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BACKGROUND: Severe malaria is associated with impaired nitric oxide (NO) synthase (NOS)–dependent vasodilation, and reversal of this deficit improves survival in murine models. Malaria might have selected for genetic polymorphisms that increase endothelial NO signaling and now contribute to heterogeneity in vascular function among humans. One protein potentially selected for is alpha globin, which, in mouse models, interacts with endothelial NOS (eNOS) to negatively regulate NO signaling. We sought to evaluate the impact of alpha globin gene deletions on NO signaling and unexpectedly found human arteries use not only alpha but also beta globin to regulate eNOS. METHODS: The eNOS-hemoglobin complex was characterized by multiphoton imaging, gene expression analysis, and coimmunoprecipitation studies of human resistance arteries. Novel contacts between eNOS and hemoglobin were mapped using molecular modeling and simulation. Pharmacological or genetic disruption of the eNOS-hemoglobin complex was evaluated using pressure myography. The association between alpha globin gene deletion and blood pressure was assessed in a population study. RESULTS: Alpha and beta globin transcripts were detected in the endothelial layer of the artery wall. Imaging colocalized alpha and beta globin proteins with eNOS at myoendothelial junctions. Immunoprecipitation demonstrated that alpha globin and beta globin form a complex with eNOS and cytochrome b5 reductase. Modeling predicted negatively charged glutamic acids at positions 6 and 7 of beta globin to interact with positively charged arginines at positions 97 and 98 of eNOS. Arteries from donors with a glutamic acid–to–valine substitution at beta globin position 6 (sickle trait) exhibited increased NOS-dependent vasodilation. Alpha globin gene deletions were associated with decreased arterial alpha globin expression, increased NOS-dependent vasodilation, and lower blood pressure. Mimetic peptides that targeted the interactions between hemoglobin and eNOS recapitulated the effects of these genetic variants on human arterial vasoreactivity. CONCLUSIONS: Alpha and beta globin subunits of hemoglobin interact with eNOS to restrict NO signaling in human resistance arteries. Malaria-protective genetic variants that alter the expression of alpha globin or the structure of beta globin are associated with increased NOS-dependent vasodilation. Targeting the hemoglobin-eNOS interface could potentially improve NO signaling in diseases of endothelial dysfunction such as severe malaria or chronic cardiovascular conditions. [ABSTRACT FROM AUTHOR]

Context.--Rare thalassemia subtypes are often undiagnosed because conventional testing methods can only identify 23 common types of a- and b-thalassemia. Objective.--To assess a comprehensive approach for the screening and diagnosis of rare thalassemia. Design.--The study cohort included 72 individuals with suspected rare thalassemia variants. Screening was conducted by next-generation sequencing (NGS) combined with third-generation sequencing (TGS) and chromosomal microarray analysis (CMA)/copy number variation sequencing. Results.--Of the 72 individuals with suspected rare thalassemia, 49 had rare a- or b-gene variants. NGS combined with gap polymerase chain reaction detected a total of 42 cases, resulting in a positive detection rate of 58.3%. Additionally, 4 a-globin genetic deletions were identified by TGS, which increased the variant detection rate by 5.6%. Two samples with a microdeletion of chromosome 16 or 11 were detected by CMA, which increased the detection rate by 2.8%. For one sample, reanalysis of the NGS and TGS data confirmed the presence of the b41-42/bN and bN/bN mosaic. The HBB:c.31512delT mutation was initially reported in Guangdong Province, China. Two HBB gene mutations (HBB:c.31515G>C and HBB:c.295G>A) and 4 rare HBA gene deletions (--11.1, -a27.6, -a2.4, and -a21.9) were initially identified in the Zhonshan region. The hematologic phenotypes of all rare cases in this study were clarified. Conclusions.--Rare thalassemia variants are more common than previously thought. Despite advancements in TGS, there is still no foolproof method for detection of all types of thalassemia. Thus, a comprehensive approach is necessary for accurate screening and diagnosis of rare thalassemia variants. [ABSTRACT FROM AUTHOR]

Background: Guizhou Province is art area with high incidence of thalassemia. However, there are few large-sample studies on the correlation between genotypes and phenotypes in Guizhou Province. In this study, the phenotypes and genotypes of 1174 patients with thalassemia in Guizhou Province were collected, and the relationship between different genotypes and phenotypes was analyzed, providing a more accurate basis for genetic counseling, prevention and control of thalassemia. Methods: A total of 1174 patients with thalassemia were collected in Guizhou Provincial People's Hospital from October 2020 to December 2021 by PCR-reverse dot blot (RDB) hybridization assay, and their red blood cell (RBC), hemoglobin (Hb), mean erythrocyte volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), red blood cell distribution width (RDW), hemoglobin (HbA), hemoglobin A2 (HbA2), and fetal hemoglobin (HbF) data were collected. The relationship between different genotypes and phenotypes was analyzed. Results: Among 1174 cases of thalassemia or carriers, there were 617 cases of a-thalassemia, 512 cases of (3-thalassemia, 45 cases of coinheritance of a- and p-tha-lassemia. The severity of anemia between a-thalassemia was positively correlated with the decrease of non-funotional copy number of a-globin gene. The degree of anemia in non-deletion a-thalassemia was greater than that in deletion a-thalassemia. In p-thalassemia, p° gene mutation did not produce p-globin, and p + mutation expressed some J3- globin, but it was lower than normal level. p°/p° had noP- globin production, and long-term blood transfusion was required to maintain life. Compared with a-thalassemia, the degree of anemia in p-thalassemia whose clinical type was same as a-thalassemia was more serious. The anemia degree of coinheritance of a- and p-thalassemia was less than that of simple a-thalassemia or p-thalassemia. Conclusions: The clinical phenotype of thalassemia is influenced by molecular mechanism, and the two kinds of thalassemia can interact with each other. The clinical severity is positively correlated with the imbalance of a peptide chain and p peptide chain. A comprehensive understanding of the hematologic phenotype differences between different genotypes and subtypes of thalassemia can provide more accurate data for genetic counseling of thalassemia. [ABSTRACT FROM AUTHOR]

