Search Results (1,157)

Xeroderma Pigmentosum group C (XP-C) is an autosomal recessive disorder caused by mutations in the XPC gene, leading to defective nucleotide excision repair. This defect leads to genomic instability and a profound cancer predisposition. To model this disease, we generated induced pluripotent stem cells (iPSCs) from an XP-C patient carrying a novel homozygous nonsense mutation in the XPC gene (c.1830C>A). The resulting iPSCs demonstrated typical pluripotent characteristics, including expression of key markers and trilineage differentiation capability. However, genomic assessment revealed progressive karyotypic instability during extended culture. While initial whole-genome sequencing detected no major chromosomal abnormalities, subsequent G-banding analysis identified acquired trisomy 12 in two lines (CL12 and CL27) and a derivative X chromosome in a third line (CL30). These abnormalities were absent in early-passage analyses, indicating that they were acquired and selected for during extended culture. The acquisition of a derivative X chromosome in CL30, alongside recurrent trisomy 12, represents a unique cytogenetic signature likely attributable to the underlying XPC defect. We hypothesize that the loss of GG-NER creates a permissive genomic environment, accelerating the accumulation of DNA damage and chromosomal missegregation under replicative stress. This temporal divergence in genomic integrity highlights how culture pressures drive chromosomal evolution in XP-C iPSCs independently of initial reprogramming. Our findings emphasize that XP-C iPSCs require continuous genomic surveillance and provide a model for investigating how DNA repair deficiencies interact with in vitro culture stress. Full article

Background: Type 2 diabetes mellitus (T2DM) remains one of the most significant public health problems, and its incidence rate is steadily increasing worldwide despite scientific and technological progress in the field of medicine. The focus of research in this area is gradually shifting from classic risk factors—such as obesity, sedentary lifestyle and genetic predisposition—toward additional, potentially modifiable contributors such as micronutrient imbalances; among them are disturbances in zinc homeostasis that may influence glucose metabolism and oxidative stress. Objective: This systematic review with narrative synthesis aims to examine the bidirectional relationship between zinc status and T2DM and to evaluate whether zinc screening and personalized nutritional support could contribute to comprehensive metabolic management. Methods: A literature search was conducted in the PubMed database and the Cochrane library for studies published between 2010 and 2024. Studies assessing zinc status or supplementation in relation to the risk, progression, or management of T2DM were included. Data were synthesized narratively, focusing on clinical and mechanistic evidence. Results: Thirty studies met the inclusion criteria. Evidence indicates that zinc imbalance (both deficiency and excess) is associated with T2DM risk and outcomes. Zinc deficiency may impair insulin synthesis and signaling, promote oxidative stress and inflammation, while excessive zinc intake may induce metabolic disturbances. T2DM itself may lead to reduced zinc status via altered absorption and increased excretion. While some studies suggest modest improvements in glycemic or lipid parameters following zinc supplementation, findings remain inconsistent and context-dependent. The prevalence of suboptimal zinc status in certain populations supports the rationale for targeted screening rather than routine supplementation. Conclusions: Zinc is mechanistically involved in insulin synthesis, antioxidant defense, and inflammation control, but current clinical evidence does not justify its use as a therapeutic agent in T2DM. Instead, assessment of zinc status and individualized correction of deficiency may represent a component of personalized nutritional support, particularly for patients with long disease duration, poor dietary quality, or genetic predispositions affecting zinc metabolism. Full article

Hereditary predisposition substantially shapes prevention and management across urologic oncology. This narrative review synthesizes contemporary, practice-oriented guidance on whom to test, what to test, how to act on results, and how to implement care equitably for hereditary forms of prostate cancer, renal cell carcinoma (RCC), urothelial carcinoma, pheochromocytoma/paraganglioma (PPGL), and adrenocortical carcinoma (ACC). We delineate between forms of indication-driven germline testing (e.g., universal testing in metastatic prostate cancer; early-onset, bilateral/multifocal, or syndromic RCC; reflex tumor mismatch repair (MMR)/microsatellite instability (MSI) screening in upper-tract urothelial carcinoma (UTUC); universal testing in PPGL; universal TP53 testing in ACC) and pair these strategies with minimum actionable gene sets and syndrome-specific surveillance frameworks. Key points include targeted prostate-specific antigen screening in BRCA2 carriers and the impact of BRCA/ATM variants on reclassification during active surveillance; major hereditary RCC syndromes with genotype-tailored surveillance and pathway-directed therapy (e.g., HIF-2α inhibition for von Hippel–Lindau disease); UTUC/bladder cancer in Lynch syndrome with tumor MMR/MSI screening, annual urinalysis (selective cytology), and immunotherapy opportunities in deficient MMR disease/MSI-H; PPGL management emphasizing universal germline testing, intensified surveillance for SDHB, cortical-sparing adrenalectomy, and emerging HIF-2α inhibition; and ACC care modified by Li–Fraumeni syndrome (minimization of radiation/genotoxic therapy with whole-body imaging surveillance). Testicular germ cell tumor remains largely polygenic, with no routine germline testing in typical presentations. Finally, we provide pre-/post-test genetic-counseling checklists and mainstreamed workflows with equity metrics to operationalize precision care and close real-world access gaps. Full article

