Search Results (131)

Background: Haemoglobinopathies are the most common monogenic disorders both in Greece and worldwide. The most effective strategies against them are carrier detection and prenatal testing following genetic risk assessment consultation for couples on the likelihood of their offspring being affected. Case Presentation: A novel alpha globin chain variant, named Hb Thessaloniki, was detected in Northern Greece. The underlying point variation HBA1:c.260T>C (ref. seq. NM_000558.5) was detected in the HBA1 gene, in heterozygosity, during a routinely performed population screening for haemoglobinopathies. The amino-acid residue Leu86 was replaced by a structure disrupting Pro residue, resulting in a hyperunstable product as shown by the isopropanol test and predicted by the Dynamut2 and Alphafold3 algorithms. The haematological phenotype, due to which genetic analysis was performed, presented with mild microcytosis and hypochromia and was also indicative of the presence of an unstable haemoglobin produced in small quantities (variant encoded by HBA1). Since the proband’s partner presented with a normal haematological phenotype, there is no risk of the couple giving birth to an affected offspring. Expanded analysis of the proband’s relatives identified biallelic variants (α^Parmaα/αα^{Τhessaloniki}) in the proband’s mother, who presented with no apparent clinical findings, expect for slightly reduced haematological indices. Conclusions: The novel Hb Thessaloniki identified, although theoretically hyperunstable, seems to have minor effects on erythrocyte function, as indicated by haematological findings on the proband and his close relatives. Future identification of co-inheritance with HBA pathogenic point variations or deletions may provide further information regarding genetic counselling. In parallel, the usage of structure–function relation-calculating algorithms may enhance our prediction capability for novel variants. Full article

Legg–Calvé–Perthes disease (LCPD) is a rare disease caused by avascular necrosis of the femoral head. Although its etiology is still not fully understood, evidence suggests that heritable prothrombotic and inflammatory factors, as well as environmental factors, may be implicated in its onset and progress. The objective of this study is to describe the genetic, biochemical, and environmental factors that may be associated with the etiology of LCPD. This study was conducted in three families and included seven related patients with an LCPD diagnosis. We evaluated the following gene alterations using real-time PCR: MTHFR, CBS, COL1A1, COL2A1, PT, FVL, FVIII, FIX, PAI-1, eNOS, IL-23R, TNF-α, RANNK, RANNK-L, OPG and IL-6. Additionally, we assessed fourteen thrombophilia-associated biochemical markers, as well as environmental factors that may be associated with the etiology of LCPD in family cases. The results show different hemostatic alterations in every individual analyzed, presenting out-of-range values in one or more parameters. Concentrations of hemoglobin and fibrinogen and the FIX activity percentage showed statistically significant differences (p < 0.001) when compared with healthy controls. All patients presented at least one mutated allele for the MTFHR (rs1801133), IL-23R (rs1569922) and OPG (rs2073618) polymorphisms, as well as isolated cases with other genetic variants. Our results show environmental elements from every family, and hemostatic and inflammatory disorders, may be involved in the development of LCPD. Furthermore, genetic variants could contribute to the onset of the disease. This study highlights the multifactorial nature of this pathology, involving various environmental, genetic, inflammatory, and prothrombotic factors in three families that included seven patients diagnosed with LCPD. Full article

Inconsistent presentation of STAT3 variants in clinical settings makes them challenging to use in diagnostics and the prevention of unfavorable outcomes. Patients harboring the STAT3^R152W variant display a range of autoimmune disorders, including type 1 diabetes, hemolytic anemia, and thrombocytopenia. Because of a complex interplay of genetic and environmental cofactors, it is difficult to discern the direct role STAT3 plays in the development of those conditions. Here, we report a mouse model of the STAT3^R152W variant and describe its hematopoietic populations throughout adulthood. We observed profound changes in both innate and adaptive immunity, including increased splenic Th17 component consistent with a gain-of-function mutation, as described in the literature. At the same time, the mice did not develop obvious symptoms of autoimmunity. R152W mutants show lowered hemoglobin and hematocrit, indicating susceptibility to anemia, but also an increased number of thrombocytes, contradictory to reports of autoimmune thrombocytopenia. We showcase how those changes develop and wane in time, and the differences between male and female animals. Our findings paint the STAT3^R152W variant as a cause of severe immune dysregulation, but only as a cofactor in the development of autoimmunity. Full article