Hemoglobinopathy is the most frequent genetic illness worldwide. Alpha thalassemia is common in Middle East. The loss of one or both HBA genes in the -globin gene cluster causes alpha-thalassemia. The countrywide prevalence and distribution of alpha globin gene mutations must be studied. Molecular screening and detection improve thalassemia-risk prenatal diagnosis and genetic counselling. This article compares different alpha thalassaemia mutations molecular and haematological characteristics in the Middle East. This cross-sectional retrospective analysis was carried out from September 2022 to June 2023. A study investigated 200 samples of alpha thalassemia patients in the Middle East using Reversed Dot Blot Hybridization-based multiplex-PCR to screen for 21 known α-globin gene abnormalities. We found 17 alpha-globin gene variants. The first prevalent anomaly was (deletional) 3.7 homozygous (34.5%), and the second was 3.7 heterozygous (18.5%). The genotype (--MED αα /α2 poly A2) was strongly linked with lower hemoglobin and RBCs levels in α-thalassemia (p-value of 0.027 and 0.042 respectively).The most prevalent alpha thalassemia abnormality is -α3.7/ -α3.7. Alleles show diversity in Middle Eastern populations. Even genotype-matched people had different haematological parameters. Haematological criteria cannot uniquely characterize any alpha thalassaemia mutation. [ABSTRACT FROM AUTHOR]

To describe a variant hemoglobin that interferes with HbA1c analysis by cation exchange HPLC. A 78 years-old Spanish male patient visited the Internal Medicine Clinic for a routine check-up, with HbA1c included to screen for diabetes. He had suffered hypertension and dyslipidemia, and the patient had no previous symptoms suggestive of diabetes such as hyperglycemia, weight loss, polydipsia, polyuria or tiredness. Diabetes screening by HbA1c measurement was assessed using cation exchange HPLC and an immunoassay point-of-care analyzer. Routine hemoglobinopathy screening was performed including CBC, HbF and HbA2 measurement by cation exchange HPLC and capillary electrophoresis (CE). Further variant characterization was undertaken by DNA sequencing. Discordant HbA1c results were obtained for our subject, with elevated HbA1c of 52 mmol/mol measured by cation exchange HPLC and a normal level of 34 mmol/mol by immunoassay. Abnormal HbA1c peak shape prompted hemoglobinopathy screening to investigate potential variant interference. A globin gene analysis was performed, and the results showed a variant hemoglobin named 'Hb Petie Salpetriere'. This variant arises from a Val → Phe substitution due to a mutation of c.103G>T of the beta-globin gene [BETA34 (B16) Val>Phe; HBB:c.103G>T]. This is the first reported case involving the Hb Petie Salpetriere variant in a Spanish patient. The present results show that the Hb Petie Salpetriere variant can affect the results of HbA1c analysis through ion-exchange HPLC, but not that obtained from the latex agglutination immunoassay. Only ion-exchange HPLC suggested the presence of the Hb variant in this case, suggesting that a careful review of the resulting chromatogram might reveal a potential variant. [ABSTRACT FROM AUTHOR]

The 3.7 kb deletion is the most common known mutation in the α-globin gene cluster worldwide. The aim of this study is to investigate the most common types of 3.7 kb deletions in the Iranian population and, on the other hand, to compare the extent of deletion of the different reported types. In this study, 50 Iranian α-thalassemia carriers in whom the 3.7 kb deletion had been previously identified by multiplex gap PCR, were further investigated by MLPA. A map of the region where the 3.7 kb deletion occurs was also created and the extents of the reported types were compared Approximately 90% of chromosomes with 3.7 kb deletion in this study had MLPA type D and 10% had MLPA type F. This study showed that subtype I of the 3.7 kb deletion reported by Higgs and his coworkers can be classified into at least 5 MLPA types. The results of this study can be used to complete the information on the distribution of the 3.7 kb deletion subtypes in different populations. Investigation of further populations using higher resolution methods may lead to more information being obtained in this field. [ABSTRACT FROM AUTHOR]

Background: Thalassemia is one of the most common blood disorders in Iran. Alpha-thalassemia is caused by the deletion of the alpha-globin gene. The frequency of deletions in the alpha-globin gene is associated with microcytosis and hypochromia, making hematological parameters valuable predictive tools in the initial identification of alpha-thalassemia patients. This study aimed to compare hematologic parameters such as Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH), red blood cell (RBC) count, and hemoglobin (HGB) levels in silent and minor patients, whose genotypes were genetically characterized, with normal patients to establish cut-off points for these groups. Materials and Methods: The study involved a total of 860 patients with alpha-thalassemia, including 267 cases of silent, 261 cases of minor, and 332 cases of normal alpha-thalassemia. Results: Analysis of blood indices based on sex revealed that the male group had higher values than the female group. Assessment of alpha-thalassemia in minor patients showed that the Cis form (-/αα) had higher microcytosis than the Trans form (-α/-α) in this group. This difference was also observed between α-3.7α/ α-3.7α and (αα)-MED/αα as two different genetic forms in minor patients, with (αα)-MED/αα being in the Cis form. Data indicated that the cut-off value was insignificant in silent patients compared to the normal group. However, minor patients with MCH≤23.7 and MCV≤74.9 had an AUC greater than 0.9 (p-value< 0.01), distinguishing them from the normal group. Conclusion: Comparing hematological parameters in these groups illustrated that MCV and MCH are the best predictor parameters for distinguishing between groups. [ABSTRACT FROM AUTHOR]

