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26 February 2026

Hb Thessaloniki, a Novel, Hyperunstable, Alpha Globin Variant Detected in Northern Greece

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1
Molecular Genetics Lab., Thalassaemia Unit, Center of Expertise in Rare Haematological Diseases (Haemoglobinopathies), Laikon General Hospital, 115 26 Athens, Greece
2
Section of Cell Biology and Biophysics, Department of Biology, School of Sciences, National and Kapodistrian University of Athens, Panepistimiopolis, 157 71 Athens, Greece
3
Haemoglobinopathy Prevention Unit, Blood Bank Center, Hippokration Hospital of Thessaloniki, 546 42 Thessaloniki, Greece
4
Thalassaemia Unit, Hippokration Hospital, Aristotle University of Thessaloniki, 541 24 Thessaloniki, Greece
Hematol. Rep.2026, 18(2), 17;https://doi.org/10.3390/hematolrep18020017
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Abstract

Background: Haemoglobinopathies are the most common monogenic disorders both in Greece and worldwide. The most effective strategies against them are carrier detection and prenatal testing following genetic risk assessment consultation for couples on the likelihood of their offspring being affected. Case Presentation: A novel alpha globin chain variant, named Hb Thessaloniki, was detected in Northern Greece. The underlying point variation HBA1:c.260T>C (ref. seq. NM_000558.5) was detected in the HBA1 gene, in heterozygosity, during a routinely performed population screening for haemoglobinopathies. The amino-acid residue Leu86 was replaced by a structure disrupting Pro residue, resulting in a hyperunstable product as shown by the isopropanol test and predicted by the Dynamut2 and Alphafold3 algorithms. The haematological phenotype, due to which genetic analysis was performed, presented with mild microcytosis and hypochromia and was also indicative of the presence of an unstable haemoglobin produced in small quantities (variant encoded by HBA1). Since the proband’s partner presented with a normal haematological phenotype, there is no risk of the couple giving birth to an affected offspring. Expanded analysis of the proband’s relatives identified biallelic variants (αParmaα/ααΤhessaloniki) in the proband’s mother, who presented with no apparent clinical findings, expect for slightly reduced haematological indices. Conclusions: The novel Hb Thessaloniki identified, although theoretically hyperunstable, seems to have minor effects on erythrocyte function, as indicated by haematological findings on the proband and his close relatives. Future identification of co-inheritance with HBA pathogenic point variations or deletions may provide further information regarding genetic counselling. In parallel, the usage of structure–function relation-calculating algorithms may enhance our prediction capability for novel variants.

1. Introduction

Haemoglobin, the oxygen-carrying tetrameric protein complex, consists of two alpha and two beta globin molecules. Both point variations and large deletions in the corresponding HBA and HBB genes have been frequently detected worldwide, with more than 3500 entries reported in the ITHANET database [1]. Deficiency in the production of α or β globins or structural variations result in thalassaemias/haemoglobinopathies, the most frequent monogenic diseases worldwide, inherited by rule in an autosomally recessive manner [2].
The most frequent genetic defects for alpha thalassaemia are the deletions of one or both HBA genes, but numerous point variations have also been reported [2]. The haematological phenotypes of heterozygotes vary, presenting a variable degree of anaemia, reduced mean corpuscular haemoglobin (MCH/pg), reduced mean corpuscular volume (MCV/fL) and a normal or slightly reduced level of HbA2. In many cases where structural variants occur, Hb variants are detected as distinct elution fractions during haemoglobin analysis by HPLC due to different retention times [3,4].
HBA1 gene expression accounts for about one third of the alpha globin produced in the erythrocyte [3]. Therefore, Hb variants formed due to HBA1 gene point variations are expected to comprise a small percentage of the total haemoglobin formed. In case unstable products are produced, the effect on erythrocyte function might be inconsequential (low penetrance). Nevertheless, co-inheritance of HBA variants, through either homozygosity or compound heterozygosity, can result in so-called non-deletional alpha thalassaemia, with clinical phenotypes varying from almost asymptomatic to severe haemolytic anaemia [1,4].
In Greece, two additional very rare neighbouring variants of HBA1 have also been detected, resulting in unstable products, namely Hb Heraklion and Hb Aghia Sophia. Regarding Hb Heraklion, a double heterozygote with αo thalassaemia was identified with a severe clinical phenotype, as reported by Traegger Synodinos et al. [5].
In order to confirm the diagnosis and offer personalised genetic counselling, genetic analysis is required, especially in couples where both partners have abnormal or atypical erythrocyte indices. Gene scanning may reveal novel point variations. In this study, we identify a new HBA1 variant in a Greek male in the context of population screening.