Fetal hemoglobin (HbF) plays a central role in mitigating the pathophysiological effects of sickle cell disease (SCD). Understanding the genetic determinants influencing HbF expression is essential for identifying the factors contributing to its modulation. This review provides an updated synthesis of evidence on HbF modulation, focusing on β^s haplotypes and their molecular characterization through Sanger sequencing, polymorphisms consistently associated with HbF levels in genome-wide association studies (GWAS), and recent advances in gene editing targeting HbF expression. An integrative review (2016–2025) was conducted using PubMed/MEDLINE, Scopus, and Web of Science, encompassing original research, experimental studies, systematic reviews, and genomic analyses. Key regulatory loci such as BCL11A, HBS1L-MYB (HMIP), and the HBB cluster explain a significant proportion of HbF variability across populations. Furthermore, additional variants in KLF1, NFIX, BACH2, and ZBTB7A have emerged as potential modulators in specific cohorts. Regarding advances in γ-globin editing, “prime editing”, although still in the experimental phase, has recently emerged as an innovative approach capable of introducing multiple HPFH-like mutations within γ-globin promoters, expanding future therapeutic possibilities in SCD. This review also provides a comparative overview of prime editing and other gene-editing strategies for HbF modulation, such as CRISPR-Cas9 and Base editing. Collectively, this work outlines the current landscape of HbF modulation and provides an informative basis for future research aimed at advancing precision-oriented therapeutic strategies in sickle cell disease. Full article

Background: A strikingly unusual pattern with a possible up-field shift in Hemoglobin A1c (HbA1c) and A0 (HbA0) peaks and an unexplained hemoglobin F (HbF) peak with capillary electrophoretic shift in the HbA1c chromatograms of a leukemia patient were found while performing a HbA1c screen. Methods: A review of the patient’s history with an exhaustive search of the literature ruled out medications as interfering factors or contributing to the abnormal findings. Other than hyperleukocytosis, the patient did not have the aberrant HbF peak noted previously in the electrophoresis or contributing factors. We hypothesized that the irregular chromatographic pattern and wrong location of the HbA1c peak, hereafter referred to as the downfield shift in the electrophoretic species, was due to various glycation or fructosamine adducts and derivatives within the HbA1c and A0 protein. Results: A literature search offered little guidance. However, the instrument troubleshooting measures suggested a hemoglobin variant or exogenous transfusion as a putative source for the HbF peak, while the downfield shift in the chromatogram remained unexplained. Full article

This study evaluated the clinical utility of a polygenic risk score (PRS)-based multigene panel test for predicting diabetes mellitus (DM) in a healthy population. A total of 302 individuals underwent genetic testing using the HelloGene™ DM panel, which includes four DM-related single nucleotide polymorphisms (CDKAL1, HHEX, KCNQ1, and TCF7L2). PRS values were calculated using an algorithm developed from the Korean Genome and Epidemiology Study (KoGES; n = 39,605), and participants were classified into four genetic risk groups (low, moderate, high, and very high). Fasting blood glucose, glycated hemoglobin (HbA1c), and body mass index were assessed at baseline and after at least three years of follow-up, and lifestyle factors including smoking, alcohol consumption, and exercise status were recorded. No significant differences in age, sex, or lifestyle habits were observed among PRS groups. The very high-risk group showed significantly higher follow-up fasting blood glucose levels (p = 0.001) and higher baseline and follow-up HbA1c levels (p = 0.0025 and p = 0.001, respectively), as well as a 4.5-fold increased risk of developing DM compared with other groups. Smoking significantly modified genetic risk, with smokers in the very high-risk group showing a 25% higher likelihood of developing DM. CDKAL1 and TCF7L2 variants were most prevalent in the moderate- and high-risk groups, while HHEX variants in the high-risk group showed the greatest susceptibility, particularly among current smokers. Overall, PRS-based genetic testing demonstrated potential clinical utility for stratifying individuals according to relative diabetes risk, highlighting a possible interaction between genetic susceptibility and lifestyle factors such as smoking Full article