Background/Objectives: Multiple primary malignancies (MPMs) are defined as the occurrence of two or more independent primary tumors in the same patient, histologically distinct and not of metastatic origin. Patients treated for Hodgkin’s lymphoma (HL) carry an increased risk of developing secondary malignancies, especially after chemotherapy and radiotherapy. The synchronous occurrence of breast and kidney carcinoma in this population is extremely rare. Methods: We present a 41-year-old female patient with a history of HL treated at the age of 23 with ABVD chemotherapy and supradiaphragmatic radiotherapy. Results: During staging for a newly diagnosed breast tumor (ER+/PR+/HER2+, pT1cN0), an incidental renal mass was identified and histologically confirmed as clear cell renal cell carcinoma (pT1aNxMx, G2). A multidisciplinary team performed simultaneous partial breast resection with sentinel lymph node biopsy and nephrectomy. The postoperative course was uneventful, and adjuvant systemic therapy was initiated according to oncological guidelines. Conclusions: Synchronous malignancies in HL survivors pose a clinical challenge, as they must be distinguished from metastatic disease and require coordinated therapeutic planning. Risk factors include prior radiotherapy, chemotherapy, genetic predisposition, and family history. This case highlights the importance of long-term surveillance of HL survivors, particularly young women, due to their elevated risk of secondary malignancies. Synchronous breast and kidney carcinomas after HL therapy are extremely rare and demand an integrated multidisciplinary approach. Early recognition and coordinated therapy are crucial for optimizing outcomes and contributing to a better understanding of the etiology and pathogenesis of multiple primary malignancies. Full article

Lymphoedema is a physically and psychologically stressful, chronic progressive disease caused by long lasting damage or malfunction of the lymphatic drainage system. It is classified as primary when caused by a genetic predisposition (inherited or congenital) directly affecting any part of the lymphatic vascular system, or, much more often, as secondary (acquired) when caused by factors outside the lymphatic system, such as tumours or their treatment. As part of the development of an S3 guideline for the diagnosis and treatment of lymphoedema in German-speaking countries, we present here the definition of lymphoedema, its epidemiology, staging, pathophysiology, aggravating comorbidities, and differentiation from other forms of oedema or volume-increasing diseases. We refer to molecular links with obesity, present a diagram of possible pathomechanistic interactions, and finally discuss approaches for potential drug therapies. More intensive molecular genetic diagnostics of primary lymphedema seem to be gaining ground in Germany currently. We recommend further strengthening these diagnostics, as this is the only way to expand therapeutic options in the future and use existing therapies more efficiently. Full article

Acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are clonal hematopoietic malignancies in which next-generation sequencing (NGS) has become integral for diagnosis, classification, risk stratification, and measurable residual disease (MRD) monitoring. Traditional cytogenetic and PCR-based assays remain useful, but targeted NGS panels now represent the standard of care, providing rapid and sensitive detection of recurrent gene mutations, structural variants, and gene fusions. Whole-genome, whole-exome, and RNA sequencing and long-read platforms expand the spectrum of detectable alterations, though targeted panels remain most practical for routine diagnostics. Bioinformatic pipelines and quality metrics—including read length, sequencing depth, and coverage—are critical for accurate variant calling, with validation often required for variants of uncertain significance or those near detection thresholds. NGS is now embedded in diagnostic frameworks, including the WHO 2022 and ICC classifications, which incorporate recurrently mutated genes such as TP53, ASXL1, RUNX1, and FLT3. These data inform prognostic models, with ELN-2022 defining adverse-risk AML subgroups for patients treated with intensive chemotherapy, ELN-2024 AML for patients treated with less-intensive therapies, and the IPSS-M refining MDS risk categories by integrating mutational data. NGS also enables MRD monitoring, with gene panels and PCR-NGS hybrid approaches (e.g., for FLT3-ITD) showing increasing clinical utility, though standardization is still lacking. Furthermore, diagnostic NGS frequently uncovers germline predisposition syndromes (e.g., DDX41, GATA2), with significant implications for treatment decisions and donor selection in transplantation. In this manuscript, we review the advantages, limitations, and future perspectives of NGS in the clinical management of AML and MDS with a particular emphasis on the biological and technical principles underlying its use in these diseases. Furthermore, we discuss how NGS findings may influence diagnosis, prognostic classification, and therapeutic decision-making within current clinical frameworks. Our aim is to provide a comprehensive overview of NGS fundamentals to support clinicians in navigating the increasing complexity of molecular data in daily practice. Full article