2. Materials and Methods

2.1. National Prevention Program for Haemoglobinopathies in Greece

In Greece, around 8% of the population are estimated to be β- thalassaemia carriers and 7% α-thalassaemia carriers. A crucial step towards strategic prevention of thalassaemias is carrier identification through population screening. The Thalassaemia Prevention Scheme in Greece has been implemented for over 40 years and consists of a network of a scientifically coordinating Central Reference/Expertise Center, where the Molecular Genetics Laboratory is based, and 14 district Population Screening Units located in high-carrier-frequency areas [6,7,8,9]. Carrier identification is carried out in all of the Thalassaemia Prevention Units following a standard scheme. Initially, a haematological test together with Hb biochemical analysis by HPLC are performed, in parallel with measurement of serum ferritin levels. Couples defined as at risk for giving birth to offspring with thalassaemia major or sickle cell disease receive genetic precounselling. Subsequent genetic analysis is performed, followed by a more detailed genetic counselling. PND is offered in couples who request it.

2.2. Haematological and Biochemical Analysis

The haematological analyzer Coulter DxH 560 (Beckman Coulter, Fullerton, CA, USA) was used to determine red cell indices (RBC, Hb, PCV, MCV, MCH, RDW).
The VARIANT™ II haemoglobin Testing System (Bio-Rad Laboratories, Hercules, CA, USA), the β-Thalassemia Short program, an automated cation exchange high-performance liquid chromatography (HPLC) instrument, was used for the quantification of haemoglobin. Hb H inclusion bodies were identified by incubating the peripheral blood for 30 min. at 37 °C with brilliant cresyl blue. Serum ferritin levels were measured by a microenzyme-linked immuno-sorbent assay (ELISA) technique (Abbott Laboratories, Longford, County Westmeath, Ireland) to exclude iron deficiency, and the NESTROFT (Naked Eye Single Tube Red Cell Osmotic Fragility Test) was also performed.
The isopropanol precipitation test, a simple test for the detection of unstable haemoglobins was used [10]. According to the method of Carrel et al., the pathological sample forms a precipitate within 5 min and confirms the existence of an unstable haemoglobin, whereas the normal Hb control remains clear.

2.3. Genomic DNA Extraction, Quantity and Quality Definition

Genomic DNA extraction was performed from 150 μL of whole peripheral blood, by using the automated Maxwell 16TM System (Promega Corporation, Fitchburg, WI, USA), according to the manufacturer’s instructions. Quantity and quality of the extracted DNA are assessed by measuring OD260 and 260/280 ratio (IMPLEN nanophotometer, Munich, Germany), respectively.

2.4. Gene Scanning by HRM Analysis

For HBA gene scanning, an in-house methodology approach has been designed, combining gap-PCR, ARMS PCR, High-Resolution Melting (HRM) analysis, hybridization probes and Sanger sequencing when required [11]. Regarding the scanning of part of the HBA genes for point variations by HRM, the following set of primers was designed by using Primer3 software: 5′CACCCCTCACTCTGCTTCTC-3′ and 5′AACCCGCGTGATCCTCTG-3′. A PCR was performed by using the LightCycler® High-Resolution Melting Master kit (Roche) with about 50 ng genomic DNA/sample and 10 μM from each primer, according to the manufacturer’s instructions. The subsequent HRM analysis was performed in LightCycler 480 (Roche). The PCR protocol precenting HRM analysis is as follows: 95 °C for 10 s, 45-cycle loop with 95 °C for 15 s—58 °C for 15 s —72 °C for 15 s. The HRM analysis protocol is as follows: 95 °C for 1 s ramp rate 4.4 °C/s, 40 °C for 1 s ramp rate 2.2 °C/s, 70 °C for 1 s ramp rate 4.4 °C/s, 95 continuous with 0.02 °C/s ramp rate and 25 acquisitions of fluorescent signal per °C. A cooling step followed (40 °C for 30 s ramp rate 2.2 °C/s). The results were analysed by the Gene Scanning analysis software provided by Roche as part of the Light Cycler® 480 Software release 1.5.1.62 SP3 (Roche Diagnostics) Difference Plot step of Light Cycler® 480 Gene Scanning Software analyzes the High Resolution Melting curve data to identify changes in the shape of the curve, which indicate the presence of sequence variations in the PCR product.