Background Hemoglobin (Hb) Hekinan II (A27; Glu-Asp) is an α-chain variant, and its interaction with the common Southeast Asian (--SEA/) α-thalassemia (α-thal) deletion is rarely reported. This study provides a clinical update of Hb Hekinan II associated with (--SEA/) α-thal. Methods A total of 11 simple heterozygotes and 20 composite heterozygotes for Hb Hekinan II and (--SEA/) α-thal were included based on molecular diagnosis. Results Hb Hekinan II exhibited a significant increase in hemoglobin, mean corpuscular volume, and mean corpuscular hemoglobin content, but a decrease in red blood cell level compared with α+ thalassemia deletion. Compared with (--SEA/) α-thal, composite heterozygotes for Hb Hekinan II and (--SEA/) α-thal showed similar erythrocyte parameters. Both heterozygotes with and without (--SEA/) α-thal showed low Hb A2 level. Hb Hekinan II showed abnormal performance in high-performance liquid chromatography but not in capillary electrophoresis. Conclusion Hb Hekinan II is a benign Hb variant. The heterozygotes exhibit clinically asymptomatic coinheritance with (--SEA/) α-thal having comparable hematological phenotype to simple (--SEA/) α-thal. The combination of hematological and molecular analysis helped to improve the detection rate of this rare variant. [ABSTRACT FROM AUTHOR]

Thalassemia is a genetics syndrome which lead to abnormal hemoglobin protein and this produce hemolysis, inefficient erythropoiesis, and moderate to severe anemia. Very few studies focus on the frequency of this disease. Therefore, the aims of current study is to determine features, and frequency of thalassemia patients at the thalassemia center in the Misan Governorate. In 2024, we performed a descriptive file-based study on 499 patients with thalassemia at the Thalassemia Center in Misan City. We reviewed the patient files and gathered the necessary data. After filling out a unique form with information about the patient's features from their medical records and from the patients or caregivers, data analysis was completed using Microsoft Excel and SPSS. The results showed that the majority of cases (78%), which were of the major type of B-thalassemia, were followed by intermediate cases (16%) and alpha-thalassemia (6%). Of these, 54% were female, and 48% were in the age range of 5-19 years. There were fewer cases in the age range of 0-4 years and older than 40 years. The study's findings also showed that 52% of patients lived in rural areas and 48% in urban areas. O had the highest blood group among the patients, followed by B, A, and AB. According to the study's findings, 64 patients had passed away, with both new and old cases accounting for 12% of all deaths. The kind of thalassemia, age group, and case outcome were statistically significantly correlated (p values were 0.006 and 0.0001, respectively). In conclusion, our research consider as the first a descriptive study at Misan province that sheds the light on B-thalassemia major. However, genetic study required next to stablish the database in Misan province. [ABSTRACT FROM AUTHOR]

Introduction: This cross-sectional study intends to analyze the physical growth of children thalassemia patients and evaluate the factors linked to their physical features. Materials and methods: This cross-sectional study tracked 44 pediatric thalassemia patients at a Central Vietnam Tertiary Pediatric Center from February to December 2023. Results: The study participants had a mean age of 7.5 ± 4.3 years and an equal gender distribution. 64.5% of these individuals had thalassemia and required blood transfusions. 43.2% of subjects had serum ferritin levels above 1000 ng/ml, and the average hemoglobin content was 67.4 ± 16.1 g/L 31.8% of the children assessed had height-for-age measurements below -2 standard deviations, while 43.2% had weight-for-age measurements below -2 standard deviations. Significant correlations were found between height-for-age, weight-for-age, blood transfusion reliance, and serum ferritin levels (p < 0.05). No significant changes were seen between physical indices and disease type or hemoglobin concentration (p > 0.05). 31.8% of juvenile thalassemia patients were found to have stunting, whereas 43.2% exhibited wasting malnutrition in this study. Conclusion: Blood transfusion reliance and serum ferritin concentration were found to be linked to a higher occurrence of stunting and wasting malnutrition in children with thalassemia

Abstract Hb H disease is the most severe form of α-thalassemia compatible with post-natal life. Compound heterozygous α0-thalassemia− SEA deletion/α+-thalassemia− 3.7kb deletion is the commonest cause of Hb H disease in Thailand. Preimplantation genetics testing for monogenic disorders (PGT-M) is an alternative for couples at risk of the disorder to begin a pregnancy with a healthy baby. This study aims to develop a novel PCR protocol for PGT-M of Hb H disease− SEA/−3.7kb using multiplex fluorescent PCR. A novel set of primers for α+-thalassemia− 3.7kb deletion was developed and tested. The PCR protocol for α0-thalassemia− SEA deletion was combined for Hb H disease− SEA/−3.7kb genotyping. The PCR protocols were applied to genomic DNA extracted from subjects with different thalassemia genotypes and on whole genome amplification (WGA) products from clinical PGT-M cycles of the families at risk of Hb Bart’s. The results were compared and discussed. The results showed three PCR products from α+-thalassemia− 3.7kb primer set, and three from α0thalassemiaSEA primer set. The results were consistent with the known thalassemia genotypes. The novel -α3.7 primers protocol was also tested on 37 WGA products from clinical PGT-M cycles giving accurate genotyping results and a satisfying amplification efficiency with the ADO rates of 2.7%, 0%, and 0% for HBA2, HBA1, and internal control fragments, respectively. This novel PCR protocol can precisely distinguish Hb H disease− SEA/−3.7kb from other genotypes. Additionally, this is the first PCR protocol for Hb H disease− SEA/−3.7kb which is optimal for PGT-M.