Acute pancreatitis (AP) is a multifactorial, complicated inflammatory process that involves the organ and the tissues around it. In children, the most common causes of acute pancreatitis are abdominal trauma, infections (mostly viruses), systemic diseases, bile duct diseases (anatomical defects and/or gallstones) and genetic mutations. The course of the disease can vary from mild to very severe with life-threatening complications. The aim of this study was to conduct a retrospective analysis of causes, clinical picture, complications and treatment of acute pancreatitis in children. Materials and methods: We retrospectively analyzed the history of 57 children hospitalized in the Department of Paediatrics, Medical University of Silesia in Katowice between 2019 and 2022 with diagnosed acute pancreatitis. Results: The analysis included 57 children (age 2–18 years, average 11.0 years, 51% boys, 49% girls) with diagnosed acute pancreatitis. The most common causes of acute pancreatitis were biliary (14/57—24.6%), genetic (10/57—17.5%) and anatomical defects (8/57—14%). In 20/57 (35.1%) children, idiopathic acute pancreatitis was diagnosed. The genetically determined causes were the following: SPINK1 mutation in 5/57 (8.7%) children, PRSS1 mutation in 4/57 (7%) patients and CPA1 mutation in 1/57 (1.8%) children. A total of 19/57 (33.3%) children had more than one episode of acute pancreatitis during the considered period. A total of 10/57 (17.5%) children were obese. The clinical picture was dominated by abdominal pain, vomiting and jaundice. Complications were observed in 9/57 (15.8%) children: peripancreatic fluid collections (6/57—10.5%), pancreatic necrosis (4/57—7%), and pleural effusion and/or pseudocysts. Conclusions: The number of children diagnosed and treated with acute pancreatitis increased over time. The most frequent causes are genetic predispositions, infections and cholelithiasis. Acute pancreatitis should be considered in every case of abdominal pain, vomiting and jaundice in children. Complications with a severe course are also observed in the pediatric population with acute pancreatitis. Full article

Autoimmune thyroid disease (AITD) exemplifies an organ-specific autoimmune disorder, including Hashimoto’s thyroiditis (HT) and Graves’ disease (GD). HT is characterized by hypothyroidism, whereas GD primarily presents as hyperthyroidism. Immunological evidence indicates that AITD pathogenesis requires both a permissive genetic background and environmental triggers to initiate and sustain disease progression. However, the exact molecular and cellular pathways through which these elements synergize to trigger and sustain autoimmune responses remain unclear. Emerging evidence suggests that epigenetic regulation serves as the key interface decoding genetic predisposition through environmental stimuli in AITD etiology. Studies show that environmental epigenetic reprogramming initiates AITD development in genetically susceptible individuals. Epigenetic regulators, including DNA methylation, histone modifications, and non-coding RNA activity, finely tune transcriptional outputs to influence disease trajectories. Beyond elucidating AITD pathogenesis, these epigenetic alterations offer clinical value as diagnostic biomarkers and modifiable therapeutic targets, facilitating precision medicine approaches from early detection to customized interventions. These epigenetic modifications not only elucidate AITD pathophysiology but also provide measurable markers for early diagnosis and molecular targets for personalized treatment strategies. Full article

