bims-conane Biomed News
on Congenital anemias
Issue of 2025–06–08
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo
  1. Three novel heterozygous ANK1 loss-of-function variants cause hereditary spherocytosis in Chinese families.
  2. Concurrent Case of Glucose-6-Phosphate Deficiency and Dehydrated Hereditary Stomatocytosis in a 4-Month-old Boy.
  3. Unraveling Hemoglobin D's Influence: A Comprehensive Analysis of Clinicopathological Parameters in Hemoglobin D Patients.
  4. Novel compound heterozygous PIEZO1 variants in dehydrated hereditary stomatocytosis initially suspected as myelodysplastic syndromes: a case report.
  5. Lifetime Risk of Liver Disease in Patients With β-Thalassemia: Data From the de-LIGHT Retrospective Cohort Study.
  6. Another Fanconi anemia gene joins the club.
  7. Erratum to: Prevalence and mortality trends of hemoglobinopathies in Italy: a nationwide study.
  8. Regeneration alters open chromatin and cis-regulatory landscape of erythroid precursors.
  9. The Fetal-to-Adult Hemoglobin Switch - Mechanism and Therapy.
  1. Ann Hematol. 2025 Jun 03.
    Three novel heterozygous ANK1 loss-of-function variants cause hereditary spherocytosis in Chinese families.
    Yang Wang, Tao Liu, Wen Wang, Yuzhuopu Li, Li Xiao, Yan Xiang, Lan Huang, Yongjie Zhang, Jie Yu.
       BACKGROUND AND PURPOSES: Hereditary spherocytosis (HS) is an inherited hemolytic anemia caused by variants in red blood cell cytoskeleton proteins. Advances in sequencing technology have revealed numerous novel variants; however, accurate genome annotation remains a significant challenge. In precision medicine, the precise identification of variants responsible for genetic diseases is crucial. This study aims to clearly delineate pathogenic variants and provide targeted pathogenicity analyses.
    METHODS: We analyzed clinical data from three unrelated Chinese families with HS. Our investigation delved into the pathogenicity and underlying mechanisms of these variants. In silico simulations and in vitro experiments were employed to assess the effects of the identified variants.
    RESULTS: We identified three novel heterozygous variants in the ANK1 gene: c.558delG (p.R187Afs*66), c.728T > G (p.L243R), and c.3157 C > T (p.R1053X). In silico analysis indicated that these variants adversely affect the ankyrin-1. Functional studies demonstrated that these variants disrupt the synthesis of ankyrin-1, weakening its interaction with other red blood cell cytoskeleton proteins, which may lead to HS due to the loss of ankyrin-1 function.
    CONCLUSIONS: Our study offers valuable insights into the molecular mechanisms associated with HS linked to three de novo ANK1 variants. These findings deepen our understanding of the pathogenesis of HS and emphasize the critical role of genetic screening in the diagnosis of this condition.
    Keywords:   ANK1 ; Hereditary spherocytosis; Loss-of-function; Novel; Variant
    DOI:  https://doi.org/10.1007/s00277-025-06408-9
  2. J Pediatr Hematol Oncol. 2025 May 29.
    Concurrent Case of Glucose-6-Phosphate Deficiency and Dehydrated Hereditary Stomatocytosis in a 4-Month-old Boy.
    Thao Minh Nguyen, Sara Sadiq, Joshua M Peterson, Leonard K Wang, Gulrukh Botiralieva, Yaroslav Chernov, Akila Muthukumar, Kirill A Lyapichev.
      Glucose-6-phosphate (G6PD) deficiency is the most prevalent enzyme deficiency and is estimated to affect 400 million people. The patients are usually asymptomatic and diagnosed following hemolytic episodes triggered by oxidative stress. Another type of hemolytic anemia known as dehydrated hereditary stomatocytosis (DHSt) is estimated to affect less than 1 per 1,000,000 people. DHSt is caused by increased cation efflux and dehydration in red blood cells, which leads to decreased flexibility making them more vulnerable to lysis. Compared with G6PD, DHSt has a mild presentation, where most patients (84%) with isolated DHSt exhibit chronic hemolysis. Both diseases, G6PD deficiency and DHSt, are inherited hemolytic anemias and to the best of our knowledge have never been reported to coexist in the same patient. Herein, we present the first case of concurrent G6PD deficiency and DHS in a 4-month-old male. We discuss the clinical presentation and hematopathology findings from this patient as well as provide a comparison literature review. We believe this presentation will add to the current body of knowledge for these conditions and help to guide future investigation and management.
    Keywords:  dehydrated hereditary stomatocytosis; glucose-6-phosphate deficiency; hemolytic anemia
    DOI:  https://doi.org/10.1097/MPH.0000000000003057
  3. Hemoglobin. 2025 Jun 01. 1-5
    Unraveling Hemoglobin D's Influence: A Comprehensive Analysis of Clinicopathological Parameters in Hemoglobin D Patients.
    Mohib Shamoon, Rafia Mahmood, Manzar Bozdar, Saad Yousof.
