bims-conane 2025-11-16 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–11–16
eight papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Clinical Spectrum and Genotypes of Children with Hemoglobin H in Northeastern Thailand.
Role of Additional Erythrocyte and Reticulocyte Parameters Offered by Sysmex XN-9000 in the Diagnostic Workup of Hereditary Spherocytosis: A New Screening Algorithm According to Age.
Screening, genetic analysis, and clinical transfusion implications of thalassaemia and glucose-6-phosphate dehydrogenase deficiency in blood donors.
Highly discriminative globin gene activation by the non-canonical BAF chromatin remodeling complex.
Catalog of 73 novel variants in thalassemia: discoveries and insights.
The application of next-generation sequencing technology in congenital haemolytic anaemia: a systematic review and meta-analysis.
Accurate diagnosis of hemoglobinopathies with machine learning based on high-throughput proteomics.
Genotypic and phenotypic characterization of rare globin variants in Northern Guangxi, China.

Mediterr J Hematol Infect Dis. 2025 ;17(1): e2025081

Clinical Spectrum and Genotypes of Children with Hemoglobin H in Northeastern Thailand.

Nattakarn Sangkha, Patcharee Komvilaisak, Arunee Jetsrisuparp, Kunanya Suwannaying, Goonnapa Fucharoen, Napat Laoaroon, Ratana Komwilaisak.



Keywords:  Hb H disease

DOI:  https://doi.org/10.4084/MJHID.2025.081
Int J Lab Hematol. 2025 Nov 10.

Role of Additional Erythrocyte and Reticulocyte Parameters Offered by Sysmex XN-9000 in the Diagnostic Workup of Hereditary Spherocytosis: A New Screening Algorithm According to Age.

Anne-Sophie Adam, Frédéric Cotton, Danai Poutakidou, Béatrice Gulbis.

   INTRODUCTION: Numerous algorithms based on recent developments of additional parameters on last generation haematology analysers have opened new perspectives for hereditary spherocytosis (HS) screening. Although some studies have demonstrated significant age-related variation for reticulocyte-derived parameters, these algorithms did not consider patients' age. Moreover, the apparent lack of short-term stability of some parameters could represent an obstacle to their use if not performed as first-line testing. This study aimed to identify robust and discriminating parameters that could be used for HS screening at any patients' age.
METHODS: After an evaluation of the reference values and stability of the additional parameters offered by the Sysmex XN-9000, we retrospectively collected and analysed the haematological parameters of 103 confirmed HS patients and 124 controls. The HS group was also compared to 116 samples from patients affected with other red blood cell or iron disorders.
RESULTS: Our findings confirm that the reticulocyte count (Ret) and its ratio to the immature reticulocyte fraction (Ret/IRF) are the most effective and robust parameters for HS screening, with stability up to 48 and 96 h at room temperature (RT) and 4°C, respectively. The Ret/IRF ratio was mostly affected by patients' age rather than haemoglobin levels. We therefore proposed different algorithms that can be adapted to the laboratory's needs and that incorporate age-specific thresholds for Ret/IRF. The combination of Ret and Ret/IRF allowed a sensitivity between 91.3% and 100% and a specificity between 77.1% and 94.2%.
CONCLUSIONS: This new age-dependent algorithm using Sysmex's most stable parameters offers an easy-to-use tool for HS screening, even in cases of delayed or residual blood analysis.

Keywords:  Sysmex analyser; automated blood count; hereditary spherocytosis; reticulocyte; screening algorithm

DOI:  https://doi.org/10.1111/ijlh.70023
Transfus Med. 2025 Nov 12.

Screening, genetic analysis, and clinical transfusion implications of thalassaemia and glucose-6-phosphate dehydrogenase deficiency in blood donors.

Zhi-Xiao Chen, Bao-Ying Chen, Rong-Huo Liu, Jian-Cheng Huang, Jia-Min Mo, Zhen-Yuan Mai, Yan-Qing Zeng, Yu-Chan Huang, Yan-Bin Cao, Bai-Ru Lai, Wei-Feng Xu, Li-Ye Yang.