Purpose: Our study aims to describe the mortality trends and disparities among individuals with thalassemia in the United States (US). Patients and Methods: We used CDC WONDER database to calculate the age-adjusted mortality rates (AAMRs) per 1,000,000 individuals and used the Joinpoint Regression Program to measure the average annual percent change (AAPC). Subgroup evaluations were performed by sex, age, race, census region, and urbanization level. Results: From 1999 to 2020, there were 2797 deaths relatd to thalassemia in the US. The AAMR of thalassemia-related death showed a decreasing trend from 0.50 (95% CI, 0.41– 0.58) in 1999 to 0.48 (95% CI, 0.41– 0.55) in 2020 with the AAPC of − 1.42 (95% CI, − 2.42, − 0.42). Asians have the highest AAMR (1.34 [95% CI, 1.20– 1.47]), followed by non-Hispanic Blacks (0.65 [95% CI, 0.59– 0.71]), non-Hispanic Whites (0.32 [95% CI, 0.30– 0.33]), and Hispanics (0.11 [95% CI, 0.08– 0.14]). Cardiovascular disease remains the leading cause of death among individuals with thalassemia. The urban population has a higher AAMR than the rural population (0.43 [95% CI, 0.41– 0.45] vs 0.29 [95% CI, 0.26– 0.32]). Conclusion: Our study calls for targeted interventions to address the racial and geographic disparities existed among individuals of thalassemia in the US. [ABSTRACT FROM AUTHOR]

This study aimed to construct an imaging genomics nomogram based on intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) to predict the status of the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene in patients with brain gliomas. We retrospectively analyzed routine MR and IVIM-DWI data from 85 patients with pathologically confirmed brain gliomas from January 2017 to May 2023. The data were divided into a training set (N=61) and a test set (N=24) in a 7:3 ratio. Regions of interest (ROIs) of brain gliomas, including the solid tumor region (rCET), edema region (rE), and necrotic region (rNec), were delineated using 3D-Slicer software and projected onto the D, D*, and f sequences. A total of 1037 features were extracted from each ROI, resulting in 3111 features per patient. Age was incorporated in the calculation of the Radscore, and a clinical-imaging genomics combined model was constructed, from which a nomogram graph was generated. Separate models were built for the D, D*, and f parameters. The AUC value of the D parameter model was 0.97 (95% CI: 0.93–1.00) in the training set and 0.91 (95% CI: 0.79–1.00) in the validation set, which was significantly higher than that of the D* parameter model (0.90, 0.82) and the f parameter model (0.89, 0.91). The imaging genomics nomogram based on IVIM-DWI can effectively predict the ATRX gene status of patients with brain gliomas, with the D parameter showing the highest efficacy. [ABSTRACT FROM AUTHOR]

Hb H disease is the most severe form of α-thalassemia compatible with post-natal life. Compound heterozygous α0-thalassemia− SEA deletion/α+-thalassemia− 3.7kb deletion is the commonest cause of Hb H disease in Thailand. Preimplantation genetics testing for monogenic disorders (PGT-M) is an alternative for couples at risk of the disorder to begin a pregnancy with a healthy baby. This study aims to develop a novel PCR protocol for PGT-M of Hb H disease− SEA/−3.7kb using multiplex fluorescent PCR. A novel set of primers for α+-thalassemia− 3.7kb deletion was developed and tested. The PCR protocol for α0-thalassemia− SEA deletion was combined for Hb H disease− SEA/−3.7kb genotyping. The PCR protocols were applied to genomic DNA extracted from subjects with different thalassemia genotypes and on whole genome amplification (WGA) products from clinical PGT-M cycles of the families at risk of Hb Bart's. The results were compared and discussed. The results showed three PCR products from α+-thalassemia− 3.7kb primer set, and three from α0thalassemiaSEA primer set. The results were consistent with the known thalassemia genotypes. The novel -α3.7 primers protocol was also tested on 37 WGA products from clinical PGT-M cycles giving accurate genotyping results and a satisfying amplification efficiency with the ADO rates of 2.7%, 0%, and 0% for HBA2, HBA1, and internal control fragments, respectively. This novel PCR protocol can precisely distinguish Hb H disease− SEA/−3.7kb from other genotypes. Additionally, this is the first PCR protocol for Hb H disease− SEA/−3.7kb which is optimal for PGT-M. [ABSTRACT FROM AUTHOR]

Background: Post‐transfusion survival of donor red blood cells (RBCs) is important for effective chronic transfusion therapy in conditions including sickle cell disease (SCD). Biotin labeling RBCs allows direct in vivo measurement of multiple donor RBC units simultaneously post‐transfusion. Study Design and Methods: In an observational trial of patients with SCD receiving monthly chronic transfusion therapy, aliquots of RBCs from one transfusion episode were biotin‐labeled and infused along with the unlabeled RBC units. Serial blood samples were obtained to measure RBC survival. Donor units were tested for RBC indices, hemoglobin fractionation, and glucose‐6‐phosphate dehydrogenase (G6PD) enzyme activity. For microcytic donor RBCs (MCV < 70 fL), HBA1 and HBA2 genetic testing was performed on whole blood. Results: We present one recipient, a pediatric patient with SCD and splenectomy who received two RBC units with aliquots from each unit labeled at distinct biotin densities (2 and 18 μg/mL biotin). One donor unit was identified to have microcytosis (MCV 68.5 fL after biotinylation); whole blood sample obtained at a subsequent donation showed 2‐gene deletion alpha‐thalassemia trait (ɑ–3.7kb/ɑ–3.7kb) and normal serum ferritin. G6PD activity was >60% of normal mean for both. The RBCs with alpha‐thalassemia RBC had accelerated clearance and increased surface phosphatidylserine post‐transfusion, as compared with the normocytic RBC (half life 65 vs. 86 days, respectively). Discussion: Post‐transfusion RBC survival may be lower for units from donors with alpha‐thalassemia trait, although the impact of thalassemia trait donors on transfusion efficacy requires further study. [ABSTRACT FROM AUTHOR]