2.5. Sanger Sequencing

Sanger sequencing was performed in PCR products, oriented by the primers 5′-TGGAGGGTGGAGACGTCCTG-3′ and 5′-CAGGAAACAGCTATGACCTGTCCACGCCCATGCCTGGCAC-3′, selectively amplifying the HBA1 exon II region by using Invitrogen Taq polymerase according to the manufacturer’s instructions. The PCR product’s purity was checked by agarose gel electrophoresis prior to sequencing reactions.
About 20 ng of total PCR products was subsequently purified with an ExoSAP-IT Express kit (Thermo Fisher Scientific, Waltham, MA, USA) before subjected to sequencing reactions by using the Thermo BigDye Terminator v3.1 kit and the above primers, according to the manufacturer’s instructions.

2.6. Structure Prediction Analysis

Various bioinformatics tools were employed to investigate how the non-synonymous Leu86Pro alpha chain variant affects the structure and stability of human haemoglobin [12,13,14,15,16]. Based on the experimentally determined high-resolution crystal structure of human haemoglobin in the oxy form [12] (PDB ID: 2DN1, deposited in Protein Data Bank) as a reference [13], the DynaMut2 web server (https://biosig.lab.uq.edu.au/dynamut2/, accessed on 1 September 2025) was utilised to predict its impact [14]. Dynamut2 integrates Normal Mode Analysis (NMA) techniques to capture protein dynamics with graph-based signatures that characterise the wild-type environment. Point variations are categorised as either stabilising or destabilising based on the calculated ΔΔGStability value, which represents the difference in predicted folding free energy between the wild-type and mutant proteins. ΔΔGStability values (in kcal/mole) below 0.0 indicate that this variation destabilises the protein structure. The structural model of human haemoglobin containing the Leu86Pro alpha chain variation was built using the AlphaFold3 server (https://alphafoldserver.com/welcome, accessed on 1 September 2025) [15]. Structural alignment of the experimentally determined wild-type human haemoglobin with the resulting model from the AlphaFold3 server containing the Leu86Pro mutation was performed with the “align” tool of the PyMol Molecular Visualization System v.2.5 (https://www.pymol.org/, accessed on 1 September 2025) [16]. In order to verify how this variation affects AHSP binding, we also utilised the AlphaFold3 server to predict the structure of the modified alpha chain of haemoglobin complex with chaperone AHSP. Pictures were also collected with the PyMol Molecular Visualization System.