   BACKGROUND: This study aims to explore the prevalence, genotypes, and clinical applications of thalassaemia and glucose-6-phosphate dehydrogenase (G6PD) deficiency among blood donors, offering scientific support for the safety of clinical blood transfusions.
MATERIALS AND METHODS: Haematological and G6PD enzyme activity tests were conducted on 1028 blood donors from one coastal city in southern China. A detailed genotypic analysis was performed on samples potentially carrying thalassaemia and G6PD deficiency, and their clinical significance was subsequently explored.
RESULTS: Among 1028 blood donors, 137 individuals were found to carry the thalassaemia gene (13.33%). The specific distribution is as follows: 111 cases of α-thalassaemia (10.80%), 21 cases of β-thalassaemia (2.04%), and five cases with both α- and β-thalassaemia (0.49%). The -SEA/αα genotype was the most common thalassaemia genotype (8.17%). Additionally, 121 individuals (11.77%) carried the G6PD deficiency gene, with the c.1388G>A variant being the most prevalent (3.7%). Compared to recipients of blood from normal donors, patients who received transfusions from donors with thalassaemia or G6PD deficiency did not exhibit significant differences in the risk of adverse reactions or the extent of haemoglobin concentration elevation.
CONCLUSION: The -SEA/αα genotype is the most prevalent in α-thalassaemia, while c.1388G>A is the most common genetic variant in G6PD deficiency. Individuals with G6PD deficiency exhibit higher MCV and MCH values. Additionally, blood donated by carriers of thalassaemia or G6PD deficiency does not increase the risk of adverse transfusion reactions. The transfusion of blood from donors with thalassaemia or G6PD deficiency showed no significant difference in haemoglobin elevation compared to that from normal donors.

Keywords:  blood donor; genotyping; glucose‐6‐phosphate dehydrogenase (G6PD) deficiency; thalassaemia; transfusion

DOI:  https://doi.org/10.1111/tme.70018
Blood. 2025 Nov 14. pii: blood.2025029429. [Epub ahead of print]

Highly discriminative globin gene activation by the non-canonical BAF chromatin remodeling complex.

Abhirup Bagchi, Sindhu Billakanti, Vanessa Shehu, Kathryn M Farrell, Sarah A Cotteta, Bailey N Godfrey, Micaela Alpert, Jacob Flores Zeranski, Krista A Budinich, Zhuangzhuang Geng, Osheiza Abdulmalik, Belinda M Giardine, Cheryl A Keller, Ross C Hardison, Junwei Shi, Eugene Khandros.

The regulation of the switch from fetal (HBG) to adult (HBB and HBD) b-globin gene expression has served as a paradigm for clinically relevant developmental transcriptional control. Mechanistic studies of this switch have predominantly focused on HBG repressors with comparatively little attention paid to potential HBG activators. We found that in adult type HUDEP2 erythroid cells, the ATP-dependent chromatin remodeler BRG1 preferentially activates the HBG genes as well as the minor adult HBD gene. BRG1 is a core catalytic subunit of three BAF complexes, canonical BAF, polybromo BAF, and non-canonical BAF (ncBAF) that regulate chromatin accessibility in distinct gene- and cell-type contexts. To dissect the specific BAF complex configuration mediating selective activation of HBG and HBD in erythroid cells, we performed CRISPR mediated targeting of individual subunits and pinpointed the regulatory activity to the ncBAF complex. Loss of the ncBAF complex subunits BRD9 and BAF60A preferentially decreased HBG and HBD transcription while accelerating terminal erythroid differentiation and hemoglobinization. Acute pharmacologic depletion of BRD9 in HUDEP2 and primary erythroid cells selectively reduced transcription of HBD and HBG, suggesting direct effects at these genes. Collectively, our unexpected findings demonstrate that the BAF complex, through distinct subcomplex configurations, can regulate selective gene expression within a multi-gene cluster. This expands the traditional view of BAF as a general co-activator, highlights its role in gene-specific regulation, and identifies a potential target for therapeutic manipulation of b-like globin genes in erythroid cell disorders.

DOI: https://doi.org/10.1182/blood.2025029429
Hum Mol Genet. 2025 Nov 10. pii: ddaf171. [Epub ahead of print]

Catalog of 73 novel variants in thalassemia: discoveries and insights.

Jungao Huang, Zhenchang Liu, Feng Miao, Liping Huang, Chunlong Xiao, Ping Zhang, Jiayu Huang, Yan Li, Xiaoyan Huang, Xiaoqin Xin.

