genomics. Overall, 62 patients were enrolled. Most of them had a clinical diagnosis of BrS (n 48, 77%). The remaining patients included in the present study had diagnosis of confirmed LQT (n 7, 11%), AR-DCM (n 4, 6.5%), ARVD (n 2, 3%), and SQT (n 1, 1.6%). Using the WES technique, 22 variants in 15 genes associated with Brugada syndrome were identified in 21 patients (34%). Among these, the SCN5A gene had the highest number of variants (6 variants, 27%), followed by KCNJ5 and CASQ2 (2 variants). Only one variant was identified in the remaining genes. In 27 patients with a clinical diagnosis of BrS, no gene variant was detected. In patients with confirmed LQT, SQT, 10 variants in 9 genes were identified. Among patients with ARVD and AR-DCM, 6 variants in 5 genes were found. Variants found in our cohort were classified as pathogenic (6), likely pathogenic (3), of uncertain significance (26), and benign (1). Two additional gene variants were classified as risk factors. In this study, 13 novel genetic variations were recognized to be associated with inherited arrhythmogenic cardiomyopathies. Our understanding of inherited arrhythmia syndromes continues to progress. The era of next-generation sequencing has advanced quickly, given new genetic evidence including pathogenicity, background genetic noise, and increased discovery of variants of uncertain significance. Although NGS study has some limits in finding the full genetic data of probands, large-scale gene sequencing can promptly be applied in real clinical practices, especially in inherited and possibly fatal arrhythmia syndromes. Full article

Introduction: The variants rs10517086 and rs1534422 are predictive of type 1 diabetes mellitus (T1DM) development and poor residual β cell function within the first year of diagnosis. However, the mechanism by which risk is conferred is unknown. We explored the impact of both variants on β cell function in vitro and assessed their relationship with C-peptide in people with T1DM and type 2 diabetes mellitus (T2DM). Methods: Using CRISPR/Cas9, the variants were introduced into a β cell line (BRIN-BD11) and a T cell line (Jurkat cells) from which the conditioned media was applied to otherwise healthy β cells to model the inflammatory environment associated with these variants. Results: Both variants significantly reduced glucose-stimulated insulin secretion, increased production of pro-inflammatory cytokines and reduced expression of several β cell markers and transcription factors (KCNJ11, KCNQ1, SCL2A2, GCK, NKX6.1, Pdx1 NGN3). However, HNF1A was significantly upregulated in the presence of both variants. We subsequently silenced HNF1A in variant expressing BRIN-BD11 cells using siRNA and found that gene expression profiles were normalised. Induction of each variant significantly increased expression of the lncRNAs they encode, which was normalised upon HNF1A silencing. Analysis of the DARE (Diabetes Alliance for Research in England) study revealed an association of rs10517086_A genotype with C-peptide in 153 individuals with T1DM, but not in 417 people with T2DM. Conclusions: These data suggest that rs1534422 and rs10517086 exert multiple insults on the β cell through excessive upregulation of HNF1A and induction of pro-inflammatory cytokines, and highlight their utility as prognostic markers of β cell function. Full article

Background and Objectives: Hypertension (HTN) constitutes a significant global health burden, yet the specific genetic variant responsible for blood pressure regulation remains elusive. This study investigates the genetic basis of hypertension in the Jordanian population, focusing on gene variants related to ion channels and transporters, including KCNJ1, WNK1, NPPA, STK39, LUC7L2, NEDD4L, NPHS1, BDKRB2, and CACNA1C. Materials and Methods: This research involved 200 hypertensive patients and 224 healthy controls. Whole blood samples were collected from each participant, and genomic DNA was extracted. The genetic distribution of the polymorphisms was analyzed. The haplotype frequencies were investigated using the SNPStats web tool, and the genotype and allele frequencies of the studied variants were assessed using the χ² test. Results: Sixteen single nucleotide polymorphisms (SNPs) from nine genes were evaluated. A significant association was observed between the rs880054 variant of the WNK1 gene and hypertension susceptibility, with the T allele elevating the risk of hypertension. This association remained important in the codominant model (p = 0.049) and the dominant model (p = 0.029). In addition, rs880054 was associated with clinical characteristics such as triglyceride levels and cerebrovascular accidents (p-value > 0.05). Conclusions: Our findings reveal a significant link between the rs880054 SNP and an increased hypertension risk, suggesting that variations in WNK1 may be crucial in regulating blood pressure. This study provides new insights into the genetic factors contributing to hypertension and highlights the potential of WNK1 as a target for future therapeutic interventions. Full article