Background/Aims: Alpha thalassemia is an autosomal recessive congenital disease resulting from a globin protein disorder encoded by genes in the alpha thalassemia gene cluster. It presents a wide range of clinical conditions, from mild anemia to hydrops fetalis. Alpha thalassemia trait is common in Middle Eastern and Mediterranean countries. It is included in the premarital screening program in Türkiye. The aim of this study was to determine the spectrum of alpha thalassemia deletions observed in Istanbul. Methods: This cohort included 169 patients who were clinically suspected to have alpha thalassemia disease or carrier, and whose mutation was detected by the Multiplex Ligation-dependent Probe Amplification (MLPA) method. Results: The identified variants were listed according to their frequencies and compared to previous studies conducted in different regions of Türkiye. In a total of 338 alleles, 61.8 % (209/338) mutations were detected. The most common variant was -α3.7 and -αMED ranked second. Conclusion: This study reports alpha thalassemia mutations in Istanbul and reveals a different spectrum for some variants compared to previous studies in the region. This situation has been evaluated as evidence that the demographic structure in Istanbul has changed as a result of migration. Additionally, presenting the detected variants and mean hematological findings will guide genetic counseling in region. [ABSTRACT FROM AUTHOR]

Objective: Presentation of a novel case of a patient with Hb Bart's hydrops fetalis, which was accurately identified by SMRT sequencing leading to expand the mutation spectrum of α-thalassemia. Case report: A 26-year-old pregnant woman and her husband underwent molecular analysis of thalassemia due to abnormal hematological results. The molecular analysis showed that the pregnant woman carried -α3.7/--SEA, while her husband exhibited a negative result. Accordingly, the pregnant woman continued the pregnancy until the 19-week gestational age. She was subsequently referred to our department for genetic counseling due to abnormal ultrasound findings in the fetus. A novel deletional α-thal mutation was detected for the husband by MLPA, and the precise location of the mutation was determined through SMRT sequencing, which revealed a 45.2 kb deletion. Later, an interventional umbilical cord blood puncture was offered for the pregnant woman. The cord blood was subjected to capillary electrophoresis, which revealed apparent Hb Bart's and Hb Portland peaks associated with Hb Bart's hydrops fetalis syndrome. Conclusion: It is imperative that Hb Bart's hydrops fetalis syndrome be diagnosed with the utmost expediency. If results of molecular analysis are not consistent with the clinical hematological findings, the presence of a novel thalassemia could be suspected. To identify the novel genotype, the SMRT sequencing represents an effective method for achieving an accurate diagnosis.

Alpha thalassemia major (ATM) is a hemoglobinopathy that usually results in perinatal demise if in utero transfusions (IUTs) are not performed. We established an international registry (NCT04872179) to evaluate the impact of IUTs on survival to discharge (primary outcome) as well as perinatal and neurodevelopmental secondary outcomes. Forty-nine patients were diagnosed prenatally, 11 were diagnosed postnatally, and all 11 spontaneous survivor genotypes had preserved embryonic zeta-globin levels. We compared 3 groups of patients; group 1, prenatally diagnosed and alive at hospital discharge (n = 14), group 2, prenatally diagnosed and deceased perinatally (n = 5), and group 3, postnatally diagnosed and alive at hospital discharge (n = 11). Group 1 had better outcomes than groups 2 and 3 in terms of the resolution of hydrops, delivery closer to term, shorter hospitalizations, and more frequent average or greater neurodevelopmental outcomes. Earlier IUT initiation was correlated with higher neurodevelopmental (Vineland-3) scores (r = -0.72, P = .02). Preterm delivery after IUT was seen in 3/16 (19%) patients who continued their pregnancy. When we combined our data with those from 2 published series, patients who received ≥2 IUTs had better outcomes than those with 0 to 1 IUT, including resolution of hydrops, delivery at ≥34 weeks gestation, and 5-minute appearance, pulse, grimace, activity, and respiration scores ≥7. Neurodevelopmental assessments were normal in 17/18 of the ≥2 IUT vs 5/13 of the 0 to 1 IUT group (OR 2.74; P = .01). Thus, fetal transfusions enable the survival of patients with ATM and normal neurodevelopment, even in those patients presenting with hydrops. Nondirective prenatal counseling for expectant parents should include the option of IUTs.

Abstract Background Thalassemias represent some of the most common monogenic diseases worldwide and are caused by variations in human hemoglobin genes which disrupt the balance of synthesis between the alpha and beta globin chains. Thalassemia gene detection technology is the gold standard to achieve accurate detection of thalassemia, but in clinical practice, most of the tests are only for common genotypes, which can easily lead to missing or misdiagnosis of rare thalassemia genotypes. Case presentation We present the case of an 18-year-old Chinese female with abnormal values of routine hematological indices who was admitted for genetic screening for thalassemia. Genomic DNA was extracted and used for the genetic assays. Gap polymerase chain reaction and agarose gel electrophoresis were performed to detect HBA gene deletions, while PCR-reverse dot blot hybridization was used to detect point mutations in the HBA and HBB genes. Next-generation sequencing and third-generation sequencing (TGS) were used to identify known and potentially novel genotypes of thalassemia. We identified a novel complex variant αHb WestmeadαHb Westmeadαanti3.7/-α3.7 in a patient with rare alpha-thalassemia. Conclusions Our study identified a novel complex variant that expands the thalassemia gene variants spectrum. Meanwhile, the study suggests that TGS could effectively improve the specificity of thalassemia gene detection, and has promising potential for the discovery of novel thalassemia genotypes, which could also improve the accuracy of genetic counseling. Couples who are thalassemia carriers have the opportunity to reduce their risk of having a child with thalassemia.