  Thalassemia is a genetic blood disorder caused by disrupted hemoglobin synthesis, posing significant public health challenges. This study aims to expand the identification of novel thalassemia variants in a large cohort from pre-marriage screenings in Ganzhou, Southern Jiangxi, China. Data from 229 246 individuals screened through Next-Generation Sequencing (NGS) from 2019 to 2022 led to the identification of 180 participants with novel variants, marking the first large-scale documentation of such variations in the population. Among them, 51.1% were male with a mean age of 27 years, and the frequency of novel thalassemia variants was 0.079%. We uncovered 180 novel variants, including 68 α-thalassemia variants across 33 types (0.0297% frequency) and 112 β-thalassemia variants belonging to 40 unique types (0.0489% frequency). The most common α-thalassemia genotype was HBA1:c.95 + 9C > T at 17.65%, while HBB:c.-180G > C was most prevalent among β-thalassemia variants at 23.21%. Ten novel α-thalassemia variants were linked to mild α-thalassemia, and clinical phenotypes were documented for 21 complex genotypes. This study catalogues 73 novel variants and highlights the genetic diversity of thalassemia, informing future preventive strategies.

Keywords:  Next-Generation Sequencing (NGS); Thalassemia; general population; novel variants

DOI:  https://doi.org/10.1093/hmg/ddaf171
Clin Exp Med. 2025 Nov 11. 25(1): 368

The application of next-generation sequencing technology in congenital haemolytic anaemia: a systematic review and meta-analysis.

Shuning Xie, Yanling Zhong.

  Congenital haemolytic anaemia (CHA) poses diagnostic challenges due to genetic heterogeneity. This systematic review and meta-analysis evaluates the diagnostic efficacy of next-generation sequencing (NGS) in CHA. We systematically searched PubMed and Web of Science until April 2025. Inclusion criteria encompassed studies applying NGS (whole-exome sequencing [WES], whole-genome sequencing [WGS], clinical exome sequencing [CES], or targeted panels) in confirmed/suspected CHA patients. Pooled positive detection rates with 95% confidence intervals (CIs) were calculated using a random-effects model. Subgroup analyses stratified by family history and disease subtypes were performed. Study quality was assessed via modified STARD criteria. Ten studies involving 885 patients were included. The pooled positive detection rate of NGS was 44.3% (95% CI: 32.4-56.3%, p < 0.001). Subgroup analysis revealed significantly higher detection rates in patients with family history (51.0%; 95% CI: 32.8-69.2%) versus sporadic cases (16.9%; 95% CI: 8.4-27.2%, p < 0.001). Disease-specific yields varied: red cell membrane disorders showed the highest rate (45.3%; 95% CI: 35.2-55.7%), followed by enzymatic disorders (26.7%; 95% CI: 18.8-35.3%). Among all positive cases, pathogenic variants in five core genes accounted for 76.82% of detected mutations: SPTB (25.06%), PKLR (17.10%), ANK1 (11.94%), SLC4A1 (11.48%), and SPTA1 (11.24%). SPTB and ANK1 mutations were most frequently identified in red cell membrane disorders, while PKLR variants were exclusive to enzymatic disorders. NGS demonstrates substantial diagnostic utility in CHA, resolving nearly half of cases overall and over 50% of familial presentations. Its efficacy is particularly pronounced in red cell membrane disorders linked to cytoskeletal genes (SPTB, ANK1, SPTA1). These findings support integrating NGS into first-line CHA diagnostics, with prioritization of core gene panels for cost-effective implementation.

Keywords:  Congenital haemolytic anaemia; Meta-analysis; Next-generation sequencing technology; Systematic review

DOI:  https://doi.org/10.1007/s10238-025-01896-5
Hemasphere. 2025 Nov;9(11): e70227

Accurate diagnosis of hemoglobinopathies with machine learning based on high-throughput proteomics.

Shaodong Wei, Annelaura Bach Nielsen, Jens Helby, Lylia Drici, Christine Rasmussen, Juanjuan Wang, Matthias Mann, Jesper Petersen, Nicolai J Wewer Albrechtsen, Andreas Glenthøj.

