bims-conane 2025-12-21 papers

bims-conane

Biomed News

on Congenital anemias

Issue of 2025–12–21
nine papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

Novel LRF/ZBTB7A variants and known HbF-modulating SNPs in transfusion-dependent β-thalassemia.
Unstable Hemoglobin, a Rare but Significant Cause of Hemolytic Anemia: Recognition of Peripheral Smear Findings Is Crucial for Diagnosis.
Correction: Platelet alloimmunization in transfusion-dependent thalassemia patients from Southern China (2014-2023).
[Dehydrated hereditary stomatocytosis in 23 cases: a single-center retrospective cohort study from Peking Union Medical College Hospital (2018-2024)].
p27Kip1 regulates γ-globin production.
Efficacy and safety of deferiprone for thalassemia: a systematic review and meta-analysis of randomized controlled trials.
Pharmacogenomic and Clinical Predictors of Deferasirox Response in Transfusion-Dependent Thalassemia Identified Using Whole-Genome Sequencing.
Iron deficiency is associated with reduced levels of inflammation and haemolysis in patients with HbSS and HbSC and reduced clinical admissions in those with HbSC.
Left ventricular strain and chamber dimensions in pediatric sickle cell disease: agerelated reduction in myocardial deformation independent of hemolysis and hydroxyurea therapy.

BMC Med Genomics. 2025 Dec 18. 18(1): 194

Novel LRF/ZBTB7A variants and known HbF-modulating SNPs in transfusion-dependent β-thalassemia.

Yunus Arikan, Tugba Karaman Mercan, Merve Embel, Erdal Kurtoglu.

   BACKGROUND: β-Thalassemia is a hereditary blood disorder with a highly variable clinical presentation that is partly influenced by genetic modifiers that regulate fetal hemoglobin levels. Elevated HbF can ameliorate the clinical symptoms of β-thalassemia, making the identification of HbF-modifying loci crucial for understanding disease variability and developing potential therapeutic strategies.
METHODS: In this study, we evaluated the distribution and effect of known HbF-associated single nucleotide polymorphisms within the BCL11A, HMIP, and XmnI-HBG2 loci in β-thalassemia patients. Our investigation was initiated by a hypothesis based on genomic data from the K562 cell line, which indicated the presence of a specific LRF/ZBTB7A variant. In addition, we explored the role of LRF/ZBTB7A, a transcription factor implicated in globin gene regulation, through Sanger sequencing and in silico analyses. A hypothetical Genetic Modifier Score was devised to quantify the cumulative effect of the five major HbF-associated QTLs.
RESULTS: While we confirmed the previously reported associations of the common SNPs with HbF levels, we also identified novel rare variants in LRF/ZBTB7A (p.Pro241Leu, p.Asp344Asp, p.Glu277del) that may influence HbF expression. XmnI-HBG2 accounted for a small yet significant proportion (7%) of HbF variability. A significant positive correlation was found between the Genetic Modifier Score and HbF levels, yet the model explained only ~ 14% of the variance, highlighting a substantial role for other modifiers such as the novel LRF/ZBTB7A variants identified here.
CONCLUSIONS: These results suggest LRF/ZBTB7A is a novel modifier of HbF. The discovery of the variants, against a backdrop of modest QTL effects, underscores its potential and warrants further functional investigation.

Keywords:  Beta thalassemia; Bioinformatics; Fetal hemoglobin; K562; ZBTB7A/LRF

DOI:  https://doi.org/10.1186/s12920-025-02275-5
Int J Lab Hematol. 2025 Dec 15.

Unstable Hemoglobin, a Rare but Significant Cause of Hemolytic Anemia: Recognition of Peripheral Smear Findings Is Crucial for Diagnosis.

Ryan C Shean, Archana Agarwal, Anton V Rets.



Keywords:  HPLC; Hb Köln; blood smear; hemolytic anemia; unstable hemoglobin

DOI:  https://doi.org/10.1111/ijlh.70043
Front Immunol. 2025 ;16 1755852

Correction: Platelet alloimmunization in transfusion-dependent thalassemia patients from Southern China (2014-2023).

Frontiers Production Office

  [This corrects the article DOI: 10.3389/fimmu.2025.1687913.].