Background: Adenomyosis and endometriosis are complex, estrogen-dependent gynecological conditions increasingly diagnosed in adolescents. While traditionally considered diseases of reproductive-age women, emerging evidence suggests a possible developmental origin in some cases, with genetic and epigenetic susceptibility playing a central role. Understanding the contribution of hereditary and molecular factors in adolescent-onset forms may offer insights into early pathogenesis, personalized risk stratification and tailored prevention strategies. Objectives: The objectives of this study were to explore the current evidence supporting a genetic contribution to the development of adenomyosis and endometriosis in adolescents and to identify specific genetic variants, molecular pathways and epigenetic mechanisms potentially involved in early-onset disease. Methods: A narrative literature review was conducted using PubMed and Scopus databases up to September 2025. Studies investigating the genetic basis of adenomyosis and endometriosis in adolescents, including familial aggregation, twin studies, GWAS and candidate gene analyses, were included. Results: Evidence from familial clustering and twin studies suggests a significant heritable component in both conditions. Genome-wide association studies have identified susceptibility loci, particularly involving WNT4, VEZT and ESR1, that may be relevant to adolescent-onset disease. Candidate gene studies further highlight the roles of estrogen signalling, inflammatory pathways, extracellular matrix remodelling and emerging epigenetic alterations, including aberrant DNA methylation and chromatin remodelling, which may influence early lesion development. However, most data are derived from adult cohorts, with limited adolescent-specific analyses. Conclusions: Genetic and epigenetic predispositions appear to contribute significantly to the pathogenesis of endometriosis and possibly adenomyosis in adolescents. Further studies targeting early-onset disease are needed to unravel developmental mechanisms and gene–environment interactions unique to this population. Full article

Eosinophilic esophagitis (EoE) is an emerging disease characterized by chronic inflammation of the esophagus. EoE is a multifactorial disorder, likely resulting from the combination of genetic predisposition, epithelial barrier dysfunction, environmental risk factors, and allergen sensitization, which lead to type 2 inflammation of the esophagus. The clinical manifestations are related to esophageal dysfunction and include dysphagia, food impaction, heartburn, regurgitation, and food refusal. These symptoms are sometimes superimposable and can often be confused with the symptoms of gastroesophageal reflux disease. To-date, EoE diagnosis relies on endoscopic examination and histological analysis of esophageal biopsies, with the diagnostic criterion defined as the presence of ≥15 eosinophils per high-power field (eos/HPF). As a result, both the diagnostic and the subsequent disease monitoring processes, including assessment of treatment, efficacy, and remission status, require repeated endoscopic procedures. These procedures are rather invasive for patients, particularly in the pediatric population, and impose a significant financial strain on healthcare systems. Therefore, in recent years, substantial efforts have been made to identify novel non-invasive or minimally invasive biomarkers. This review aims at synthesizing the current findings and at categorizing the most promising biomarkers according to the different biological sources to ultimately enable earlier detection, reduce patient discomfort, and guide personalized treatment strategies. Full article

Inherited arrhythmias and cardiomyopathies are a group of potentially lethal genetic cardiac disorders which are often passed down through generations and pose risks to several family members. While individually rare, these conditions are collectively common and pose significant challenges for clinical management given their variable severity, age of onset, and response to treatments. Earlier genetic analyses revealed crucial insights into the main genetic culprits of these disorders, such as SCN5A for Brugada syndrome, and MYH7 and MYBPC3 for hypertrophic cardiomyopathy, which have revolutionized diagnosis, risk stratification, and medical management. Nonetheless, issues such as variable expressivity and penetrance, low yield of genetic testing, and relative lack of disease-modifying therapies remain significant hurdles for clinical management. The revolution of genome-wide association studies GWASs has transformed our understanding of inherited arrhythmias and cardiomyopathies, shifting the view of these disorders from a monogenic Mendelian inheritance towards a more complex, often polygenic inheritance with nuanced interplay between genetics and environment. Moreover, GWASs have enabled the quantification of polygenic predisposition to disease using polygenic risk scores, which are often complementary to and independent of monogenic risk. In this review, we highlight how GWASs have transformed the field of inherited arrhythmias and cardiomyopathies, with a particular focus on the polygenic risk scores developed and their clinical utility for the four disorders which have been impacted by GWASs—hypertrophic cardiomyopathy, dilated cardiomyopathy, Brugada syndrome, and long QT syndrome. Full article

Chronic Kidney Disease (CKD) is among the most frequent and clinically relevant metabolic disorders in cats, affecting a substantial proportion of the adult and geriatric feline population. The prevalence of CKD increases with age, being estimated at 20–50% in cats over 10 years of age. The etiology of this disorder involves genetic predisposition, dietary factors, as well as exposure to toxins or concomitant diseases that may accelerate the progression of renal lesions. The present study synthesizes data from the scientific literature together with clinical-epidemiological analyses performed on a cohort of 120 cats over a four-year period. The results highlighted an overall prevalence of CKD in the studied cohort, with a significantly higher frequency in cats over nine years of age, particularly affecting purebred animals. A slightly higher prevalence was observed in males compared to females, while reproductive status indicated an increased risk of CKD in neutered patients. Living environment and nutritional status were also influential, with a higher disease prevalence in indoor-only cats and in those fed nutritionally deficient diets. The multifactorial nature of CKD pathogenesis, combined with the nonspecific clinical manifestations in its early stages, explains the frequent late diagnosis of most cases. Consequently, an in-depth understanding of the epidemiology and associated risk factors constitutes an essential prerequisite for the development of preventive strategies, early screening protocols, and personalized therapeutic management aimed at optimizing quality of life and longevity in feline patients. Full article

