Search Results (200)

Gene therapy has emerged as a promising treatment for several eye diseases since it may restore vision and stop blindness. Many eye diseases, including retinitis pigmentosa and macular degeneration, have historically been rather difficult to treat and usually cause permanent vision loss. However, thanks to advances in gene therapy, many disorders can now be effectively targeted and genetically changed, providing a safer, more direct, maybe even curative approach. By introducing, altering, or repairing specific genes inside the eye, gene therapy seeks to fix the defective genes causing these disorders, thereby improving general eye health and visual ability. Voretigene neparvovec is one FDA- and EMA-approved treatment for RPE65 mutations. Retinitis pigmentosa, age-related macular degeneration, X-linked retinoschisis, choroideremia, and Stargardt disease are among the several eye disorders still under clinical trials, and experimental treatment is in progress. As research on gene therapy develops, it opens the path for groundbreaking treatments that could fundamentally change the ophthalmic care scene. Full article

Duchenne muscular dystrophy (DMD) is a severe X-linked disorder characterized by progressive muscle degeneration due to mutations in the dystrophin gene. Despite major advancements in understanding its pathophysiology, there is still no curative treatment. This review provides an up-to-date overview of current and emerging therapeutic approaches—including antisense oligonucleotides, gene therapy, gene editing, corticosteroids, and histone deacetylases(HDAC) inhibitors—aimed at restoring dystrophin expression or mitigating disease progression. Special emphasis is placed on the importance of early diagnosis, the utility of genetic screening, and the innovations in pre-and post-natal testing. As the field advances toward personalized medicine, the integration of precision therapies with cutting-edge diagnostic technologies promises to improve both prognosis and quality of life for individuals with DMD. Full article

Hemophilia, an X-linked bleeding disorder, is characterized by a deficiency in coagulation factors. It manifests as spontaneous bleeding, leading to severe complications if not properly managed. In contrast, acquired hemophilia is an autoimmune condition marked by the development of inhibitory antibodies against coagulation factors. Both forms present significant diagnostic and therapeutic challenges, highlighting the need for advanced genetic, molecular, laboratory, and clinical assessments. Recent advances in artificial intelligence have opened new avenues for the management of hemophilia. Machine learning and deep learning technologies enhance the ability to predict bleeding risks, optimize treatment regimens, and monitor disease progression with greater precision. Artificial intelligence-driven applications in medical imaging have also improved the detection of joint damage and hemarthrosis, ensuring timely interventions and better clinical outcomes. Moreover, the integration of artificial intelligence into clinical practice holds the potential to transform hemophilia care through predictive analytics and personalized medicine, promising not only faster and more accurate diagnoses but also a reduction in long-term complications. However, ethical considerations and the need for data standardization remain critical for its widespread adoption. The application of artificial intelligence in hemophilia represents a paradigm shift towards precision medicine, with the promise of significantly improving patient outcomes and quality of life. Full article

The prevalence, pathogenesis, and long-term consequences of hypertension differ significantly across the sexes, and pregnancy is a special physiological stress test that can reveal a woman’s underlying cardiovascular sensitivity. In addition to being direct risks to the health of the mother and fetus, hypertensive disorders of pregnancy (HDPs), especially preeclampsia, are also reliable indicators of future hypertension and cardiovascular disease in those who are afflicted. Fetal sex has a substantial impact on maternal vascular adaptation, according to new data from placental transcriptomics and epigenetics. This may be due to variations in the expression of angiogenic, immunomodulatory, and vasoactive genes. Sex-specific patterns of placental function, inflammation, and endothelium control are specifically influenced by X-linked gene dosage, escape from X-inactivation, and sex chromosomal composition. These biological variations highlight the placenta’s potential function as a mediator and indicator of maternal cardiovascular risk, and they may help to explain why the incidence and severity of hypertensive pregnancy challenges vary depending on the fetal sex. The purpose of this review is to summarize the state of the art regarding how placental genetics and fetal sex influence maternal hypertensive risk both during and after pregnancy. Additionally, it will investigate how these findings may influence sex-specific cardiovascular screening, prediction, and prevention methods. Full article