Background: Hemoglobin Rothschild (Hb Rothschild), NM_000518.5(HBB):c.112T>C, is an ultra-rare low-oxygen-affinity hemoglobin variant that persistently causes reduced peripheral oxygen saturation on pulse oximetry despite normal arterial oxygenation. Fewer than ten cases have been reported worldwide, and only one involved a child—an asymptomatic carrier identified incidentally. Methods: The patient underwent clinical examination, growth assessment, blood tests, hemoglobin electrophoresis, chest CT, abdominal ultrasound, echocardiography, and pulmonary perfusion scintigraphy. Whole genome sequencing (WGS) of the proband and parents was performed, followed by bioinformatic analysis and ACMG-based variant interpretation. A PRISMA-guided PubMed literature review was conducted. Results: We report on the first pediatric case exhibiting a symptomatic clinical course. A 4-year-old boy was referred for chronically low peripheral oxygen saturation (SpO₂), 78–86%, on pulse oximetry and recurrent lower respiratory tract infections. Early developmental history revealed episodes of apnea in infancy, perioral cyanosis, poor exercise tolerance, and low weight gain. Repeated cardiopulmonary assessments, chest computed tomography (CT), echocardiography, and pulmonary perfusion scintigraphy yielded unremarkable findings. Arterial blood gas analysis consistently showed normal arterial partial pressure of oxygen (PaO₂), excluding true hypoxemia. Hemoglobin electrophoresis revealed an abnormal HbD fraction; WGS identified a heterozygous variant NM_000518.5(HBB):c.112T>C inherited from the patient’s asymptomatic father. This variant increases the partial pressure of oxygen at which hemoglobin is 50% saturated (p50), thereby decreasing hemoglobin’s oxygen affinity and shifting the oxyhemoglobin dissociation curve to the right. These alterations explain the discordance between low peripheral oxygen saturation (SpO₂) and preserved oxygen delivery to tissues. Conclusions: This case expands the clinical spectrum of Hb Rothschild and demonstrates that symptomatic presentation may occur in early childhood. Awareness of low-affinity hemoglobin variants is essential to avoid misdiagnosis and unnecessary cardiopulmonary interventions. Early genetic testing facilitates accurate diagnosis and appropriate counseling. Full article

Polyethylene terephthalate-derived fluorescent carbon quantum dots (PET-CQDs) are promising nanomaterials for sensing and biomedical uses, yet their biological interactions after metal doping require careful evaluation. Here, we report an in silico assessment of pristine and dual-site (via graphitic [G] and carbonyl [O]) metal-doped PET-CQDs (Ca, Mg, Fe, Zn) using molecular docking against eight human proteins: HSA (distribution), CYP3A4 (metabolism), hemoglobin (systemic biocompatibility), transferrin (uptake), GST (detoxification), ERα (endocrine regulation), IL-6 (inflammation), and caspase-3 (cytotoxic signaling) together with ADMET profiling and DFT–docking correlation analysis. Docking affinities were compared with controls and ranged from −7.8 to −10.4 kcal·mol⁻¹ across systems, with binding stabilized by π–π stacking, hydrogen bonding and metal–ligand coordination involving residues such as arginine, tyrosine and serine. Importantly, top-performing CQD variants differed by target: PET-CQDs, MgG_PET-CQDs and FeG_PET-CQDs were best for GST; ERα interacted favorably with all doped variants; IL-6 bound best to CaO_PET-CQDs and FeO_PET-CQDs (≈−7.1 kcal·mol⁻¹); HSA favored CaG_PET-CQDs (−10.0 kcal·mol⁻¹) and FeO_PET-CQDs (−9.9 kcal·mol⁻¹); CYP3A4 bound most strongly to pristine PET-CQDs; hemoglobin favored MgG_PET-CQDs (−9.6 kcal·mol⁻¹) and FeO_PET-CQDs (−9.3 kcal·mol⁻¹); transferrin favored FeG_PET-CQDs; caspase-3 showed favored binding overall (pristine −6.8 kcal·mol⁻¹; doped −7.4 to −7.6 kcal·mol⁻¹). ADMET predictions indicated high GI absorption, improved aqueous solubility for some dopants (~18.6 mg·mL⁻¹ for Ca-O/Mg-O), low skin permeability and no mutagenic/carcinogenic flags. Regression analysis showed frontier orbital descriptors (HOMO/LUMO) partially explain selective affinities for ERα and IL-6. These results support a target-guided selection of PET-CQDs for biomedical applications, and they call for experimental validation of selected dopant–target pairs. Full article

