Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method

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Thalassemia was diagnosed using the Hb analysis results. However, the single nucleotide variant (SNVs) database for the Indonesian population, which leads to β-thalassemia disease, has not been extensively studied. This study aimed to profile the genetic variations in Indonesian β-thalassemia patients and conduct in silico characterization of their functional effects. Methods Twenty thalassemia patients were recruited for this study. The sample collected from the respondents was whole blood in EDTA tubes, with a minimum collection time of 14 days after blood transfusion. Genomic DNA (gDNA) was extracted using a commercial kit, directly amplified using Polymerase Chain Reaction (PCR) with specific primers for β-globin and sequenced using Sanger Sequencing. All variants located in exon regions were analyzed using FinchTV, BioEdit, and Biovia Discovery Studio to determine their functional impact. Results Ten reported pathogenic variants were observed along with one rare variant. Genetic variations found according to its common name and nomenclature based on Human Genome Variation Society (HGVS) are IVS1nt.1 (HGVS: c.92+1G>A), IVS1nt.1 (HGVS: c.92+1G>T), IVS1nt.2 (HGVS: c.92+2G>T), IVS1nt.5 (HGVS: c.92+5G>C), IVS2nt.654 (HGVS: c.316-197C>T), Cd15 (HGVS: c.47G>A), Cd26 (HGVS: c.79G>A), Cd30 (HGVS: c.92G>C), Cd41/42 (c.126_129delCTTT), and Cd35 (HGVS: c.110delC). Analysis of amino acid interactions revealed that disease-causing mutations were clinically relevant in each subject. Conclusions This study has bioinformatically proven the effect of genetic mutations and predicted their effect on amino acid interactions. These findings contribute to the study of Indonesian thalassemia and require further research. 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F1000Research 2026, 15 :235 ( https://doi.org/10.12688/f1000research.169153.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Research Article Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] Sri Mufti Ardani 1,2 , Nadhifa Tazkia Ramadhani https://orcid.org/0009-0006-5348-4119 1,3 , Yulia Ariani https://orcid.org/0000-0002-6640-8530 1,4 , Budi Wiweko 1,5 , Pustika Amalia Wahidiyat 1,6 Sri Mufti Ardani 1,2 , Nadhifa Tazkia Ramadhani https://orcid.org/0009-0006-5348-4119 1,3 , [...] Yulia Ariani https://orcid.org/0000-0002-6640-8530 1,4 , Budi Wiweko 1,5 , Pustika Amalia Wahidiyat 1,6 PUBLISHED 11 Feb 2026 Author details Author details 1 Universitas Indonesia, Depok, West Java, Indonesia 2 Doctoral Program in Biomedical Science Faculty of Medicine Universitas Indonesia, Central Jakarta, Indonesia 3 Indonesia Medical Education and Research Institute, Central Jakarta, Indonesia 4 Department of Medical Biology, Universitas Indonesia, Central Jakarta, Indonesia 5 Human Reproductive, Infertility, and Family Planning Research Centre, Indonesia Medical Education and Research Institute, Central Jakarta, Indonesia 6 Department of Pediatrics, Rumah Sakit Dr Cipto Mangunkusumo, Central Jakarta, Jakarta, Indonesia Sri Mufti Ardani Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Nadhifa Tazkia Ramadhani Roles: Conceptualization, Formal Analysis, Methodology, Software, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Yulia Ariani Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing Budi Wiweko Roles: Supervision, Writing – Review & Editing Pustika Amalia Wahidiyat Roles: Conceptualization, Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Genomics and Genetics gateway. Abstract Introduction Indonesia is located along the “Thalassemia Belt,” a hotspot region for hemoglobinopathies, including beta thalassemia, with approximately 3–10% of the Indonesian population diagnosed with this disease. Thalassemia was diagnosed using the Hb analysis results. However, the single nucleotide variant (SNVs) database for the Indonesian population, which leads to β-thalassemia disease, has not been extensively studied. This study aimed to profile the genetic variations in Indonesian β-thalassemia patients and conduct in silico characterization of their functional effects. Methods Twenty thalassemia patients were recruited for this study. The sample collected from the respondents was whole blood in EDTA tubes, with a minimum collection time of 14 days after blood transfusion. Genomic DNA (gDNA) was extracted using a commercial kit, directly amplified using Polymerase Chain Reaction (PCR) with specific primers for β-globin and sequenced using Sanger Sequencing. All variants located in exon regions were analyzed using FinchTV, BioEdit, and Biovia Discovery Studio to determine their functional impact. Results Ten reported pathogenic variants were observed along with one rare variant. Genetic variations found according to its common name and nomenclature based on Human Genome Variation Society (HGVS) are IVS1nt.1 (HGVS: c.92+1G>A), IVS1nt.1 (HGVS: c.92+1G>T), IVS1nt.2 (HGVS: c.92+2G>T), IVS1nt.5 (HGVS: c.92+5G>C), IVS2nt.654 (HGVS: c.316-197C>T), Cd15 (HGVS: c.47G>A), Cd26 (HGVS: c.79G>A), Cd30 (HGVS: c.92G>C), Cd41/42 (c.126_129delCTTT), and Cd35 (HGVS: c.110delC). Analysis of amino acid interactions revealed that disease-causing mutations were clinically relevant in each subject. Conclusions This study has bioinformatically proven the effect of genetic mutations and predicted their effect on amino acid interactions. These findings contribute to the study of Indonesian thalassemia and require further research. READ ALL READ LESS Keywords Thalassemia, genetic variations, in silico, amino acid, molecular technique Corresponding Author(s) Pustika Amalia Wahidiyat ( [email protected] ) Close Corresponding author: Pustika Amalia Wahidiyat Competing interests: No competing interests were disclosed. Grant information: This research was financially supported by Universitas Indonesia through the PUTI Q1 research grant 2022 batch 2 period with contract number as follows (NKB-1120/UN2.RST/HKP.05.00/2022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2026 Ardani SM et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Ardani SM, Ramadhani NT, Ariani Y et al. Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.12688/f1000research.169153.1 ) First published: 11 Feb 2026, 15 :235 ( https://doi.org/10.12688/f1000research.169153.1 ) Latest published: 11 Feb 2026, 15 :235 ( https://doi.org/10.12688/f1000research.169153.1 ) Introduction Thalassemia is one of the most common monogenic hemoglobinopathy disorders worldwide as a result of inbreeding that started in the Mediterranean region. This disease was first recognized in 1925 by an American doctor named dr. Thomas Benton Cooley, whose name is used for this disease, which is Cooley's Anemia. 1 Currently there are more than 350 genetic variations of thalassemia are observed and reported. This disease is inherited in an autosomal recessive manner following Mendelian rules. Clinically, thalassemia is divided into thalassemia major, thalassemia intermedia, and thalassemia minor. 2 Individuals with thalassemia have various clinical symptoms, including pale skin color, fatigue and weakness, dark urine production, irregular heartbeat, irregular menstrual schedule, hepatosplenomegaly, pale conjunctiva, malocclusion of the maxillary bone, and stunted growth. 3 , 4 Thalassemia can be diagnosed early by performing a Complete Blood Count (CBC) or hemoglobin test. The Complete Blood Count test measures the amount of hemoglobin and various types of blood cells, such as red blood cells, from an individual. Individuals with thalassemia have a lower red blood cell (RBC) volume than normal individuals. 5 Determining genetic variations in thalassemia subjects also plays an important role, but has not been extensively studied in Indonesia. Worldwide, it is estimated that approximately 320.000 babies are born with hemoglobinopathies each year, and 80% of these occur in low- or middle-income countries. 4 Indonesia, one of the countries located along the “Thalassemia Belt, is home to more than 260 million people. Approximately 5% of this population is thought to carry the thalassemia gene, also known as the β-globin gene. With a birth rate of approximately 20% annually, according to Wahidiyat, 3 there are approximately 2.500 new thalassaemia major cases per year, making Indonesia a hot spot for thalassemia. This study aimed to provide mutation analysis data for thalassemia subjects in Indonesia. Based on the data obtained from this study, we also provide a bioinformatics analysis of amino acid interactions from the variants found. Materials and methods Sample collection, consent statement, and storage of blood samples Twenty participants were recruited for this study from the Thalassemia Center on Cipto Mangunkusumo Hospital (RSCM), Central Jakarta, DKI Jakarta, Indonesia. All the participants already signed an assent form. The content of informed assent is being explained verbally to the participant. Informed assent was written in paper and signed by the participant under supervision from the parents and the researcher team. This study was approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia (No. KET-600/UN2.F1/ETIK/PPM.00.02/2023). Blood samples were collected in ethylenediaminetetraacetic acid (EDTA) tubes. Blood samples were collected from thalassemia subjects by collecting 3 mL of blood before transfusion. The minimum time interval between the last transfusion and sample collection was 2 weeks. The samples were stored at 4 o C until genomic DNA (gDNA) extraction. Genomic DNA (gDNA) extraction Raw samples (515 μL) were placed in a 1.5 ml microtube. A volume of 930 μL of RBC Lysis Buffer reagent (Geneaid Biotech Ltd., Taiwan) 6 was added to the sample. The samples were then incubated for 19 minutes. The microtubes were then centrifuged (Eppendorf 5424R, Germany) at 3,000 g for 5 min. A white precipitate formed at the bottom of the microtubes. The supernatant was then discarded. A volume of 100 μL of RBC Lysis Buffer (Geneaid Biotech Ltd, Taiwan) and 200 μL of GB Buffer were added (Geneaid Biotech Ltd, Taiwan) and mixed thoroughly by shaking the microtubes. The samples were incubated for 11 min at 65 o C heater block (Stuart SBH130D, England) and then transferred to a new sterile GD Column. Samples were then centrifuged in an Eppendorf 5424R (Germany) for 5 min at 15,000 × g (room temperature), and the supernatant was transferred to a fresh, sterilized microcentrifuge tube. A volume of 400 μL W1 Buffer (Geneaid Biotech Ltd., Taiwan) was added. The samples were then centrifuged in an Eppendorf 5415R centrifuge at 15,000 × g (room temperature) for 1 min at room temperature. A volume of 600 μL of Wash Buffer (Geneaid Biotech Ltd, Taiwan) was added. The samples were then centrifuged (Eppendorf 5415R) at 15,000 × g (room temperature), again for 1 min. After replacing the GD column with a fresh collection tube, 100 μL of Elution Buffer (Geneaid Biotech Ltd, Taiwan) was added carefully, and the sample was incubated for 3 min. After 3 min of incubation, the tubes were centrifuged (Eppendorf 5415R) for 1 min at 15,000 × g (room temperature). Genomic DNA (gDNA) samples were frozen at −20°C for further use. Concentration and purity determination Genomic DNA concentration and purity were quantitatively assessed using a spectrophotometric assay with a Varioskan microplate reader (Thermo Fisher Scientific, United States). 