Keywords:  cross-matching; platelet antibody; specificity of antibody; transfusion; transfusion-dependent thalassemia (TDT)

DOI:  https://doi.org/10.3389/fimmu.2025.1755852
Zhonghua Xue Ye Xue Za Zhi. 2025 Nov 14. 46(11): 1014-1019

[Dehydrated hereditary stomatocytosis in 23 cases: a single-center retrospective cohort study from Peking Union Medical College Hospital (2018-2024)].

Q Wang, H Cai, L L Lin, J Li, B Han, M Chen.

  Objective: Dehydrated hereditary stomatocytosis (DHS), a rare condition caused by pathogenic PIEZO1 or KCNN4 mutations, remains under-recognized. This study aimed to improve the diagnosis and management of DHS in China by retrospectively analyzing clinical and genetic characteristics. Methods: Patients diagnosed with DHS at Peking Union Medical College Hospital between 2018 and 2024 were included. All had suspected congenital hemolytic anemia and were confirmed by next-generation sequencing to harbor pathogenic PIEZO1 or KCNN4 mutations. Clinical features, genotypes, iron overload, and treatment outcomes were collected and analyzed. Results: Twenty-three DHS patients were identified, including 21 with PIEZO1 and 2 with KCNN4 mutations. Common manifestations were splenomegaly, jaundice, cholelithiasis, and secondary iron overload. Mild and moderate anemia occurred in 8.7% and 17.4% of patients, respectively, and stomatocytes were present in only 17.4%. The median time from symptom onset to diagnosis was 11 years. The predominant PIEZO1 variants were c.7367G > A and c.6328C > T, with nine novel mutations identified. Both KCNN4 mutations involved c.1055G > A. No clear genotype-phenotype correlation was observed. Secondary hepatic iron overload was found in 21.7% of patients. Conclusion: DHS is often underdiagnosed or misdiagnosed. Genetic testing enables accurate identification, and regular monitoring for secondary hepatic iron overload is crucial for long-term management.

Keywords:  Dehydrated hereditary stomatocytosis; Genotype; Iron overload

DOI:  https://doi.org/10.3760/cma.j.cn121090-20250312-00132
Blood. 2025 Dec 18. pii: blood.2025028895. [Epub ahead of print]

p27Kip1 regulates γ-globin production.

Ginette Balbin-Cuesta, Claire Drysdale, Claire Kerpet, Lei Yu, Greggory Myers, Zesen Lin, Beth McGee, Ann Friedman, Xiaofeng Liu, Sharon A Singh, James Douglas Engel, Laura Buttitta, Rami Khoriaty.

Sickle cell disease (SCD) and β-thalassemia are devastating genetic disorders resulting from defects in the β-globin subunit of adult hemoglobin (HbA). Both disorders are ameliorated by the induction of γ-globin, a component of fetal hemoglobin (HbF). Therefore, the development of safe, effective, and widely available inducers of HbF is needed. Here, we discovered that slow cycling erythroid cells exhibit increased γ-globin expression. To understand the molecular basis of this, we screened all cyclin-dependent kinase inhibitors (CDKIs) for their ability to induce HbF using CRISPR activation (CRISPRa). We found that overexpression of CDKN1B, which encodes p27Kip1 (but not overexpression of other CDKIs), induces γ-globin expression at the transcriptional level. CDKN1B mutants expressing proteins unable to bind/inhibit CDKs and/or cyclins revealed that γ-globin induction by p27Kip1 depends largely on the domains involved in its cell cycle function. Pharmacological inhibition and genetic reduction of CDK4/6 also results in increased HbF. In genetic rescue experiments, we show that p27Kip1 induces HbF by inhibiting CDK4/6, through a mechanism that is likely BCL11A and ZBTB7A independent. Furthermore, palbociclib, an oral CDK4/6 inhibitor, significantly increases HbF in a murine SCD model at doses that are well tolerated. Moreover, we show that HbF induction by hydroxyurea, a drug currently in use to treat SCD, may be mediated in part by CDK4/6 inhibition. Overall, our findings establish a causal relationship between CDK4/6 activity and γ-globin production and suggest that single or dual CDK4/6 inhibitors might be therapeutically beneficial for SCD and β-thalassemia.

DOI: https://doi.org/10.1182/blood.2025028895
Syst Rev. 2025 Dec 16.