During the early months of the COVID-19 pandemic, treatment protocols varied substantially among countries and even between hospitals. This study compared the clinical characteristics, management strategies, and outcomes of hospitalized COVID-19 patients treated in tertiary centers in Türkiye and Bosnia and Herzegovina. We retrospectively analyzed 1338 adults hospitalized with laboratory-confirmed SARS-CoV-2 infection: 657 patients in Tuzla (Bosnia and Herzegovina, June–December 2020) and 681 in İstanbul (Turkiye, April–May 2020). Demographic, clinical, and laboratory data, treatment details (including favipiravir use), need for invasive or non-invasive mechanical ventilation, and in-hospital mortality were extracted from medical records. Patients in Bosnia and Herzegovina were older (61.6 ± 14.4 vs. 56.9 ± 15.8 years; p < 0.001) and had longer hospital stays (9.0 ± 5.5 vs. 7.7 ± 6.1 days; p < 0.001). In the Bosnian cohort, leukocyte, neutrophil, platelet, ferritin, CRP, troponin, creatinine, AST, and ALT levels were significantly higher, whereas hemoglobin and D-dimer levels were lower. The need for ventilatory support was greater in Bosnia and Herzegovina (15.1% vs. 12.2%, p < 0.001), and overall mortality was higher (25.7% vs. 9.3%, p < 0.001). No mortality difference was observed between patients treated and not treated with favipiravir. Despite similar inclusion criteria, patients in Bosnia and Herzegovina exhibited more severe disease, greater organ involvement, and higher mortality than those in Turkiye. Favipiravir use did not influence survival. Inter-country comparisons highlight how differing patient profiles and treatment protocols may impact COVID-19 outcomes; however, interpretation should consider that the two centers contributed data from different phases of the 2020 pandemic, and that country-level differences in circulating variants, healthcare capacity, hospital strain, and evolving clinical guidelines may also have influenced the observed patterns. Full article

We present a proof-of-concept study using a laser trapping (LT) approach to characterize hemoglobin variants through controlled dielectric breakdown of red blood cell membranes. Using a 1064 nm infrared laser, we analyzed 62 cells from each of four hemoglobin types (Hb AS, Hb FA, Hb FSC, Hb AC), measuring the ionization time, cell area, and trap displacement to calculate the apparent threshold ionization energy (TIE*) and apparent threshold radiation dose (TRD*). Post-ionization trajectories and radiation intensity measurements provided charge distribution profiles for each variant. Our results indicate variant-specific differences in TRD* and charge-to-volume ratios across adults and infants (p < 0.05), while the TIE* values remained largely consistent. Charge analysis revealed statistically significant variation between some groups, suggesting that TRD* and charge-based parameters may offer sensitive markers of hemoglobin heterogeneity. This work demonstrates the feasibility of laser trapping as a complementary single-cell method for hemoglobin analysis. While limited in sample size, the approach highlights the potential of TIE* and TRD* measurements for differentiating hemoglobin variants and suggests future applications in hemoglobinopathy screening and diagnostic research. Full article