7 Absorbance was measured at wavelengths of 260 and 280 nm (A260 and A280, respectively). The absorbance quotient (OD260/OD280) was used to estimate the DNA purity. An absorbance quotient ratio between 1.8 and 2.0 was considered good for the purified gDNA. A ratio 2.0 indicated RNA contamination. β-globin gene and primer design The gene used in this study was β-globin (NM_000518.5), located on chromosome 11p15.5, which consists of three exons. The FASTA sequence of the gene was obtained from NCBI ( https://www.ncbi.nlm.nih.gov/gene/3043 ), whereas the FASTA coding sequence (CCDS) was obtained from Ensembl! ( https://www.ncbi.nlm.nih.gov/CCDS/CcdsBrowse.cgi?REQUEST=CCDS&DATA=CCDS7753 ). All FASTA sequences were annotated using Benchling ( https://www.benchling.com/ ), primers for polymerase chain reaction (PCR) were designed, and the quality was assessed using NetPrimer ( http://www.premierbiosoft.com/NetPrimer/AnalyzePrimer.jsp ) and NCBI Primer Blast ( https://www.ncbi.nlm.nih.gov/tools/primer-blast/ ). PCR and Sanger sequencing PCR for the β-globin gene was performed using the following primer pair: forward 5’AGGTACGGCTGTCATCACT’3 and reverse 5’ TGGACTTAGGGAACAAAGG’3. A PCR mix of i-MAX II (iNTRON Biotechnology) was used. The PCR program consisted of pre-denaturation at 94°C for 2 min, denaturation at 94°C for 30 s, annealing at 58°C for 30 s, extension at 72°C for 55 s, repeated for 35 cycles, and a final extension at 72°C for 10 min. Agarose gel electrophoresis was performed to verify the quality of PCR products. The PCR products were separated on a 0.8% agarose gel at 100 volts for 45 min (Bio-Rad, United States). The gels were visualized using a gel documentation system (Accuris Instruments). 8 Data analysis Sequencing result obtained was analyzed using FinchTV version 1.4 (downloaded from https://finchtv.software.informer.com/1.4/#google_vignette ) and BioEdit version 7.2 (downloaded from https://bioedit.software.informer.com/7.2/ ) software to align its genes. Wild-type FASTA sequences were obtained from the NCBI database ( https://www.ncbi.nlm.nih.gov/nuccore/NG_059281.1?report=fasta&from=5001&to=6608 ). Computational and predictive data were obtained by assessing the clinical significance of each variant using Varsome consensus scoring ( https://varsome.com/ ). The classification is divided into pathogenic, likely pathogenic, uncertain significance (VUS), likely benign, and benign. The effects of each variant on amino acid interactions, bonding, and side chains were analyzed using Biovia Discovery Studio 24 (downloaded from https://discover.3ds.com/discovery-studio-visualizer-download ). The wild-type amino acid sequences were obtained from the Alphafold Protein Structure Database ( https://alphafold.ebi.ac.uk/search/text/HBB ). The wild-type sequence of the β-globin gene was imported to Biovia Discovery Studio 24 and the mutation point on the amino acid sequence was annotated to analyze the change in its interactions. Results and discussion Genetic variations in Indonesia thalassemia subject This study reported all results from 20 respondents who had been diagnosed with β/β thalassemia and β/HbE thalassemia. Respondents recruited for this study were aged 10 years. The majority of the tribes from all respondents were Javanese, Sundanese, and Betawinese. One respondent was Chinese. According to Table 1 , 10 genetic variations were observed in the Sanger Sequencing analysis. Several variants are classified as intronic variants that disrupt the splice site, whereas the others are missense, nonsense, and frameshift variants. Mutation found in this study is reported using its common name alongside with its nomenclature according to Human Genome Variation Society (HGVS). The most common variants found in this study is the Cd26 (HGVS: c.79G>A; p.(Glu27Lys)) and IVS1nt.5 (HGVS: c.92+5G>C; p.(?)) This is partly in accordance with a study by Wahidiyat et al. (2022). This implies that both Indonesian and Melanesian people are likely to share a common origin. Table 1. Tabular list of β-globin gene variants found in Indonesia thalassemia subject. Variant Annotation Amino acid change Variant type Classification rsID (dbSNP) Common name HGVS IVS1nt.1 c.92+1G>A Unknown Intronic Pathogenic rs33971440 IVS1nt.1 c.92+1G>T Unknown Intronic Pathogenic rs33971440 IVS1nt.2 c.92+2T>G Unknown Intronic Pathogenic rs33956879 IVS1nt.5 c.92+5G>C Unknown Intronic Pathogenic rs33915217 IVS2nt.654 c.316-197C>T Unknown Intronic Pathogenic rs34451549 Cd15 c.47G>A p.(Trp16Ter) Nonsense Pathogenic rs63750783 Cd26 c.79G>A p.(Glu27Lys) Missense Pathogenic rs33950507 Cd30 c.92G>C p.(Arg31Thr) Missense Pathogenic rs33960103 Cd41/42 c.126_129delCTTT p.(Phe42Leufs*17) Frameshift Pathogenic rs80356821 Cd35 c.110delC p.