Introduction: Hemoglobinopathy Sβ-thalassemia (HbSβ-thal) has a wide range of clinical and laboratory severity. There is limited information on the natural history of HbSβ-thal and its modulating factors. We described the molecular, hematological, and clinical characteristics of a cohort of children with HbSβ-thal and estimated its incidence in Minas Gerais, Brazil. Methods: Laboratory and clinical data were retrieved from medical records. Molecular analysis was performed by HBB gene sequencing, PCR-RFLP, gap-PCR, and MLPA. Results: Eighty-nine children were included in the study. Fourteen alleles of β-thal mutations were identified. The incidence of HbSβ-thal in the state was 1 per 22,250 newborns. The most common βS-haplotypes were CAR and Benin. The most frequent βthal-haplotypes were V, II, and I. Coexistence of 3.7 kb HBA1/HBA2 deletion was present in 21.3 % of children. β-thalassemia mutations were associated with several clinical and laboratory features. In general, the incidence of clinical events per 100 patient-years was similar for children with HbSβ0-thal, IVS-I-5 G>A, and IVS-I-110 G>A. Children with HbSβ+-intermediate phenotypes had a more severe laboratory and clinical profile when compared with those with HbSβ+-mild ones. βS-haplotypes and α-thalassemia did not meaningfully influence the phenotype of children with HbSβ-thal. Conclusion: The early identification of β-thalassemia alleles may help the clinical management of these children.

Background: Thalassemias represent some of the most common monogenic diseases worldwide and are caused by variations in human hemoglobin genes which disrupt the balance of synthesis between the alpha and beta globin chains. Thalassemia gene detection technology is the gold standard to achieve accurate detection of thalassemia, but in clinical practice, most of the tests are only for common genotypes, which can easily lead to missing or misdiagnosis of rare thalassemia genotypes. Case presentation: We present the case of an 18-year-old Chinese female with abnormal values of routine hematological indices who was admitted for genetic screening for thalassemia. Genomic DNA was extracted and used for the genetic assays. Gap polymerase chain reaction and agarose gel electrophoresis were performed to detect HBA gene deletions, while PCR-reverse dot blot hybridization was used to detect point mutations in the HBA and HBB genes. Next-generation sequencing and third-generation sequencing (TGS) were used to identify known and potentially novel genotypes of thalassemia. We identified a novel complex variant αHb WestmeadαHb Westmeadαanti3.7/-α3.7 in a patient with rare alpha-thalassemia. Conclusions: Our study identified a novel complex variant that expands the thalassemia gene variants spectrum. Meanwhile, the study suggests that TGS could effectively improve the specificity of thalassemia gene detection, and has promising potential for the discovery of novel thalassemia genotypes, which could also improve the accuracy of genetic counseling. Couples who are thalassemia carriers have the opportunity to reduce their risk of having a child with thalassemia. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Thalassemia and hemoglobin (Hb) variants are the most common hereditary red blood cell disorders worldwide. Alpha-thalassemia and alpha-globin variants are caused by mutations of the alpha-globin genes (HBA2 and HBA1), resulting in impaired alpha-globin production and structurally abnormal globin, respectively. Clinical severity of alpha-thalassemia correlates with the number of affected alpha-globin genes, yielding a spectrum of clinical manifestations from mild to severe anemia. Routine diagnosis involves Hb analysis and PCR-based methods, yet identifying rare variants necessitates comprehensive clinical and hematologic laboratory data. The knowledge of phenotype and genotype correlation is useful for genetic counseling and treatment planning. Case Report: A 59-year-old Thai woman presented with chronic anemia. Her baseline Hb level ranged between 8.0 and 9.0 g/dL, with no history of transfusion. Physical examination showed mild pallor, without enlarged liver and spleen. Laboratory investigations showed microcytic, hypochromic anemia and abnormal Hb peak by Hb analysis (retention time 4.58 min by HPLC method). Common alpha-globin gene deletions, including the Southeast-Asian/Thai 3.7 kb and 4.2 kb deletions were tested using gap-PCR, with none of these deletions detected. Direct DNA sequencing revealed a compound heterozygosity of Hb Jax (HBA2: c.44G>C) and Hb Constant Spring (HBA2: c.427T>C). Conclusions: Compound heterozygosity of Hb Jax and Hb Constant Spring results in microcytic anemia. Hb Jax can be identified by Hb analysis, and diagnosis can be confirmed by direct DNA sequencing method. Coinheritance of Hb Jax and alpha-globin variants should be considered in cases with microcytic anemia and a specific Hb peak seen in Hb chromatogram. [ABSTRACT FROM AUTHOR]