      This prospective cross-sectional study was conducted at the Department of Hematology at Armed Forces Institute of Pathology Rawalpindi, Pakistan, from July 2023 to February 2025 after approval from Ethical Review Committee of the institute. Individuals being investigated for hemoglobinopathies in whom Hemoglobin D was detected, were included in the study. After detailed history and examination, investigations were performed including Complete Blood Counts (on Sysmex XN-3000), Capillary Zone Electrophoresis (on Sebia Capillarys 2 Flex-Piercing), High Performance Liquid Chromatography (on Bio-Rad D10) for differentiating Hb D-Punjab and D-Iran. Molecular studies (using PCR) were performed on samples in which a co-existing β thalassemia mutation was suspected on hemoglobin electrophoresis. Data collected was analyzed on Jamovi v2.4. Over 18 months, 2,171 individuals were tested for hemoglobinopathies, and Hb D, after excluding concomitant iron deficiency anemia, was detected in 106. Among these, 76 were found to have Hb D trait, 3 with homozygous Hb D disease, and 27 with compound heterozygous conditions. The compound heterozygous group included 21 patients of Hb D/β-thalassemia, 4 patients of Hb S/D, and 2 patients of Hb D/E. Hb D-Punjab accounted for 71% of the Hb D patients, and Hb D-Iran for the remaining 29%. Linear regression analysis revealed that MCH and RBC count showed significant positive correlations with Hb D levels. Molecular analysis identified specific β-thalassemia mutations in the Hb D/β-thalassemia cases, with IVS1-5 and FR 8-9 being the most common.
    Keywords:  Hb D-Iran; Hb D-Punjab; Hb electrophoresis; Hemoglobinopathies; clinico-hematological profiles; hemoglobin D
    DOI:  https://doi.org/10.1080/03630269.2025.2510442
  4. Front Oncol. 2025 ;15 1574518
    Novel compound heterozygous PIEZO1 variants in dehydrated hereditary stomatocytosis initially suspected as myelodysplastic syndromes: a case report.
    Yongcheng Sun, Tao Wang, Shuyan Wang, Yan Chen, Zhijuan Xu, Cong Shi, Zanzan Wang, Guifang Ouyang.
       Introduction: Dehydrated hereditary stomatocytosis (DHS) is a rare autosomal dominant congenital non-immune hemolytic anemia caused by pathogenic variants in the PIEZO1 gene. Its clinical presentation often overlaps with other hematological disorders, leading to diagnostic challenges and potential mismanagement.
    Case presentation: A 22-year-old man presented with a 7-year history of anemia initially misdiagnosed as myelodysplastic syndrome (MDS) due to hypercellular bone marrow findings and MDS-like features. Over time, his condition progressed to include cerebral venous sinus thrombosis (CVST), a severe complication. Comprehensive genetic testing at our hospital using whole-exome sequencing (WES) revealed novel compound heterozygous PIEZO1 variants: NM_001142864.4: c.6622A>G (p.Ile2208Val) and NM_001142864.4: c.3160C>A (p.Leu1054Met). These findings confirmed the diagnosis of DHS. The patient underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT), resulting in resolution of his hematological abnormalities and symptoms.
    Conclusion: This case underscores the importance of considering DHS in patients with unexplained anemia and MDS-like features, particularly when associated with thrombotic complications. It highlights the critical role of genetic testing in diagnosing rare hereditary anemias and demonstrates that allo-HSCT can be a curative treatment in selected cases.
    Keywords:  DHS; PIEZO1; allo-HSCT; case report; compound heterozygous
    DOI:  https://doi.org/10.3389/fonc.2025.1574518
  5. Eur J Haematol. 2025 Jun 04.
    Lifetime Risk of Liver Disease in Patients With β-Thalassemia: Data From the de-LIGHT Retrospective Cohort Study.
    Khaled M Musallam, Angela Vitrano, Alessandro Inzerillo, Rosario Di Maggio, Rita Barone, Antonino Giangreco, Maria Concetta Renda, Emanuela Fecarotta, Antonio Troia, Antonino Giambona, Giovan Battista Ruffo, Efthymia Vlachaki, Theodora M Venou, Paolo Ricchi, Brunella Ziello, Marilena Serra, Elena Colizzi, Filomena Longo, Martina Culcasi, Aurelio Maggio.
       BACKGROUND: Liver disease is common in patients with β-thalassemia, but data on lifetime incidence and risk factors are limited.
    METHODS: We conducted a retrospective cohort study of 557 patients with β-thalassemia followed from diagnosis for a median of 38 years. Predictive, survival, and regression analyses were used to determine the association between liver disease and potential risk factors.