Introduction: In hemoglobinopathies, the amount of globin synthesis in hemoglobin (Hb) or its structure is altered. Clinical features are related to the rate and kind of structural aberrations. The heterozygous form of the Lepore syndrome resembles minor thalassemia both clinically and hematologically. On electrophoresis, abnormal Hb Lepore fractions are found at a rate of 5–15%, with a mildly higher percentage of HbF and lower HbA. In general, Hb Lepore heterozygotes are asymptomatic. Case presentation: A 32-year-old male was admitted to our hospital with complaints of pain and swelling in multiple large joints and high-grade fever for 11 days. His past history was unremarkable; one of his sisters had the β-thalassemia trait. On physical examination, he was moderately anemic, with mild hepatomegaly and normal spleen; both knees and ankles were tender and swollen. Laboratory showed mild microcytic hypochromic anemia with variables similar to the thalassemia trait and signs of inflammation with very high CRP, serum ferritin, and leukocytosis. Blood sugars were increased. Hb electrophoresis showed an abnormal pattern with mild elevation in HbS, normal Hb F, mild reduction in HbA, and high HbA2, compatible with heterozygosity for the Hb Lepore beta chain variant. He was initially diagnosed with diabetes (treated with insulin) and sepsis from unknown origin, but fever and joint pains did not respond to NSAIDs or antibiotics. He had very good response on high-dose methylprednisolone. Undifferentiated arthritis was diagnosed in the patient with Hb Lepore, and he was treated with oral prednisolone and sulfasalazine (SSZ). At follow up, the patient was doing well. He refused further investigations and did not allow testing on his family members. In summary: Hb Lepore is a rare hemoglobinopathy linked to thalassemia, which may manifest with musculoskeletal problems. Our patient with the Hb Lepore trait presented with undifferentiated polyarthritis and fever, but in our case, a causal relationship remains unclear. This is one of the first adult cases of Hb Lepore in Bangladesh and the first with arthritis of unknown origin. The prevalence of Hb Lepore in Bangladesh is unknown. Full article

The hitherto unknown thiol-disulfide redox potential (E₀′) of the β93Cys residue in the HbS (β^6Glu→Val) variant of human hemoglobin was calculated by MALDI-ToF mass spectrometry, which analyzes blood from a heterozygous carrier. To calculate the (E₀′) value, a redox equilibrium model was adopted, and the previously calculated value for wild-type β-Hb chain (E₀′ −121 mV) was used. An E₀′ value of −130.5 ± 1.7 mV for the β93Cys residue of HbS was obtained, thus a more reducing value than E₀′ in the wild-type isoform. Glutathionylation from this residue in the HbS tetramer lowers the extent of protein aggregation in fibrils and the clinical consequences, such as painful capillary occlusion and hemolysis. This finding confirmed the peculiar property of HbS as a more reactive scavenger of glutathione sulphinic acid (E₀′ = −264 mV), which forms in the cytoplasm of red blood cells and reacts with structural and regulatory proteins, including hemoglobin. The ability to assess the erythrocyte oxidative status in sickle cell carriers can be developed into an additional functional test to rationally assess the effect of drug treatment and antioxidant dietary interventions on improving disease control. Full article

Background/Objectives: Gaucher disease type 1 is an autosomal recessive lysosomal storage disorder caused by pathogenic variants in the GBA1 gene. Although enzyme replacement therapy has improved patient outcomes, there is limited long-term real-world data on taliglucerase alfa. This study aimed to evaluate the long-term efficacy and safety of taliglucerase alfa in both treatment-naïve and previously treated patients with Gaucher disease type 1 over a 10-year period. Methods: This prospective, single-centre cohort study involved 29 patients (13 treatment-naïve and 16 previously treated with imiglucerase) who received taliglucerase alfa from 2015 to 2024. Clinical, hematological, visceral, skeletal, and biochemical parameters were assessed at baseline and at 12, 60, and 120 months. Biomarkers included chitotriosidase and glucosylsphingosine. Safety was evaluated through adverse event reporting and anti-drug antibody testing. Results: Hemoglobin and platelet counts improved or remained stable in all patients. By 60 months, liver volume had normalised in treatment-naïve patients (mean reduction: 23.1%), while spleen volume had decreased by up to 47.3%. Lyso-Gb1 levels decreased by 86.1% in patients who had not previously received treatment and by 59.5% overall, with a strong correlation to adherence. Bone mineral density improved in most cases. 137 adverse events were reported, 24% of which were mild infusion-related reactions. Anti-drug antibody developed in two patients, including one with a reduced therapeutic response. Conclusions: Taliglucerase alfa offers sustained long-term clinical, hematological and biochemical benefits in both treatment-naïve and previously treated Gaucher disease type 1 patients, with a favorable safety profile. Glucosylsphingosine proved to be a highly sensitive biomarker for monitoring therapeutic efficacy and detecting treatment response. Full article