3. Results

A 29-year-old lady (partner), at the 13th week of gestation, was referred, together with her 30-year-old husband (proband), for screening for haemoglobinopathies, as their ethnic and regional background were at high risk for thalassaemia.
The proband’s blood film was abnormal, with anisocytosis and microcytosis, and following incubation, typical inclusion bodies were revealed. Moreover, his blood film osmotic fragility was normal, and the isopropanol test was positive, suggesting the presence of an unstable haemoglobin variant, although no unknown fraction was detected in the HPLC analysis (Figure 1). The haematological data of the couple are depicted in Table 1.
Figure 1. HPLC results of the proband.
Table 1. The haematological data of the couple.
Gene scanning by HRMA revealed an unknown pattern in the amplicon spanning the second exon of the HBA genes (Figure 2A,B). Sanger sequencing of the HBA1 and HBA2 genes revealed the point variant HBA1: c.260T>C (ref. seq. NM_000558.5) in heterozygosity (Figure 2C). Surprisingly, this variant had not been reported in ITHANET, HbVar, ClinVar and other databases which were examined.
Figure 2. (A) Scheme of alpha globin cluster genomic structure where HBA1 gene organisation is also depicted. (B) High-Resolution Melting Analysis of HBA1 exon II spanning amplicon revealed a sample with a distinct melting profile (green line, arrow), compared to wild type (blue line) and a positive control (αα33bpDel/αα) (red line). (C) Sanger sequencing revealed a heterozygosity (Y) in nucleotide position c.260 (ref. seq. NM_000558.5) indicated by the arrow, corresponding to Leu86 residue (CD86 CTG>CCG [Leu>Pro]). (D) Hb Thessaloniki variant description as entered in ITHANET database. Entry #4098. Depicted in red colour in brackets and yellow highlighted is the point variation (T>C) responsible for Hb Thessaloniki production. Hb Thessaloniki protein variant’s primary structure is also depicted.
We sought to name the coincidental discovery of this new variant Hb Thessaloniki [CD86 CTG>CCG (Leu>Pro)], and reported it in the ITHANET database (Itha ID 4098) (Figure 2D).
Interestingly, the replacement of leucine by proline residue occurs next to the heme binding proximal histidine, probably affecting the stability of the protein.
The α-subunits and β-subunits of haemoglobin are classified as all-α proteins according to the SCOP database, because they have a three-dimensional shape that is almost entirely made up of α-helices [17]. They consist of 7 and 8 α-helices, respectively, labelled as A–H [18]. Leu86 is located in the F helix of the alpha chain, which is critical for the stability and function of haemoglobin. To gain deeper insight into how Leu86Pro alpha chain point variation affects the structure of haemoglobin, a computational model of the variant protein was constructed using the AlphaFold3 server. Structural alignment of the resulting model with the experimentally determined structure of human haemoglobin in the oxy form (PDB ID: 2DN1) was also performed in order to identify any differences between the two structures. Visual inspection of the resulting model and the subsequent structural alignment reveals that this variation causes disruption of the F helix (Figure 3), which is subsequently replaced by a large loop that occupies the space where heme must be located. Furthermore, in order to determine whether this single-nucleotide variation stabilises or destabilises the structure of haemoglobin, protein thermodynamic stability changes were assessed through Gibbs free energy calculations (ΔΔG). The ΔΔGStability value for this variation was calculated using DynaMut2 by employing the experimentally determined structure of wild-type human haemoglobin (PDB ID: 2DN1) as a reference. The ΔΔGStability value for the Leu86Pro variation was −0.96 kcal/mole, which is a clear indication that this substitution destabilises protein structure. Finally, the effect of this variation on the interaction with chaperone AHSP was also studied. We utilised the AlphaFold3 server in order to predict the structure of the alpha chain—the AHSP dimer and the resulting model indicate that AHSP interacts with helices G and H of the alpha chain containing the mutation in the same way the wild-type alpha chain of Hb does (Figure 4). Our results are in accordance with previous studies where it has been identified that AHSP primarily binds to the G and H helices of the alpha-haemoglobin (αHb) chain and the key residues involved in the interaction are Lys99, His103, and Phe117 [19,20].
Figure 3. Cartoon representation of the structural alignment of wild-type human haemoglobin (PDB id: 2DN1) alpha chain, coloured in green with the resulting model (blue), containing the Leu86Pro mutation, from the AlphaFold3 server. Residues Pro86 and His87 in the mutated haemoglobin are underlined.
Figure 4. Cartoon representation of haemoglobin alpha chain, containing the Leu86Pro mutation colored in blue, in complex with chaperone AHSP (green) as predicted from AlphaFold3 server. Residues Lys99, His103 and Phe117of alpha chain that interact with AHSP are presented as stick models.
Genetic analysis of the proband’s partner did not detect any variations in HBA genes, covering 96% of variants detected in the Greek population. In combination with her normal haematological profile, the couple was informed, in the context of genetic counselling, that there was no estimated risk of giving birth to a thalassaemic offspring.
We sought to examine the proband’s relatives in order to confirm the mild haematological phenotype of the proband and also investigate potential co-inheritance with other HBA variants. As shown in the following table, both the proband’s mother and siblings presented with almost normal haematological phenotypes. Quite interestingly, the following genetic analysis revealed that the proband’s mother is a compound heterozygote for Hb Thessaloniki and Hb Parma (CD 59 GGC>AGC [Gly>Ser], HBA2:c.178G>A, IthaID: 2409), a variant previously reported in databases. The proband’s brother is a heterozygote of Hb Thessaloniki while his sister is a heterozygote of Hb Parma (Table 1).