(Pro37Leufs*23) Frameshift Pathogenic rs267607297 All variants observed in this study were classified as pathogenic, as confirmed by Varsomes and ClinVar. Missense variants reported in this study consist of Cd26 (c.79G>A) and Cd30 (c.92G>A), which are known to have an impact on amino acid translation from mRNA, leading to a change from glutamine at position 27 to Lysine and Arginine at position 31 to threonine. The nonsense variant reported in this study is c.47G>A, which leads to a premature stop codon starting at amino acid position 16. Nonsense variants are predicted to cause greater severity in thalassemia subjects than in those with missense variants only. The most common variant, IVS1nt.5 (c.92+5G>C), is an intronic pathogenic variant of β-globin gene. Functional analysis using Human Splicing Finder showed that this variant loses the canonical splicing donor site, which consequently leads to loss of the start codon (ATG) and excision of exon 1 from the open reading frame (ORF). Owing to the altered mRNA splicing pattern, this variant encodes a shortened mRNA and may result in the loss of protein expression. Other intronic variants observed in this study are also predicted to disrupt the splicing site, leading to clinical observations in thalassemia subjects. 9 The genotypes of the thalassemia subjects recruited for this study are summarized in Table 2 . The most frequent genotype observed was HbE/IVS1nt.5 (HGVS: c.79G>A/c.92+5G>C). followed by homozygous variant of IVS1nt.5/IVS1nt.5 (HGVS: c.92+5G>C/c.92+5G>C). Referring to a previous study by Wahidiyat et al. (2022), 10 all variants identified including IVS1nt.5 (HGVS: c.92+5G>C), IVSIInt.654 (HGVS: c.316-197C>T), Cd26 (HGVS: c.79G>A); IVS1nt.1 (c.92+1G>T). According to Sanger sequencing analysis, this study also discovered rare mutations in Indonesian populations, such as Cd35 (HGVS: c.110delC; p.(Pro37Leu)), and reported ClinVar as a pathogenic variant. Table 2. Genotype profile of Indonesia thalassemia subject. Genotype Zygosity n (N=20) Allele 1 Allele 2 c.79G>A c.92+5G>A Compound heterozygote 4 c.92+5G>A c.92+5G>A Homozygote 3 c.92+1G>T c.92+5G>C Compound heterozygote 3 c.79G>A c.110delC Compound heterozygote 2 c.92+1G>T c.79G>A Compound heterozygote 1 c.92+1G>A c.92+5G>C Compound heterozygote 1 c.92+2G>T c.92+5G>C Compound heterozygote 1 c.316-197C>T c.79G>A Compound heterozygote 1 c.79G>A c.126_129delCTTT Compound heterozygote 1 c.79G>A c.47G>A Compound heterozygote 1 c.92+5G>A c.110delC Compound heterozygote 1 c.79G>A c.92G>C Compound heterozygote 1 The initial study on 23 thalassemia subjects in Northern Vietnam using sequence analysis also mainly detected c.79G>A, c.124-127delTTCT, and c.52A>T, in addition to an indigenous mutation in Vietnam, c.287_288insA. 11 Recently, a small report from 22 β-thalassemia subjects in Central Vietnam showed that the three mutations c.79G>A, c.52A >T, and c.124_127delTTCT accounted for 29.2%, 25.0%, and 18.8% of the mutant alleles, respectively. 12 However, it should be noted that in Myanmar, 13 Thailand, 14 and China, 15 the most common mutation was c.124-127delTTCT, not c.79G>A, similar to the Indonesian population. The genotype of Indonesian thalassemia subjects mostly consisted of compound heterozygous variants, including missense/missense, intronic/missense, missense/nonsense, intronic/frameshift, and missense/frameshift. Only a small number of subjects are known to have homozygous variants. However, all subjects received a 2 weeks blood transfusion with an Hb level < 9 g/dL. In this study, we concluded that every variant causes a severe type of thalassemia. Rare frameshift variant in Indonesia population The term of “rare” in a genetic variant is defined as a variant that is not commonly discovered in a specific population. According to the results of Sanger Sequencing, there are nucleotide changes that lead to frameshifts in nucleotide reads, as shown in Figure 1 . This novel variant showed changes in the coding sequence (CDS) position of 110. Changes in nucleotides are deletions of cytosine and frameshift of thymine, located immediately after the nucleotide at position 110 (HGVS: c.110delC; p.(Pro37Leufs*23)). This also caused frameshift nucleotide reads in the rest of the sequencing results. These changes manifested in amino acid changes from proline at position 37 to leucine, and a premature stop codon occurred after 23 amino acid translations. The classification of all variants reported, including this frameshift variant, was based on the American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology. 16 Figure 1. Nucleotide changes in β-globin gene rare variant c.110delC in Indonesia populations. According to Rujito et al. (2015), 17 only two of 209 subjects were observed to have this mutation. This frameshift variant was also found in Malay populations. The genotype observed by Rujito et al. (2015) 17 was compound heterozygous with IVS1nt.5 (HGVS: c.92+5G>C). 17 However, this study found that this variant was observed in Cd26 (HGVS: c.79G>A). The frameshift variant found in this study may lead to loss of function (LoF). According to the gnomAD database, this variant is absent in normal populations. Functional in silico characterization The protein structure of β-globin gene is shown in Figure 2 . Full-length amino acid translation consisted of 174 amino acids. The β-globin gene consists of a nucleotide encoding a protein called beta-globin. β-globin is a component (subunit) of a larger protein called hemoglobin, which is located inside red blood cells. In adults, hemoglobin consists of four protein subunits: two subunits of beta-globin and two subunits of a protein called alpha-globin, which is produced from another gene called HBA (both HBA1 and HBA2 ). Each of these protein subunits is attached (bound) to an iron-containing molecule called heme, and