Viticulture is facing challenges, like the impact of climate change and various pests and pathogens. Alongside powdery and downy mildew, black rot is one of the most prevalent fungal diseases in European wine-growing regions. The focus of grapevine breeding research has so far been mainly on resistance to mildew diseases, and marker-assisted selection (MAS) in breeding material is possible for the most important resistance loci. However, only a few loci have been described for black rot resistance and these cannot yet be used for MAS. Thus, the characterization of genetic resistance to black rot and the establishment of closely linked genetic markers is important for the breeding of cultivars with multifungal resistances. In this study, an improved SSR marker-based genetic map of the biparental mapping population V3125 (‘Schiava Grossa’ x ‘Riesling’) x ‘Börner‘ (Vitis riparia x Vitis cinerea) was used to perform QTL analysis for black rot resistance. A total of 195 F1 individuals were analyzed at 347 SSR marker positions distributed on all 19 chromosomes. QTL analysis detected two QTLs conferring resistance to black rot on linkage groups 14 (Rgb1) and 16 (Rgb2). Our results revealed for the first time that Rgb1 and Rgb2 are derived from the wild species V. riparia. The presence of both loci in F1 individuals showed a clear additive effect for black rot resistance, supporting the breeding strategy of pyramiding two or more resistance factors to achieve a stronger overall resistance. Full article

Introduction: Multiple sclerosis (MS) is a chronic immune-mediated disease of the central nervous system (CNS) that leads to inflammation and demyelination, manifesting in either a relapsing–remitting or progressive form. As a multifactorial disease, MS involves both genetic and environmental factors, with a known significant contribution from human leukocyte antigen (HLA) genes, mainly represented by the HLA-DRB1 and HLA-DQB1 loci, which have been linked to either susceptibility or protection, but variably across populations and ethnic groups. We aimed to study the distribution and polymorphism of HLA-DRB1 and HLA-DQB1 alleles in a population with MS from the southern Moroccan region, in comparison with healthy controls. Materials and Methods: A cross-sectional study was conducted over a period of 2 years (2022–2024) in a MS cohort including 40 patients and 100 healthy controls. DRB1 and DQB1 HLA genotyping was performed using a high-resolution reverse sequence-specific oligonucleotide (SSO) method, based on the Luminex system (xMAP technology, One lambda^®). Data were analyzed using SPSS 26; differences in allele frequencies were evaluated by the Chi-square test and Fisher’s exact test. OR (95% CI) was calculated, and FDR corrections were applied for multiple testing. Results: Among the various HLA-DRB1 and DQB1 alleles studied, including those considered as predisposing to MS, the DQB1*02:01 and DRB1*15:01 alleles were more prevalent in MS patients, with 40% and 8.8% vs. 16% and 4.08% in controls respectively, although these differences were not statistically significant (p = 0.06 and p = 0.12). Likewise, the DRB1*15:01-DQB1*06:02 association was significantly more prevalent in the MS group (9%, p = 0.004). In contrast, the DRB1*07:01 allele, linked to protection against MS in many populations, was significantly predominant in controls (17%, p = 0.004). Similarly, the DRB1*07:01–DQB*02:01 combination was rather more frequent in controls (12%, p = 0.01). Confronted to MS clinical forms, we remarkably noted that the DRB1*13:03 allele was found only among relapsing–remitting MS (RRMS) patients (6%, p = 0.003), while DQB1*02:01 was significantly associated with RRMS (42.1%) and primary progressive MS (41%, p = 0.001), with an intermediate Expanded Disability Status Scale (EDSS) score, which may indicate a possible link with disease progression and severity. Conclusions: The results of our study highlighted particular HLA alleles, DRB1 and DQB1, alone or in combination, as potential immunogenic factors of susceptibility to MS in a population from southern Morocco, while other alleles seem rather to protect against the disease. This HLA polymorphism is also reflected in the clinical forms of the disease, showing a tendency toward severity for certain alleles. However, such preliminary results need to be consolidated and confirmed by studies carried out on a larger population sample, and compared with others on a national scale. Full article