Efficacy and safety of deferiprone for thalassemia: a systematic review and meta-analysis of randomized controlled trials.

Gofarana Wilar, Cecep Suhandi, Ichiro Kawahata.

   BACKGROUND: Thalassemia is a genetic hemoglobin disorder commonly associated with iron overload and cardiac complications from repeated transfusions. Deferiprone (DFP), an oral iron chelator, has shown potential in reducing body iron and improving cardiac function. This systematic review and meta-analysis evaluates the efficacy and safety of DFP in thalassemia patients.
METHODS: A systematic search of PubMed, MEDLINE, and Scopus was conducted from inception to June 8, 2025. Eligible randomized controlled trials (RCTs) enrolled thalassemia patients receiving iron chelation therapy and compared DFP (alone or in combination) with deferoxamine, deferasirox, placebo, or no chelation. Non-randomized studies, those without comparators, or lacking sufficient data were excluded. Risk of bias was assessed using the Cochrane RoB 2 tool, and certainty of evidence by GRADE. Pooled standardized mean differences (SMDs) the inclusion criteria; 18 were included in the meta-analysis. DFP significantly improved left ventricular ejection -effects model.
RESULTS: Twenty-three RCTs (n = 1,005) met the inclusion criteria; 18 were included in the meta-analysis. DFP significantly improved left ventricular ejection fraction (SMD: 0.55) and shortening fraction (SMD: 0.37). Non-significant improvements were observed in urinary iron excretion and right ventricular ejection fraction. No significant effects were found for serum ferritin, liver iron concentration, or cardiac T2* MRI. DFP increased the risk of adverse events (RR: 1.37), but not mortality (RR: 0.30). Evidence certainty was moderate for cardiac function and adverse events, and low for other outcomes.
CONCLUSION: DFP improves cardiac function and iron excretion with an acceptable safety profile in thalassemia. Further high-quality RCTs are warranted to confirm its role and optimize regimens.
SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD420251028324.

Keywords:  Cardiac function; Deferiprone; Iron chelation therapy; Iron overload; Meta-analysis; Thalassemia

DOI:  https://doi.org/10.1186/s13643-025-03019-3
Clin Transl Sci. 2025 Dec;18(12): e70441

Pharmacogenomic and Clinical Predictors of Deferasirox Response in Transfusion-Dependent Thalassemia Identified Using Whole-Genome Sequencing.

Kittika Yampayon, Watchara Sakares, Krittin Pitinanon, Chanin Limwongse, Somdet Srichairatanakool, Pimpisid Koonyosying, Chonlaphat Sukasem, Kwankom Triparn, Jittima Piriyapongsa, Supachai Ekwattanakit, Vip Viprakasit, Varalee Yodsurang.

  Deferasirox is a widely used oral iron chelator in patients with transfusion-dependent thalassemia, but considerable variability in treatment response remains a clinical challenge. This study applied whole-genome sequencing to investigate genetic predictors of deferasirox response in 88 Thai patients. This approach enabled comprehensive detection of both known and novel variants across eight key genes involved in deferasirox metabolism and transport. Two novel intronic variants in ABCC2 emerged as strong and clinically relevant predictors of treatment response. The homozygous TG deletion variant rs3047477 in ABCC2 (MAF 31.8%) was significantly associated with greater reductions in liver iron concentrations and increased iron excretion, whereas the rare variant rs188034361 was linked to poorer outcomes. Haplotype analysis identified a 69-kilobase linkage block comprising 12 tightly linked variants, grouped into distinct clusters. Clusters 3.4 and 4.4 were associated with greater reductions in serum ferritin, whereas clusters 2.2, 2.3, and 4.5 predicted suboptimal response. Two variants in UGT1A3 were found to have novel associations with deferasirox response. Specifically, the rs33979061 variant (MAF 6.8%) was associated with poorer treatment outcomes, whereas the rs540607993 variant (MAF 1.1%) predicted enhanced ferritin reduction. Previously reported associations involving UGT1A1 (*28, *6) and UGT1A3 (rs3806596) were also confirmed. Clinical factors, including baseline iron overload, transfusion intensity, body mass index, and age, also contributed to treatment variability. These findings support the implementation of pharmacogenetic profiling to guide personalized chelation strategies in patients with transfusion-dependent thalassemia.