the iron in the center of each heme can bind to one oxygen molecule. Hb within red blood cells binds to oxygen molecules in the lungs. These cells then travel through the bloodstream and deliver oxygen to the tissues throughout the body. A full-length protein will also have normal function, whereas a mutation in the gene will lead to disease. Figure 2. Protein structure of β-globin gene. Source: Uniprot. All exonic variants found in this study lead to amino acid changes that affect their interactions. According to Figure 3 , a variant occurs in c.79, with nucleotide changes from guanine (G) to adenine (A), leading to an amino acid change at position 27. The amino acid change from glutamine (Glu) to lysine (Lys) is predicted to disrupt hemoglobin function. According to the analysis depicted in Figure 3A , in normal protein translation, glutamine at position 27 has a conventional hydrogen bond with Glycine30 (3.36 Å), Arginine31 (2.85 Å), and Glutamine23 (2.95 Å), as shown by the green dotted line. The carbon-hydrogen bond is also present between Glutamine27 and Histidine117 (3.55 Å), as indicated by the grey dotted line. An important interaction is the salt-bridge interaction between Glutamine27 and Arginine31 (2.71 Å), shown with a brown dotted line. Salt-bridge interactions are known to maintain this protein in equilibrium. While the variant Cd26 (HGVS: c.79G>A) led to a change from Glutamine27 to Lysine27, this structure is depicted in Figure 3B . Conventional hydrogen bonds remain; however, there are no salt-bridge interactions. The salt-bridge interaction changes to an alkyl interaction between Lysine27 and Arginine31 (5.31 Å) and Lysine27 and Valine114 (4.15 Å), as indicated by the pink dotted line. Loss of salt-bridge interactions causes an imbalance in protein structure. Figure 3. Amino acid changes at c.79G>A; p.(Glu27Lys) leads to loss of salt bridge interaction. Variants occur at c.47, which is commonly known as the Cd15 mutation, and nucleotide changes from guanine (G) to adenine (A) lead to amino acid changes at position 16. This variant resulted in amino acid changes from Tryptophan to “terminated” amino acid, known as premature stop codon. This leads to incomplete protein translation because the final product has only 16 amino acids, whereas the normal protein translation from the β-globin gene has 147 amino acids. This amino acid change is depicted in Figure 4A , while the normal protein structure was depicted beforehand ( Figure.2 ). Another variant observed in this study was a nonsense variant, Cd30 (HGVS: c.92G>A); the nucleotide changes from Guanine to Adenine lead to amino acid changes at position 31. According to the analysis depicted in Figure 4B , on normal protein translation, arginine at position 31 has a conventional hydrogen bond with Valine34 (3.37 Å), Valine35 (2.84 Å), and Glutamine27 (2.85 Å and 2.77 Å) also Arginine31, and Histidine117 (4.10 Å), shown with a green dotted line. The salt-bridge interaction between Arginine31 and Glutamine27 (2.71 Å) is indicated by a brown dotted line. An alkyl interaction was also observed between Arginine31 and Valine110 (4.98 Å). The variant Cd30 (HGVS: c.92G>A) leads to a change from Arginine31 to Threonine31, this structure is depicted in Figure 4C . The conventional hydrogen bond still remains; however, both salt-bridge and alkyl interactions are not observed due to amino acid changes. Loss of both salt bridges and alkyl interactions disrupts the overall protein structure and function. Figure 4. (A) Amino acid changes at c.47G>A; p.(Trp16Ter); (B) and (C) Amino acid changes at c.92G>A; p.(Arg31Thr). One frameshift variant (common name Cd41/42 (HGVS: c.126_129delCTTT)) leads to amino acid changes from proline at position 42 to leucine, and a premature termination codon occurs after translation of 17 amino acids, as depicted in Figure 5A . This frameshift variant produced a shorter protein product, which is in accordance with the severity of the subject. A rare variant observed in this study was c.110delC, which led to an amino acid change from proline at position 37 to leucine, followed by a premature stop codon after 23 amino acid translations. According to the analysis depicted in Figure 5B , genetic variations shortened the end-protein product. This strengthens the prediction that frameshift variants greatly influence overall protein structure, interactions, and bonds. In addition, the subject's clinical condition matched all variants found in this study. Figure 5. (A) Amino acid changes at c.126_129delCTTT; p. (Pro42Leufs*17); (B) Amino acid changes at c.110delC; p. (Pro37Leufs*23). Conclusions Thalassemia is the most common inherited hemoglobinopathy in Indonesia. Ten pathogenic variants were identified in this study. The variants observed consisted of intronic variants, missense variants, nonsense variants, and frameshift variants. The most common variant found was IVS1nt.5 (HGVS: c.92+5G>C; p.(?)) and Cd26 (HGVS: c.79G>A; p.