Pathogenic variants in type IV collagen genes (COL4A3, COL4A4, COL4A5) are classically associated with Alport syndrome (AS), a hereditary nephropathy primarily affecting the glomerular basement membrane (GBM). Recent findings, however, suggest a broader phenotypic spectrum that includes renal cyst formation, raising questions about overlapping mechanisms with other cystic kidney diseases. Clinically, renal cysts have been increasingly reported in patients with autosomal dominant and X-linked forms of Alport syndrome, particularly in association with glycine missense variants. The most recent studies focusing on the cystic phenotype in Alport syndrome provide growing support for the idea that variants in type IV collagen genes are associated with an increased likelihood of developing renal cysts, likely through mechanisms involving the structural integrity of renal basement membranes. In this review, we explore evidence from murine models and human studies indicating defects in collagen IV and discuss their contribution to cystogenesis. These observations underscore the need for broader genetic screening strategies and further investigation into the molecular mechanisms underlying this emerging phenotype. Full article

Genetic variations in the COL1A1 and COL1A2 genes have been linked to bone mineral density (BMD) and metabolic disorders. This study analyzed the associations of COL1A1 (rs1107946, rs1800012) and COL1A2 (rs42524) polymorphisms with BMD, obesity, and type 2 diabetes (T2D) in 554 postmenopausal women. Dual-energy X-ray absorptiometry assessed BMD, and genotyping was performed alongside an evaluation of metabolic and lifestyle factors. The COL1A1 rs1107946 AA genotype was associated with higher femoral neck BMD (p < 0.05), an over 10-fold increased obesity prevalence (p = 0.038), and a 3.5-fold higher T2D risk (p = 0.011)—a novel finding. The rs1800012 polymorphism showed age-dependent BMD effects: A allele carriers had lower femoral neck BMD in the 60–69 age group but higher total hip BMD in the 70–79 age group. Additionally, COL1A2 rs42524 GG homozygotes had a significantly higher incidence of maternal fractures (p < 0.05). These results highlight COL1A1 rs1107946 as a potential marker for both skeletal and metabolic risk, demonstrate the age-specific effects of rs1800012 on BMD, and identify rs42524 as a possible genetic indicator of familial fracture risk. These insights may inform personalized approaches to osteoporosis and metabolic disease prevention. Full article

Hemoglobin disorders are among the most common inherited diseases worldwide. Their clinical manifestations range from anemia to more severe forms associated with neurological impairments. These complications can result as secondary consequences of the disease’s clinical manifestations or be directly linked to genetic mutations. In this study, we present two families with neurological impairments who were referred to us for complementary hematological and biochemical analyses. Complete blood count, methemoglobin level, and methemoglobin reductase activity were assessed. Molecular analyses were performed using whole-exome sequencing, and the segregation of the identified mutations was confirmed with direct sequencing. Their pathogenicity and conservation were evaluated using various bioinformatics tools. Clinical and hematological findings suggested X-linked alpha-thalassemia/impaired intellectual development syndrome in the first family and recessive congenital methemoglobinemia type II in the second. This was confirmed by the identification of pathogenic mutations ATRX: p.Arg2131Gln and CYB5R3: p.Ala179Thr, respectively. Although these variants have been previously reported worldwide, they were identified for the first time in our population. Our results contribute to the understanding of the pathogenesis of these rare disorders and provide a basis for diagnosis, treatment, and genetic counseling. The mechanisms by which these mutations contribute to neurological symptoms are discussed. Full article