Background: Carrier screening is the most effective method to block the occurrence of thalassemia. However, due to differences in race and genotype, MCV, MCH, HbA2 and other indicators are far from each other. The purpose of this study is to evaluate the common screening indicators of a, P and aP-compound thalassemia carriers in Hunan Province, and try to use the relevant formulas in the existing literature to predict and distinguish different types of thalassemia carriers. Methods: Receiver operating characteristic curve (ROC curve) combined with Youden index was utilized to analyze results of blood routine examination, hemoglobin electrophoresis, and literature-related formulas for 1111 a-thalassemia carriers, 464 P-thalassemia carriers and 24 aP-thalassemia carriers. Results: For a-thalassemia carriers, no matter which screening index or formula, the screening efficiency was not ideal. For P-thalassemia minor carriers, RBC, RDW-CV, HBA2, HbF and formula 5-7 could be used, and for compound thalassemia, RBC, RDW-CV, HbA2 and formula 5-6 are suitable. HbA2 has high efficiency in the screening of P-thalassemia minor and aP-thalassemia. For the screening of P-thalassemia minor, if the cut-off value of HbA2 is set to 3%, the detection rate of 93.32% can be obtained at the positive rate of 9.6%, and if it is set to 3.15%, the detection rate can also reach 81.68% at the positive rate of 2.89%. For aP-thalassemia, if the cut-off value of HbA2 is set to 3%, the detection rate of 95.83% can be obtained under the positive rate of 8.08%. Conclusion: Different screening indicators and formulas have different efficiencies for different thalassemia carriers, a-thalassemia carriers are easily missed by screening indicators or corresponding formulas. HbA2 is a better screening indicator for both p-thalassemia minor carriers and otJB- thalassemia carriers, and formulas 5, 6, and 7 are suitable for p-thalassemia minor carriers, and formulas 5 and 6 are better for ap-thalassemia carriers. To fully and objectively understand each screening index, data support has been provided for clinical and laboratory tests. [ABSTRACT FROM AUTHOR]

Objectives: Our study evaluated the association of the polymorphism rs724016 in the ZBTB38 gene, previously associated with height in other populations, with predictors of height, clinical outcomes, and laboratory parameters in sickle cell anemia (SCA). Methods: Cross-sectional study with individuals with SCA and aged between 3 and 20 years. Clinical, laboratory, molecular, and bone age (BA) data were evaluated. Levels of IGF-1 and IGFBP-3 were adjusted for BA, target height (TH) was calculated as the mean parental height standard deviation score (SDS), and predicted adult height (PAH) SDS was calculated using BA. Results: We evaluated 80 individuals with SCA. The homozygous genotype of the G allele of rs724016 was associated with a lower height SDS (p

Two cases of rare α thalassemia gene mutation were reported. The results of blood routine showed the decreased mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH), and the normal hemoglobin (Hb). Hemoglobin electrophoresis showed that the first patient had normal HbA2 and elevated HbF, and the second patient had normal HbA2 and HbF. Common mutations of α and β thalassemia gene were not detected in both patients. Because the blood phenotype and genotype did not match, the α thalassemia carriers were suspected. Three rare α thalassemia types, including--THAI, -α27.6 and -α21.9, were further detected by GapPCR. However, the results did not show abnormality. Sanger sequencing method was then used to directly sequence the DNA of the study subjects. It was found that the two patients carried rare mutations of α globin gene, namely CD26 (GCG>GGG) heterozygous mutation and CD104 (TGC>TAC) heterozygous mutation, respectively. In this study, two rare α thalassemia gene mutations were reported, which enriched the gene mutation spectrum of the Chinese population, with a guiding significance for the screening diagnosis and genetic counseling of the disease. [ABSTRACT FROM AUTHOR]

α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.

The present study aimed to evaluate the prevalence of alpha-thalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency in sickle cell trait (SCT) patients to determine its effect on red blood cells (RBC) parameters. This cross-sectional study was conducted on 102 blood samples obtained from children and teenagers with SCT aged between 5 and 18 years old who were referred to Shahid Beqaei Hematology and Oncology Hospital and Abuzar Children's Hospital in Ahvaz city (Iran) from October 2021 to November 2022. About 5 mL of blood was collected via venipuncture from each patient and used to run G6PD, complete blood count, and hemoglobin (Hb) electrophoresis tests. The data were analyzed using SPSS version 22, and the significance level in all tests was considered less than 0.05. Results showed that the prevalence of heterozygous and homozygous alpha-thalassemia and iron deficiency anemia (IDA) in the examined sample was 18.63%, 18.63%, and 10.78%, respectively. Also, 13.72% of patients suffered from G6PD deficiency. The results imply that G6PD deficiency may increase the severity of anemia in SCT patients. Therefore, it is necessary to screen all SCT patients for G6PD deficiency to ensure that their condition is not exacerbated during unexpected events such as diseases or stress.

The article presents a study which introduced a Thai boy with rare deletional HbH genotype caused by a novel insertion-deletion (indel) within the α-globin gene cluster. Topics discussed include reason that new cases of deletional HbH disease and Hb Bart's hydrops fetalis have been being reported and misdiagnosed, results of multiplex ligation-dependent probe amplification (MLPA) analysis, and diagnosis of the proband with uncommon deletional HbH disease.

Background: Patients with homozygous or compound heterozygous β0 thalassemia may present either with thalassemia major or intermedia. This phenotypic variability is the consequence of several genetic modifiers in different populations. We aimed to assess the frequency and the impact of coinheritance of α-thalassemia on phenotype in Iraqi Kurds. Methods: A total of 125 patients characterized as homozygous or compound heterozygous β0 thalassemia were recruited in thalassemia center Duhok. They were classified based on age of starting and the frequency of transfusion (thalassemia major or intermedia). All patients had their DNA extracted and Gap-PCR performed to identify 3 deletions namely: ‒α 3.7, ‒α 4.2, and ‒ ‒MED. Results: The patients had a median age of 12 years (Range 2.0-35), with 63 males and 62 females. 96 patient with thalassemia major and 29 with intermedia. The most frequent β-mutations were IVS-2.1 (G>A), Codon 44 (-C), codon 5 (-CT) and codon 8 (-AA). Gap PCR identified α-thalassemia in 9 patients (7.2%), including ‒α 3.7 /αα in 8 cases and ‒α 4.2/αα in one patient, while none had a double α-gene deletions. The frequency of α-thalassemia was higher in thalassemia intermedia at 13.8% compared to 5.2% in major. This difference was statistically insignificant (P=0.228). Conclusions: The patients not appear to be a significant with homozygous or compound heterozygous β0 thalassemia. This may be attributed to low background frequency of αthalassemia, it being mainly due to a single α-gene deletion. Further studies including more patients with extended β-genotypes and other genetic modifiers may be worthwhile. [ABSTRACT FROM AUTHOR]