4. Discussion

Following abnormal haematological phenotypes, DNA analysis may detect novel Hb variants. In Greece, a country of approximately 11 million people, haemoglobinopathies are the most frequent genetic diseases. The spectrum of HBA variants in Greece is quite heterogeneous, with the relative incidence being approximately 7.0%.
In the next-generation sequencing era, gene scanning by HRM analysis may prove to be a quite rapid, sensitive, easy-to-perform, and economical alternative for point variations and detecting small indels. Based on such screening, this is the first global report of a novel variant (Hb Thessaloniki) detected in a Greek male. Since, in the majority of cases, structural modification directly affects function, it is important to study function modifications in order to predict the expected phenotype and, if required, provide the most appropriate genetic council to couples at risk.
In Greece, although quite rare, a number of unstable HBA1 variants have been reported [5]. For example, Hb Adana, an HBA1 point variation involving a glycine excess at the region of the E helix that is closely attached to a glycine residue of the B helix, significantly alters the stability and integrity of the erythrocyte’s Hb, leading to abnormal precipitates on the red cell membrane, resulting in diverse degrees of haemolysis and ineffective erythropoiesis [21]. Moreover, Hb Heraklion, caused by the deletion of Proline37(C2), is also predicted to result in severe instability of the variant haemoglobin [22,23]. In addition, Hb Aghia Sophia, a variant due to deletion of Val62 (E11) residue, also forms an unstable haemoglobin [23]. The above-mentioned variants, when co-inherited with either point HBA2 variants such as Hb Constant Spring or deletions of HBA genes, result in severe phenotypes [24]. In contrast, another HBA1 variant, Hb Natal, a shortened polypeptide chain produced due to a premature stop codon formation in codon 140, does not seem to significantly affect protein stability [25].
The case of Hb Thessaloniki, a hyperunstable Hb as calculated by structure–function prediction algorithms, is in accordance with the haematological phenotype noted. More precisely, the F helix, present on both the α- and β- globin subunits of haemoglobin, is a crucial structural component because it contains a histidine residue which binds to the heme group’s iron atom, making it essential for oxygen binding. Its stability and orientation are vital for the function of haemoglobin; structural changes in this helix can significantly affect oxygen affinity and the overall cooperative binding of oxygen in both fetal (HbF) and adult (HbA) haemoglobin. Interestingly, the replacement of leucine by proline residue (Leu86Pro) in the alpha chain occurs next to the heme binding proximal histidine at position F8 (residue 87 in the alpha chain or His87) which directly coordinates with the heme iron. As is evident in the resulting model from the AlphaFold3 server, shown in blue (Figure 3), the Leu86Pro substitution disrupts the formation of the F helix while the side chain of His87 is oriented to the outer side of the structure and does not interact with heme’s iron atom, in contrast to the wild-type haemoglobin, shown in green (Figure 3). The orientation of His87 in the hydrophobic pocket where heme resides is crucial for the binding of heme’s iron atom, and in the case of Hb Thessaloniki, it adopts a different conformation while the F helix is also disrupted. This may justify the fact that the Hb Thessaloniki variant is hyperunstable, while the finding is further supported by the results of Dynamut2 that classifies this variation as destabilising. It must be noted that these results verified the haematological phenotype noticed. Therefore, structural simulation may prove to be quite supportive in understanding the novel variant’s behaviour.
Nevertheless, the haematological phenotype of the proband’s mother, who was found to be a compound heterozygote of Hb Thessaloniki and Hb Parma, shows that despite its calculated instability, Hb Thessaloniki does not seem to significantly reduce HbA production. This phenomenon could be, at least partially, attributed to the relatively reduced expression of the HBA1 gene. The detection of a compound heterozygote with either pathogenic point variants or deletions may provide valuable information for genetic counselling. In addition, further future investigation of Hb Thessaloniki’s biochemical properties, oxygen dissociation curve, red blood cell lifespan and sensitivity to oxidative stress may lead to further understanding of its function in the erythrocyte.
Of course, given the rapid technological advances in massive parallel sequencing technologies, haematological phenotypes may follow genetic scanning, but in countries where these technologies are not easily adopted, a combined methodology using more classical molecular biology approaches may still be quite useful in order to detect underlying genetic variants, explain abnormal phenotypes and provide appropriate genetic counselling and embryo diagnosis choices.
In conclusion, population screening schemes should be tailored to each country and region’s specific needs as well as to the diagnostic approaches available. Despite rapid progress in gene editing technologies, and the challenge of identifying novel variants with unknown functions, population screening for thalassaemia/haemoglobinopathy carrier detection followed by prenatal embryo diagnosis, is still the most effective strategy against the disease worldwide.

Author Contributions

E.B. conceived the study, wrote and reviewed the manuscript, contributed to the development and evaluation of the HRMA HBA gene scanning approach, analysed and evaluated the genetic analysis results, and deposited Hb Thessaloniki in the Ithanet Database. N.P. performed in silico structural analysis and evaluated the results, and contributed to writing and reviewing the manuscript. G.M. performed the haematological and biochemical tests and reviewed the manuscript. A.B. designed and evaluated a Sanger-seq approach specific to HBA genes, contributed to the development and evaluation of the HRMA HBA gene scanning approach and reviewed the manuscript. C.C., together with E.B. and A.B., designed and evaluated the HRMA approach. M.D., E.V. and A.V. reviewed the study. S.T. conceived the study, analysed haematological and biochemical data, and wrote and reviewed the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Ethical approval was not required for this case report in accordance with the national policy (LAW N 2619).

Data Availability Statement

Data supporting the findings are subject to privacy and ethical restrictions and, therefore, cannot be made publicly available.

Acknowledgments

The authors would like to acknowledge Thomai Tzantzali, Georgia Tsitsou and Panayotis Kyriazopoulos of the Molecular Genetics Laboratory for their technical support. The authors would also like to acknowledge Google DeepMind and Isomorphic Labs for the use of AlphaFold3 via AlphaFold Server regarding the prediction of the structural models reported in this work.

Conflicts of Interest

The authors report no conflicts of interest. The authors are responsible for the content and the writing of the paper.

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