Anderson Fabry disease (AFD) is an X-linked hereditary lysosomal abnormality that causes the accumulation of glycosphingolipids in body fluids and tissues, leading to progressive organ damage and a shortened life span. More than 1000 mutations in the GLA gene have been identified, promoting many different clinical pictures. For this reason, diagnosing AFD can be difficult, especially because of the great diversity of atypical clinical presentations that can simulate the disease. Some of these variants of the GLA gene have been described as non-pathogenic. For example, the D313Y variant is one of the most controversial, even if there are several case reports of D313Y patients presenting with signs and symptoms consistent with AFD without any other etiological explanation. This work aimed to clarify whether the presence of the D313Y variant affects α-Gal A activity and causes AFD symptoms and organ involvement in two patients from different families. The presence of the D313Y variant resulted in clinical manifestations of AFD in both patients and a decrease in alpha-galactosidase activity in the male patient. Two patients (one female and one male) from two unrelated families were examined. Sequencing of all seven GLA exons and the adjacent 5′ and 3′ exon–intron boundaries identified the D313Y variant in exon 6, as well as the genetic variation g.1170C>T in the flanking 5′ UTR in patient 1 only. Our results suggest that the D313Y variant is causative for the disease and that the clinical phenotype can be enhanced by the presence of other variants modulating protein expression. Full article

Background/Objectives: According to the International Classification of Hereditary Skeletal Diseases (2019), osteogenesis imperfecta (OI) is classified as a disorder resulting from impaired formation of the cortical layer density of diaphyses and metaphyseal modeling. OI comprises a heterogeneous group of genetic diseases, with most cases inherited in an autosomal dominant manner, while others follow autosomal recessive or X-linked recessive inheritance patterns. Accurate DNA testing is essential for precise medical and genetic counseling, ensuring reliable prognostic assessments for patients’ descendants and siblings. As part of a medical genetic study of the population of the Republic of the North Ossetia Alania, specifically in the Mozdok district, specialists from the Laboratory of Genetic Epidemiology at the Research Centre for Medical Genetics (RCMG) examined a family with 13 affected individuals with OI across four generations. Methods: A comprehensive clinical assessment was performed, followed by molecular genetic analysis using whole-exome sequencing (WES). Segregation analysis within the family was conducted via Sanger sequencing. Results: Clinical evaluation suggested a diagnosis of OI, which was subsequently confirmed by genetic testing. The severity and spectrum of symptoms varied considerably among affected family members and were influenced by age and specific nuclear family lineage. Molecular analysis in the proband identified a heterozygous pathogenic variant in the COL1A1 gene variant (c.1243C>T, p.(Arg415*)), confirming a diagnosis of OI type IV. The variant was found to co-segregate with the disease within the family. Conclusions: Molecular diagnosis enabled precise risk assessment for affected offspring in family members with mild phenotypic manifestations. Additionally, pediatric patients were referred for standard bisphosphonate therapy to manage the condition effectively. Full article

Background: Quercetin, a dietary flavonoid and a widely used supplement, has hepatoprotective properties. Given its urate-lowering effects and epidemiological evidence linking elevated serum urate levels to liver cancer risk, we tested whether quercetin reduces liver cancer risk via modulation of urate levels by bioinformatics methods. Methods: We employed drug-target Mendelian randomization using genome-wide association study summary statistics from public databases (e.g., MRC-IEU) to assess genetic associations, and integrated these findings with GEO datasets (such as GSE138709 and GSE179443) and immune infiltration analyses using tools like xCell, TIMER. Results: Our analyses identified ABCG2-mediated urate elevation as a causal risk factor for hepatocellular carcinoma (OR = 1.001, p < 0.01), cholangiocarcinoma (OR = 3.424, p < 0.01), and liver fibrosis (OR = 2.528, p < 0.01). Single-cell transcriptomics revealed elevated ABCG2 expression in cholangiocarcinoma endothelial cells, while immune infiltration analysis showed significant associations between ABCG2 expression and both endothelial cell and macrophage infiltration. Survival analysis further indicated that ABCG2 was not associated with poor prognosis in cholangiocarcinoma or hepatocellular carcinoma. Conclusions: Considering quercetin’s multifaceted interactions with BCRP/ABCG2, our findings support its potential use as a preventive dietary supplement for hepatic diseases rather than as an adjunctive therapy for established liver cancer. Full article