Myxomatous mitral valve disease (MMVD) is the most prevalent cardiac disorder in small and toy breed dogs, with the Cavalier King Charles Spaniel (CKCS) showing exceptionally high predisposition and early onset of the disease. MMVD is characterized by progressive mitral valve degeneration, volume overload, and eventual development of congestive heart failure (CHF). Given the strong hereditary component in CKCS, considerable research has focused on elucidating the genetic basis of MMVD in this breed. This review article summarizes the current state of knowledge on the phenotypic features, inheritance, and candidate loci potentially responsible for early onset and severe course of the disease. The pathogenesis of the disease, its classification, and the effects of breeding programs aimed at reducing the occurrence of MMVD have been described. Key findings include associations between MMVD severity and polymorphisms in genes such as NEBL, ACE, CDK6, HEPACAM2, COL5A1, and FAH, as well as evidence implicating dysregulated TGF-β signaling, serotonin signaling, and extracellular matrix remodeling pathways. The current state of knowledge on the role of miRNA in the pathogenesis of MMVD was also summarized. Despite these findings, no specific high-penetrating mutation has been identified. MMVD is a complex, polygenic condition shaped by regulatory variants and breed-specific genetic bottlenecks. Comparative studies underscore the translational relevance of canine MMVD to human mitral valve disease, while genomic insights may be basis for the future selective breeding strategies and therapeutic approaches. Further large-scale, integrative studies combining genomics, transcriptomics, and functional validation are needed to clarify disease mechanisms and support targeted treatment in CKCS as well as the development of new breeding strategies and programs. Full article

Peptic ulcer disease and gastric cancer are influenced by both environmental factors and genetic background. One such genetic factor is changes in the BAX gene, where G-248A decreases the activity of the BAX gene promoter, thereby inhibiting apoptosis and promoting carcinogenesis. The relationship between the BAX gene and the risk of developing these diseases has not been fully elucidated. In this study, genotyping G-248A was performed by restriction fragment-length polymorphism, and real-time PCR was employed to quantify BAX mRNA expression. An in silico analysis was performed using publicly available databases. The findings reveal a significant prevalence of the AA genotype in the gastric cancer group compared to healthy individuals, suggesting a potential genetic predisposition to malignancy. When peptic ulcer group and healthy controls were compared, no significant association was found. Further, in silico analyses demonstrated elevated BAX expression in gastric cancer tissues, correlating with advanced histological grades and improved overall survival rates. Elevated BAX expression, however, is associated with gastric cancer onset and could be a promising prognostic indicator. This study underlines the complex correlation between genetic factors and disease, highlighting the potential of the BAX gene as a biomarker for gastric cancer prognosis and therapeutic targeting. Full article

Peri-implantitis is a multifactorial inflammatory disease that can compromise the longevity of dental implants. Several studies have investigated the association between genetic variants. This systematic review aimed to assess the contribution of genetic polymorphisms to the risk of developing peri-implantitis. A systematic search was conducted in the PubMed database up to 2025 following the PICO strategy and PRISMA guidelines. Eligible studies met the following inclusion criteria: articles written in English, addressing genetic associations with peri-implantitis in human subjects, designed as clinical trials or observational (prospective or retrospective) studies, with full-text availability, and published within the last ten years. Exclusion criteria included studies in languages other than English, those not addressing the main research question, publications older than ten years, studies without full text, and secondary research such as meta-analyses or review articles. Selection and data extraction were performed independently by two reviewers. Risk of bias was evaluated qualitatively for control studies. Twenty-three studies met the inclusion criteria. Polymorphisms in genes related to inflammatory cytokines (e.g., IL-1β +3954 C/T, IL-10, TNF-α), bone metabolism (OPG, BMP4, FGF10), and immune regulation (CD14 rs2569190, miR-27a-3p) were frequently reported. IL-1β +3954 C/T, ET-1 and IL-1β, MMP-8 rs11225395 (T allele), MMP8 (−799 C/T), and CD14 rs2569190 showed consistent associations with increased peri-implantitis risk, while the results for TNF-α −308 G/A were inconsistent across populations. These findings suggest a potential role of genetic predisposition in peri-implantitis development. Identifying genetic biomarkers may help predict susceptibility and personalize management strategies. Full article