    RESULTS: The crude incidence of liver disease was 26.4% (fibrosis/cirrhosis 24.2%, median age 34.4 years; hepatocellular carcinoma 2.3%, median age 45.4 years, 38.5% not preceded by cirrhosis). Among evaluated risk factors, only hepatitis C virus (HCV) infection (adjusted hazard ratio [HR]: 2.195, p < 0.001) and lifetime serum ferritin level (adjusted HR per 100-ng/mL increase: 1.030, p < 0.001) were significantly associated with liver disease, with a lifetime serum ferritin level > 1500 ng/mL being the best predictor (p = 0.001). Liver disease-free survival was significantly shorter in patients who had both versus either or neither risk factor (p < 0.001). Mostly severe and persistent but not mild-moderate or temporary/fluctuating elevation in liver enzymes was associated with liver disease development.
    CONCLUSION: Patients with β-thalassemia have a considerably increased lifetime risk of liver disease that is primarily driven by HCV infection and/or uncontrolled iron overload, especially in the 4th-5th decades of life.
    Keywords:  cirrhosis; fibrosis; hepatitis; hepatocellular carcinoma; iron overload
    DOI:  https://doi.org/10.1111/ejh.14446
  6. J Clin Invest. 2025 Jun 02. pii: e192382. [Epub ahead of print]135(11):
    Another Fanconi anemia gene joins the club.
    Claire C Homan, Hamish S Scott, Parvathy Venugopal.
      Fanconi anemia (FA) is the most common inherited bone marrow failure disorder, caused by pathogenic variants in genes involved in the FA DNA repair pathway. In this issue of the JCI, two studies report three germline homozygous loss-of-function variants in FAAP100, a key component of the FA core complex, identified in three unrelated families. These variants result in severe developmental phenotypes that are among the most extreme reported in FA to date. Harrison et al. described individuals from two families with recurrent pregnancy loss and neonatal death due to homozygous FAAP100 frameshift and truncating variants, respectively. Kuehl et al. identified a homozygous missense variant in a fetus with congenital malformations consistent with FA. Collectively, both studies provide robust functional evidence from ex vivo and in vitro assays with animal models supporting the pathogenicity of these variants and establish FAAP100 as a causative FA gene.
    DOI:  https://doi.org/10.1172/JCI192382
  7. Haematologica. 2025 Jun 01. 110(6): 1449-1450
    Erratum to: Prevalence and mortality trends of hemoglobinopathies in Italy: a nationwide study.
    Barbara Gianesin, Frédéric B Piel, Khaled M Musallam, Susanna Barella, Maddalena Casale, Elena Cassinerio, Rosario Di Maggio, Antonia Gigante, Maria Rita Gamberini, Giovanna Graziadei, Roberto Lisi, Filomena Longo, Aurelio Maggio, Raffaella Origa, Annamaria Pasanisi, Silverio Perrotta, Antonio Giulio Piga, Valeria Maria Pinto, Rosamaria Rosso, Giacomo Robello, Giovanna Russo, Marco Zecca, Lucia De Franceschi, Gian Luca Forni.
      
    DOI:  https://doi.org/10.3324/haematol.2025.287581
  8. Genome Res. 2025 Jun 02.
    Regeneration alters open chromatin and cis-regulatory landscape of erythroid precursors.
    Yichao Zhou, Venkatasai Rahul Dogiparthi, Hannah L Harris, Suhita Ray, Avik Choudhuri, Song Yang, Yi Zhou, Leonard I Zon, M Jordan Rowley, Kyle J Hewitt.
      Stress erythropoiesis elevates the rate of red blood cell (RBC) production as a physiological response to stressors such as anemia or hypoxia. In acute anemia, RBC progenitors and precursors temporarily rewire their transcriptome, up- and downregulating hundreds of genes to accelerate the production of mature RBCs. Effective regeneration requires communication between critical cytokine signals (e.g., BMP4) and cis-regulatory elements on chromatin which coordinate transcriptional changes. To identify cis-regulatory changes that underlie anemia-specific gene expression and cellular responses, we analyzed chromatin accessibility in populations of cells enriched for red blood cell precursors isolated from mice at a range of time points after anemia induction. Early in the anemia response, chromatin is transiently open at AP-1-containing regions, correlated with increased Jun and Fos transcript/protein levels. Jun knockdown ex vivo decreases the percentage of KIT+ erythroid precursors after anemia induction. We observe a second rewiring event at time points consistent with anemia resolution, involving repression of GATA factor-accessible regions and activation of ETS factor-accessible regions. In both mouse in vivo models and human CD34+ cells stimulated with BMP4, accessibility changes at regions with prior associations to human blood phenotypes. Dozens of BMP4- and anemia-activated loci are sensitive to natural human variation. The representation of red blood cell trait-associated loci in ATAC-seq data remains durably elevated more than 1 month after anemia resolution. Together, these findings provide a framework to understand the early establishment and late resolution of a regeneration-dependent transcriptome in RBC precursors.
    DOI:  https://doi.org/10.1101/gr.279949.124
  9. N Engl J Med. 2025 Jun 05. 392(21): 2135-2149
    The Fetal-to-Adult Hemoglobin Switch - Mechanism and Therapy.
    Stuart H Orkin.
      
    DOI:  https://doi.org/10.1056/NEJMra2405260
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