Abnormalities in X chromosomes, either numerical or structural, cause X-linked disorders, such as Duchenne muscular dystrophy (DMD). Recent molecular and cytogenetic techniques can help identify DMD gene mutations. The accurate diagnosis of Duchenne is crucial, directly impacting patient treatment management, genetics, and the establishment of effective prevention strategies. This review provides an overview of X chromosomal disorders affecting Duchenne and discusses how mutations in Dystrophin domains can impact detection accuracy. Firstly, the efficiency and use of cytogenetic and molecular techniques for the genetic diagnosis of Duchenne disease have, thus, become increasingly important. Secondly, artificial intelligence (AI) will be instrumental in developing future therapies by enabling the aggregation and synthesis of extensive and heterogeneous datasets, thereby elucidating underlying molecular mechanisms. However, despite advances in diagnostic technology, understanding the role of Dystrophin in Duchenne disease remains a challenge. Therefore, this review aims to synthesize this complex information to significantly advance the understanding of DMD and how it could affect patient care. Full article

Background/Objectives: Duchenne muscular dystrophy (DMD) is an X-linked inherited muscle disease. Patients with DMD demonstrate improved prognosis with angiotensin-converting enzyme inhibitors and beta-blockers at the time of cardiac dysfunction. However, most deaths due to DMD are due to cardiac dysfunction. Fragmented QRS (fQRS) is an abnormal finding that forms a notch in the QRS wave on electrocardiography (ECG) and is associated with fibrosis and scarring of the myocardium. Methods: Patients with DMD were examined for the number of leads of fQRS, their sites of appearance, changes in cardiac dysfunction, and age using the chest leads of a synthesized 18-ECG. A retrospective analysis of 184 patients under 20 years of age with DMD and known genetic mutations was performed; they were divided into three age groups: 3–10, 11–15, and 16–20 years. The chest leads of the ECG were defined as follows: V1-3, anterior leads; V4-6, lateral leads; V7-9, posterior leads; and V3R-V5R, right-sided chest leads. Cardiac dysfunction was defined as a left ventricular (LV) ejection fraction <53% on the same day, and echocardiography was performed. LV dilation was defined as dilation beyond the normal range, considering the body surface area. Results: In 167 of 184 patients (91%), fQRS was present in one or more chest leads. The number of fQRS leads in the anterior and lateral walls was significantly higher in 16–20-year-olds than in 3–10-year-olds. The total number of chest leads with fQRS was 4.9 ± 3.1 in the cardiac dysfunction group and 3.5 ± 2.5 in the preserved group. The cardiac dysfunction group had a significantly greater number of fQRS leads than did the preserved group (p = 0.003). The group with LV dilation had a significantly greater number of fQRS leads than did the non-dilation group (p = 0.009). Conclusions: The fQRS site is associated with age, cardiac dysfunction, and LV dilation. Multivariate regression analysis revealed that the number of anterior leads of the fQRS correlated with age and that of lateral leads of the fQRS with cardiac dysfunction and LV dilation. The number of fQRS leads on the lateral wall marks cardiac dysfunction and LV dilation. Full article

Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by mutations in the GLA gene, leading to α-galactosidase A deficiency and subsequent accumulation of glycosphingolipids, including globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3), in multiple organs. This accumulation can result in multisystemic disease and life-threatening complications. FD presents with a broad phenotypic spectrum, ranging from the classic form, with early and severe symptoms, to a later-onset form with variable manifestations. The severity of the disease in females is more variable due to X-chromosome inactivation (XCI). Renal involvement is a key feature, and kidney biopsy remains a valuable tool for diagnosing FD and assessing the extent of nephropathy. Although molecular genetic testing is the gold standard for diagnosis, kidney biopsy aids in confirming renal involvement, detecting coexisting conditions, and determining the pathogenicity of variants of uncertain significance (VUSs). Moreover, kidney biopsy can serve as a prognostic tool by identifying early markers of nephropathy, such as foot process effacement and glomerular sclerosis, which predict disease progression. Emerging technologies, including machine learning, offer the potential to enhance the analysis of renal histology, improving diagnostic accuracy and patient stratification. Despite the challenges posed by overlapping diseases and potential misdiagnoses, kidney biopsy remains an essential component of FD diagnosis and management, facilitating early detection, the monitoring of disease progression, and the evaluation of therapeutic responses. Full article