Background/Objectives: Type 2 diabetes (T2D) is a clinically and genetically heterogeneous disease. In this study, we aimed to stratify patients with T2D from the Volga-Ural region of Eurasia into distinct subgroups based on clinical characteristics and to investigate the genetic underpinnings of these clusters. Methods: A total of 254 Tatar individuals with T2D and 361 ethnically matched controls were recruited. Clinical clustering was performed using k-means and hierarchical algorithms on five variables: age at diagnosis, body mass index (BMI), glycated hemoglobin (HbA1c), insulin resistance (HOMA-IR), and β-cell function (HOMA-B). Genetic association analysis was conducted using logistic regression under an additive model, adjusted for age and sex, and corrected for multiple comparisons using the Benjamini–Hochberg method. Results: Four distinct T2D subtypes were identified—mild age-related diabetes (MARD, n = 25), mild obesity-related diabetes (MOD, n = 72), severe insulin-resistant diabetes (SIRD, n = 66), and severe insulin-deficient diabetes (SIDD, n = 52)—each with unique clinical and comorbidity profiles. SIDD patients exhibited the highest burden of microvascular complications and lowest estimated glomerular filtration rate. Nine genetic variants showed significant associations with T2D and/or specific subtypes, including loci in genes related to neurotransmission (e.g., HTR1B, CHRM5), appetite regulation (NPY2R), insulin signaling (TCF7L2, PTEN), and other metabolic pathways. Some variants demonstrated subtype-specific associations, underscoring the genetic heterogeneity of T2D. Conclusions: Our findings support the utility of clinical clustering in uncovering biologically and clinically meaningful T2D subtypes and reveal genetic variants that may contribute to this heterogeneity. These insights may inform future precision medicine approaches for T2D diagnosis and management. Full article

Background: Vitamin D receptor (VDR) polymorphisms may influence immune regulation and musculoskeletal health, but their perioperative role is not well understood. This study investigated the rs2228570 (FokI) variant in relation to inflammatory, hematologic, and patient-reported outcomes in orthopedic patients. Methods: We genotyped 300 orthopedic patients and 200 healthy controls using real-time PCR. Regression models in patients adjusted for age and body mass index (BMI) examined associations between rs2228570 genotypes and laboratory as well as clinical outcomes. Results: The CC genotype (homozygous cytosine) was associated with higher white blood cell count (β = 0.52, p = 0.0435), higher lymphocyte count (β = 0.26, p = 0.00025), higher hemoglobin (β = 0.57, p = 0.00197), and higher hematocrit (β = 1.42, p = 0.01102). The TT genotype (homozygous thymine) was associated with higher C-reactive protein (β = 10.90, p = 0.00329), lower mean corpuscular volume (β = −1.63, p = 0.04909), and higher health-related quality of life assessed by the 36-Item Short-Form Health Survey (SF-36) (β = 6.31, p = 0.00009). Conclusions: The rs2228570 polymorphism in the VDR gene is associated with distinct perioperative inflammatory, hematologic, and patient-reported profiles. These findings support the potential clinical utility of VDR genotyping, in combination with routine laboratory tests, to refine perioperative risk stratification and guide personalized rehabilitation in orthopedic patients. Full article