(Glu27Lys)) variants. Functional in silico analysis was performed for each exonic variant, and the amino acid changes in the interactions and translations were explained. Ethical considerations This study was approved by the Ethics Committee of the Faculty of Medicine, Universitas Indonesia (No. KET-600/UN2.F1/ETIK/PPM.00.02/2023). All subjects recruited for this study signed an assent form. Consent to participate All participant recruited for this study is already signed a written consent form. The consent form has been explained verbally to all the participant before the signage. All participant already understands the research and all the content included within the written consent form. Data availability The dataset is available on Figshare: Dataset for Thalassemia Beta. 10.6084/m9.figshare.30506150. This project contains the following underlying data: Raw Data for F1000.xlsx – This file contains research data including: subject data, DNA concentration data, DNA purity data, and genotyping results. The data are available under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) license . Ardani, et al. Dataset for Thalassemia Beta [dataset]. Figshare; 2025. Available from: 10.6084/m9.figshare.30506150. 18 Acknowledgements SMA, NTW, PAW, YA, and BW designed this study. SMA and NTR conducted the experiments under the supervision of PAW, YA, and BW. SMA and NTR prepared the first draft of this manuscript. All authors have finalized the manuscript. All authors have read and approved the final manuscript. References 1. Marengo-Rowe AJ: The thalassemias and related disorders. Proc (Bayl Univ Med Cent). 2007; 20 (1): 27–31. PubMed Abstract 2. Husna N, Sanka I, Al-Arif A, et al. : Prevalence and distribution of thalassemia trait screening. J. Med. Sci. 2017; 49 (3): 106–113. 3. Wahidiyat PA, Sari TT, Rahmartani LD, et al. : An insight into Indonesian current thalassemia care and challenges. ISBT Sci. Ser. 2020; 15 : 334–341. Publisher Full Text 4. Argawal S, Gupta A, Gupta UR, et al. : Prenatal diagnosis in beta-thalassemia: An indian experience. Fetal Diagn. Ther. 2003; 18 : 328–332. 5. Chakrabarti I, Sinha SK, Ghosh N, et al. : Beta-thalassemia carrier detection by NESTROFT: an answer in rural scenario. Iran. J. Pathol. 2012; 7 (1): 19–26. 6. Geneaid: Geneaid DNA extraction kit for blood and tissue. Geneaid; [cited 2023 Sep 29]. Reference Source 7. Thermo Fisher Scientific: Microplate readers. DNA Genotek.[cited 2023 Sep 28]. Reference Source 8. Wittmeier P, Hummel S: Agarose gel electrophoresis to assess PCR product yield: comparison with spectrophotometry, fluorometry and qPCR. Biotechniques. 2022; 72 (4): 155–158. PubMed Abstract | Publisher Full Text 9. Ellingford JM, Ahn JW, Bagnall RD, et al. : Recommendations for clinical interpretation of variants found in non-coding regions of the genome. Genome Med. 2022; 14 (73): 1–22. Publisher Full Text 10. Wahidiyat PA, Sari TT, Rahmartani LD, et al. : Thalassemia in Indonesia. Hemoglobin. 2022; 46 (1): 39–44. Publisher Full Text 11. Filon D, Oppenheim A, Rachmilewitz EA, et al. : Molecular analysis of β-thalassemia in Vietnam. Hemoglobin. 2000; 24 : 99–104. PubMed Abstract | Publisher Full Text 12. Doro MG, Casu G, Frogheri L, et al. : Molecular characterization of β-thalassemia mutations in Central Vietnam. Hemoglobin. 2017; 41 : 96–99. PubMed Abstract | Publisher Full Text 13. Win N, Harano T, Harano K, et al. : A wider molecular spectrum of beta-thalassaemia in Myanmar. Br. J. Haematol. 2002; 117 : 988–992. PubMed Abstract | Publisher Full Text 14. Panichchob P, Iamdeelert P, Wongsariya P, et al. : Molecular spectrum of β-Thalassemia mutations in Central to Eastern Thailand. Hemoglobin. 2021; 45 : 97–102. PubMed Abstract | Publisher Full Text 15. Zhao J, Li J, Lai Q, et al. : Combined use of gap-PCR and next-generation sequencing improves Thalassaemia carrier screening among premarital adults in China. J. Clin. Pathol. 2020; 73 : 488–492. PubMed Abstract | Publisher Full Text | Free Full Text 16. Richards S, Aziz N, Bale S, et al. : Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.2015. 17. Rujito L, Basalamah M, Mulatsih S, et al. : Molecular Scanning of β-Thalassemia in the Southern Region of Central Java, Indonesia; a Step Towards a Local Prevention Program. Hemoglobin. 2015; 39 (5): 330–333. PubMed Abstract | Publisher Full Text 18. Ardani SM, Ramadhani NT, Ariani Y, et al. : Dataset for Thalassemia Beta. [dataset]. Figshare. 2025. Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 11 Feb 2026 ADD YOUR COMMENT Comment Author details Author details 1 Universitas Indonesia, Depok, West Java, Indonesia 2 Doctoral Program in Biomedical Science Faculty of Medicine Universitas Indonesia, Central Jakarta, Indonesia 3 Indonesia Medical Education and Research Institute, Central Jakarta, Indonesia 4 Department of Medical Biology, Universitas Indonesia, Central Jakarta, Indonesia 5 Human Reproductive, Infertility, and Family Planning Research Centre, Indonesia Medical Education and Research Institute, Central Jakarta, Indonesia 6 Department of Pediatrics, Rumah Sakit Dr Cipto Mangunkusumo, Central Jakarta, Jakarta, Indonesia Sri Mufti Ardani Roles: Conceptualization, Formal Analysis, Investigation, Methodology, Writing – Original Draft Preparation, Writing – Review & Editing Nadhifa Tazkia Ramadhani Roles: Conceptualization, Formal Analysis, Methodology, Software, Validation, Writing – Original Draft Preparation, Writing – Review & Editing Yulia Ariani Roles: Conceptualization, Methodology, Supervision, Validation, Writing – Review & Editing Budi Wiweko Roles: Supervision, Writing – Review & Editing Pustika Amalia Wahidiyat Roles: Conceptualization, Funding Acquisition, Investigation, Project Administration, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This research was financially supported by Universitas Indonesia through the PUTI Q1 research grant 2022 batch 2 period with contract number as follows (NKB-1120/UN2.RST/HKP.05.00/2022). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 11 Feb 2026, 15:235 https://doi.org/10.12688/f1000research.169153.1 Copyright © 2026 Ardani SM et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Ardani SM, Ramadhani NT, Ariani Y et al. Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.12688/f1000research.169153.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 11 Feb 2026 Views 0 Cite How to cite this report: KHAILANY RA. Reviewer Report For: Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.5256/f1000research.186440.r460594 ) The direct URL for this report is: https://f1000research.com/articles/15-235/v1#referee-response-460594 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 26 Mar 2026 Rozhgar A. KHAILANY , University of Salahaddin, Erbil, Kurdistan Region of Iraq, Iraq Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.186440.r460594 This study provides valuable insights into the genetic variants of β-thalassemia in the Indonesian population. While the scientific content is strong, the manuscript would benefit from clearer sentence structure, consistent terminology, uniform HGVS formatting, and a more concise presentation of ... Continue reading READ ALL This study provides valuable insights into the genetic variants of β-thalassemia in the Indonesian population. While the scientific content is strong, the manuscript would benefit from clearer sentence structure, consistent terminology, uniform HGVS formatting, and a more concise presentation of results to improve readability and overall clarity. The methodology lacks critical details, including the exact DNA extraction kit and protocol steps, complete PCR conditions and controls, and full Sanger sequencing parameters, all of which should be clarified to ensure reproducibility and methodological rigor. Regarding Table 1, I suggest several improvements to enhance clarity and scientific accuracy: add ClinVar IDs, as many variants at the same position share identical rs IDs; indicate that the amino acid changes of intronic variants are “absent” rather than “unknown”; rename the column “Variant Type” to “Molecular Consequence” for a more scientific description; and update the classification of the c.110delC variant to “P/LP” (pathogenic/likely pathogenic). The notation “(HGVS: c.92+5G>C; p.(?))” should be corrected by removing the question mark, as it is unnecessary and may cause confusion, and the protein-level change should be indicated only if known or omitted if not applicable. The term “varsomes” should be corrected to “VarSome,” which is the proper name of the genomic variant interpretation platform. Regarding the proteomic section, we are not familiar with proteomics and therefore cannot provide comments. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests: No competing interests were disclosed. Reviewer Expertise: Medical Genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT KHAILANY RA. Reviewer Report For: Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.5256/f1000research.186440.r460594 ) The direct URL for this report is: https://f1000research.com/articles/15-235/v1#referee-response-460594 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Faisal A. Reviewer Report For: Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.5256/f1000research.186440.r463304 ) The direct URL for this report is: https://f1000research.com/articles/15-235/v1#referee-response-463304 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 05 Mar 2026 Anwer Faisal , Mustansiriyah University, Baghdad, Iraq Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.186440.r463304 The authors present valuable data on the genetic variations of $\beta$-thalassemia in the Indonesian population. The in silico approach provides a good perspective on the structural impact of these mutations. I have a few questions and constructive suggestions to help ... Continue reading READ ALL The authors present valuable data on the genetic variations of $\beta$-thalassemia in the Indonesian population. The in silico approach provides a good perspective on the structural impact of these mutations. I have a few questions and constructive suggestions to help clarify the methodology and strengthen the manuscript before indexing. With a cohort of 20 patients, I am curious if the authors consider this a preliminary or pilot study for this specific region? It would be helpful to add a brief sentence or two in the Methods or Discussion section justifying the sample size. The methodology states that blood was collected at least 14 days post-transfusion. Since genomic DNA is extracted from nucleated cells (leukocytes), and transfused blood is primarily composed of anucleated packed red blood cells, could you clarify if and how the transfusion timing actually impacts the gDNA extraction process? Adding a quick explanation would clarify this for the readers. The manuscript concludes that "every variant causes a severe type of thalassemia." Because the provided clinical data is largely limited to the patients receiving blood transfusions and having hemoglobin levels below 9 g/dL, I recommend either softening this conclusion slightly or, ideally, providing a supplementary table detailing the specific clinical phenotypes of the 20 subjects to fully support this claim. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: microbiology and medical genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Faisal A. Reviewer Report For: Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.5256/f1000research.186440.r463304 ) The direct URL for this report is: https://f1000research.com/articles/15-235/v1#referee-response-463304 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 11 Feb 2026 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 Version 1 11 Feb 26 read read Anwer Faisal , Mustansiriyah University, Baghdad, Iraq Rozhgar A. KHAILANY , University of Salahaddin, Erbil, Iraq Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 KHAILANY R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 26 Mar 2026 | for Version 1 Rozhgar A. KHAILANY , University of Salahaddin, Erbil, Kurdistan Region of Iraq, Iraq 0 Views copyright © 2026 KHAILANY R. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This study provides valuable insights into the genetic variants of β-thalassemia in the Indonesian population. While the scientific content is strong, the manuscript would benefit from clearer sentence structure, consistent terminology, uniform HGVS formatting, and a more concise presentation of results to improve readability and overall clarity. The methodology lacks critical details, including the exact DNA extraction kit and protocol steps, complete PCR conditions and controls, and full Sanger sequencing parameters, all of which should be clarified to ensure reproducibility and methodological rigor. Regarding Table 1, I suggest several improvements to enhance clarity and scientific accuracy: add ClinVar IDs, as many variants at the same position share identical rs IDs; indicate that the amino acid changes of intronic variants are “absent” rather than “unknown”; rename the column “Variant Type” to “Molecular Consequence” for a more scientific description; and update the classification of the c.110delC variant to “P/LP” (pathogenic/likely pathogenic). The notation “(HGVS: c.92+5G>C; p.(?))” should be corrected by removing the question mark, as it is unnecessary and may cause confusion, and the protein-level change should be indicated only if known or omitted if not applicable. The term “varsomes” should be corrected to “VarSome,” which is the proper name of the genomic variant interpretation platform. Regarding the proteomic section, we are not familiar with proteomics and therefore cannot provide comments. Is the work clearly and accurately presented and does it cite the current literature? Partly Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Partly If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Yes Competing Interests No competing interests were disclosed. Reviewer Expertise Medical Genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) KHAILANY RA. Peer Review Report For: Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.5256/f1000research.186440.r460594) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/15-235/v1#referee-response-460594 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2026 Faisal A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 05 Mar 2026 | for Version 1 Anwer Faisal , Mustansiriyah University, Baghdad, Iraq 0 Views copyright © 2026 Faisal A. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions The authors present valuable data on the genetic variations of $\beta$-thalassemia in the Indonesian population. The in silico approach provides a good perspective on the structural impact of these mutations. I have a few questions and constructive suggestions to help clarify the methodology and strengthen the manuscript before indexing. With a cohort of 20 patients, I am curious if the authors consider this a preliminary or pilot study for this specific region? It would be helpful to add a brief sentence or two in the Methods or Discussion section justifying the sample size. The methodology states that blood was collected at least 14 days post-transfusion. Since genomic DNA is extracted from nucleated cells (leukocytes), and transfused blood is primarily composed of anucleated packed red blood cells, could you clarify if and how the transfusion timing actually impacts the gDNA extraction process? Adding a quick explanation would clarify this for the readers. The manuscript concludes that "every variant causes a severe type of thalassemia." Because the provided clinical data is largely limited to the patients receiving blood transfusions and having hemoglobin levels below 9 g/dL, I recommend either softening this conclusion slightly or, ideally, providing a supplementary table detailing the specific clinical phenotypes of the 20 subjects to fully support this claim. Is the work clearly and accurately presented and does it cite the current literature? Yes Is the study design appropriate and is the work technically sound? Yes Are sufficient details of methods and analysis provided to allow replication by others? Yes If applicable, is the statistical analysis and its interpretation appropriate? I cannot comment. A qualified statistician is required. Are all the source data underlying the results available to ensure full reproducibility? Yes Are the conclusions drawn adequately supported by the results? Partly Competing Interests No competing interests were disclosed. Reviewer Expertise microbiology and medical genetics I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Faisal A. Peer Review Report For: Mutational and Functional Impact of β-globin Gene Mutation in Indonesian Thalassemia Patients using in Silico Method [version 1; peer review: 2 approved with reservations] . F1000Research 2026, 15 :235 ( https://doi.org/10.5256/f1000research.186440.r463304) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. 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