Keywords:  drug transport; efficacy; enzymes; haplotype; hematology; pharmacogenomics; polymorphism; precision medicine

DOI:  https://doi.org/10.1111/cts.70441
Br J Haematol. 2025 Dec 14.

Iron deficiency is associated with reduced levels of inflammation and haemolysis in patients with HbSS and HbSC and reduced clinical admissions in those with HbSC.

Simone Villaboni, Sara Stuart-Smith, Arne De Kreuk, David C Rees, John N Brewin.

  Evidence suggests that iron deficiency may reduce sickle cell disease (SCD) complications by decreasing sickle haemoglobin polymerization through reduced red cell haemoglobin concentration. The aim is to investigate the effects of iron deficiency in SCD patients. We reviewed clinical and laboratory data from 512 patients (408 HbSS, 104 HbSC) at King's College Hospital (2008-2020). Outpatient data were collected from patients with no blood transfusions or hydroxyurea (hydroxycarbamide) use in the prior 90 days. Patients were categorized as hypoferritinaemic (<45 μg/L), normoferritinaemic (45-800 μg/L) or hyperferritinaemic (>800 μg/L) and analysed for laboratory markers and clinical complications. In HbSC patients, hypoferritinaemia was associated with significantly fewer hospital admissions and inpatient days per year compared to normoferritinaemia. Although this was not seen in HbSS patients, hypoferritinaemia correlates with lower haemolysis and inflammation markers, with no differences in total haemoglobin or erythropoietin in both groups. In HbSS patients, haemoglobin F was significantly lower in hypoferritinaemic compared to normoferritinaemic patients. Iron deficiency may reduce inflammation and haemolysis in both HbSS and HbSC, with clinical benefits demonstrable in HbSC. Low ferritin levels were not associated with increased anaemia, suggesting improved red cell survival. Iron-restricted erythropoiesis may benefit SCD patients in certain circumstances.

Keywords:  HbSC; HbSS; iron deficiency; sickle cell disease (SCD)

DOI:  https://doi.org/10.1111/bjh.70262
Haematologica. 2025 Dec 18.

Left ventricular strain and chamber dimensions in pediatric sickle cell disease: agerelated reduction in myocardial deformation independent of hemolysis and hydroxyurea therapy.

Ziad Bulbul, Rana Zareef, Tania Abi Nassif, Theresia Tannouri, Francesca Rodigari, Hani Tamim, Maya El Khoury, Fadi F Bitar, Miguel R Abboud.

Sickle cell disease (SCD) is associated with cardiovascular complications. Speckle-tracking echocardiography enables early detection of myocardial dysfunction before abnormalities appear in conventional echocardiographic parameters. This study evaluated left ventricular (LV) global longitudinal strain (GLS) in pediatric SCD patients, and its relationship with traditional LV function indices, disease complications, hemolysis markers, and diseasemodifying therapy. We retrospectively analyzed 278 echocardiograms from 185 participants (118 SCD patients, mean age 12.2 years; 67 age- and sex-matched controls, mean age 11.8 years) obtained between 2015 and 2023. Among the SCD cohort, 66.1% had the HbSS genotype, 9.3% had HbSβ°-thalassemia, and 17.8% had HbSβ⁺-thalassemia; the majority (83.9%) were on hydroxyurea. Compared to controls, SCD patients had significantly lower, but still normal, GLS (-21.5% vs. -22.3%; p < 0.001), along with significantly larger chamber diameters, elevated mitral valve E velocity, E/A ratio, and tricuspid regurgitation maximal velocity. Prior stroke (β = 0.9) and avascular necrosis (β = 1.51) were independently associated with worse GLS. The different genotypes did not exhibit significant difference in GLS. The strain values did not correlate with hemolysis markers, suggesting that other mechanisms may underlie myocardial impairment. A significant age-related decline in GLS was detected, with an inflection point at approximately 9.9 years. Longitudinal analysis of LV strain in the SCD cohort demonstrated a small decline from -21.6% to -21.2% over a 3.7-year follow-up period. Finally, pediatric SCD patients exhibit significant cardiac remodeling and diastolic dysfunction with preserved, yet lower, LV GLS, underscoring the need for further research in this population.

DOI: https://doi.org/10.3324/haematol.2025.288573