Hemoglobinopathies, such as sickle cell disease and thalassemias, impose a substantial global burden, particularly in endemic regions. Current diagnostic methods, such as high-performance liquid chromatography (HPLC), capillary electrophoresis, and genetic testing, can be time-consuming, expensive, or limited in detecting all variants. This study introduces a novel diagnostic framework that combines high-throughput proteomics with machine learning to address these challenges. We processed red blood cells, whole blood, and plasma samples from 82 individuals (development cohort) and 45 individuals (validation cohort) with structural hemoglobin variants (hemoglobin S, hemoglobin C, hemoglobin D, and hemoglobin E) or β-thalassemia trait, as confirmed by standard clinical testing. Tryptic peptides were analyzed using data-independent acquisition mass spectrometry, and random forest classifiers were trained to identify structural variants or β-thalassemia trait. Model performance was evaluated across 100 Monte Carlo cross-validations. For structural variants, the classifier achieved an area under the receiver-operating characteristic curve (AUC) of 1.000 and 99.9% prediction accuracy in the validation cohort, when comparing our proteomics-based diagnostics to standard testing with HPLC and Sanger sequencing (gold standard). For β-thalassemia trait, the mean AUC was 1.000, and the prediction accuracy was 96.9% in the validation cohort, and a single peptide alone yielded 92% accuracy in a simple decision tree. This high-throughput proteomics approach offers a rapid, scalable, and potentially cost-effective alternative to existing diagnostic workflows, requiring minimal sample preparation while reducing manual interpretation. By combining peptide-level data with machine learning, it enables precise classification of hemoglobinopathies and demonstrates a compelling path for routine clinical evaluation of hereditary anemias.

DOI: https://doi.org/10.1002/hem3.70227
Front Immunol. 2025 ;16 1695120

Genotypic and phenotypic characterization of rare globin variants in Northern Guangxi, China.

Wei-Jia Yang, Qing-Ping Kang, Li-Ming Liang, Qian Zhou, Xiao-Min Gong, Min Dou, Cui-Juan Huang, Ying Lin.

   Objective: The aim of this study is to examine the relationship between hematological parameters, hemoglobin electrophoresis findings, and phenotypic characteristics in individuals carrying rare thalassemia gene variants in Northern Guangxi, China.
Methods: Peripheral blood samples were collected from 3,890 individuals (including 834 couples) who tested positive for thalassemia at the Prenatal Diagnosis Center of Guilin People's Hospital between March 2019 and March 2025. Standard thalassemia genotyping was performed using Gap-PCR and PCR-reverse dot blot (PCR-RDB) assays to detect common α- and β-thalassemia mutations prevalent in southern China. Participants with negative results genotype-phenotype discordance underwent extended molecular testing to detect rare thalassemia variants. In cases where both partners were identified as carriers, amniotic fluid samples were collected from pregnant women for prenatal diagnosis.
Results: Thalassemia major was diagnosed in 13 fetuses, with elective termination of two affected pregnancies. The detection rate for common thalassemia mutations was 44.27% (1,722/3,890), while rare variants were identified in 1.72% (67/3,890). Among participants with negative results from conventional genotyping, the detection rate of rare mutations increased to 26.38% (67/254). A total of 42 rare thalassemia variants were found, including 25 α-thalassemia, 14 β-thalassemia, and 3 δ-thalassemia mutations. A novel 4.3 kb deletion (chr16:176935-181274DEL), encompassing the α1 gene and a recombined non-functional gene-X-Y-Z segment, was reported for the first time. The -α4.3/-SEA genotype was associated with HbH disease.
Conclusion: A substantial frequency of rare thalassemia gene mutations was identified in the Northern Guangxi population, contributing to the regional mutational landscape. These rare genotypes were associated with distinctive hematological and hemoglobin electrophoretic features. Characteristic phenotypic patterns, combined with specific laboratory parameters, facilitated preliminary inference of genotypes and supported the application of targeted diagnostic approaches. This strategy may improve diagnostic accuracy, reduce missed or incorrect diagnoses, and enhance prenatal and postnatal management strategies.

Keywords:  genotype thalassemia; hemoglobin electrophoresis; molecular diagnosis; phenotype; rare globin variation

DOI:  https://doi.org/10.3389/fimmu.2025.1695120