Objective Since the global outbreak of the novel coronavirus disease 2019 (COVID-19), there have been increasing reports of children developing a croup-like cough associated with concurrent COVID-19 infection. Currently, there is not much information available regarding newborn infants and COVID-19 infection and the incidence of vertical transmission is thought to be rare. This novel case report depicts a term newborn infected at the time of birth with COVID-19 and includes details about the course of their complicated hospitalization. Study Design A term infant, found to be infected at birth with COVID-19, developed respiratory distress resulting in transfer to our neonatal intensive care unit. Due to the increasing respiratory support requirements, endotracheal intubation was required on day of life (DOL) 7. Later, when the infant was extubated, on DOL 21, a croup-like cough developed. Results Despite respiratory treatment with albuterol, budesonide, racemic epinephrine, lidocaine, dornase alfa, and a 10-day course of dexamethasone, the cough persisted. A prolonged hospitalization was required and eventually the infant was discharged home on 0.4 L/minute of oxygen via nasal cannula on DOL 95. Conclusion As the COVID-19 virus mutates over time, there are some seemingly different presentations in both the pediatric and adult populations. The hypervigilance and sharing of new findings among providers are paramount in the treatment of infants with COVID-19 disease. Key Points Term infant with COVID-19 developed a croup-like cough. Usual respiratory treatment not effective with croup-like cough and COVID-19. COVID-19 present at birth later requiring intubation. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate the prevalence of alphathalassemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency in sickle cell trait (SCT) patients to determine its effect on red blood cells (RBC) parameters. This cross-sectional study was conducted on 102 blood samples obtained from children and teenagers with SCT aged between 5 and 18 years old who were referred to Shahid Beqaei Hematology and Oncology Hospital and Abuzar Children's Hospital in Ahvaz city (Iran) from October 2021 to November 2022. About 5 mL of blood was collected via venipuncture from each patient and used to run G6PD, complete blood count, and hemoglobin (Hb) electrophoresis tests. The data were analyzed using SPSS version 22, and the significance level in all tests was considered less than 0.05. Results showed that the prevalence of heterozygous and homozygous alpha-thalassemia and iron deficiency anemia (IDA) in the examined sample was 18.63%, 18.63%, and 10.78%, respectively. Also, 13.72% of patients suffered from G6PD deficiency. The results imply that G6PD deficiency may increase the severity of anemia in SCT patients. Therefore, it is necessary to screen all SCT patients for G6PD deficiency to ensure that their condition is not exacerbated during unexpected events such as diseases or stress. [ABSTRACT FROM AUTHOR]

Gliomas are the most common malignancies of the central nervous system. Two molecular profiles involved in gliomagenesis are isocitrate dehydrogenase (IDH) and alpha-thalassemia X-linked intellectual disability (ATRX). Inactive mutations in the ATRX gene are associated with tumorigenesis via the alternative telomere lengthening pathway as well as with IDH and tumor protein p53 mutation. The present study aims to determine the relationship between ATRX mutation and histopathological grading in IDH-mutant gliomas. This is a cross-sectional study using formalin-fixed paraffin-embedded blocks to examine the data of patients with an IDH-mutant glioma admitted to the Sardjito General Hospital between January 2017 and March 2022. The IDH-mutant status and ATRX mutation were determined via a polymerase chain reaction-sequencing examination and immunohistochemistry analysis. The association between ATRX mutation and histopathological grading was tested using the chi-square test. A total of 39 glioma samples from patients with IDH-mutant status were included in this study. Of these, 26 were obtained from men (66.67%). The age range of all patients was 20--66 years. A total of 19 samples (48.72%) showed immunopositivity to ATRX. The bivariate analysis revealed that ATRX mutation was not associated with histopathological grading (P > 0.05). The ATRX mutations were not associated with IDH-mutant glioma grading in the present study. [ABSTRACT FROM AUTHOR]

BackgroundThalassemia is a genetic hemoglobinopathy in which a defective globin chain can cause transfusion-dependent anemia and other complications. As genotype interactions lead to variations in the clinical course among patients with thalassemia, clinical factors may help predict survival in the types of thalassemia complicated by gene interactions.AimThis study aimed to determine the clinical factors associated with survival in patients with thalassemia. We retrospectively reviewed the medical records of patients with thalassemia older than 15 years between 2002 and 2020 that were available at the Rajavithi Hospital. Data on the clinical parameters, laboratory tests, treatments, and survival status were collected and analyzed.ResultsOf the 478 thalassemia patients included, 68.8% were women, and the mean age was 41 ± 17 years. The most common type of thalassemia was β-thalassemia (53.3%). Male sex, low body mass index, the thalassemia type, comorbidities, low hemoglobin level, high ferritin level, and regular blood transfusion were significantly associated with short-term survival. However, only the thalassemia type (β-thalassemia, p = 0.048) and the co-inheritance of the α- and β-thalassemia genotypes (p = 0.03) were independently associated with death. The overall survival rates among patients with α-thalassemia, β-thalassemia, and co-inheritance of the α- and β-thalassemia genotypes were 98.1%, 90.6%, and 75.0%, respectively. The death rate was 6.3%, and the most common cause of death was infection.ConclusionThe thalassemia genotype was a predictive factor of survival, and co-inheritance of the α- and β-thalassemia genotypes results in a shorter-term survival compared with other types, especially transfusion-dependent thalassemia. These results can be applied in clinical settings to predict and possibly extend the life expectancy of patients with thalassemia.