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A prognostic scoring system that can differentiate β-thalassemia patients based on mortality risk is lacking. We analysed data from 3145 β-thalassemia patients followed through a retrospective cohort design for the outcome of death. An a priori list of prognostic variables was collected. β Coefficients from a multivariate cox regression model were used from a development dataset (n = 2516) to construct a formula for a Thalassemia International Prognostic Scoring System (TIPSS) which was subsequently applied to a validation dataset (n = 629). The median duration of observation was 10.0 years. The TIPSS score formula was constructed as exp (1.4 × heart disease + 0.9 × liver disease + 0.9 × diabetes + 0.9 × sepsis + 0.6 × alanine aminotransferase ≥42 IU/L + 0.6 × hemoglobin ≤9 g/dL + 0.4 × serum ferritin ≥1850 ng/mL). TIPSS score thresholds of greatest differentiation were assigned as <2.0 (low-risk), 2.0 to <5.0 (intermediate-risk), and ≥5.0 (high-risk). The TIPSS score was a good predictor for the outcome of death in the validation dataset (AUC: 0.722, 95%CI: 0.641-0.804) and survival was significantly different between patients in the three risk categories (P < 0.001). Compared to low-risk patients, the hazard ratio for death was 2.778 (95%CI: 1.335-5.780) in patients with intermediate-risk and 6.431 (95%CI: 3.151-13.128) in patients with high-risk. This study provides a novel tool to support mortality risk categorization for patients with β-thalassemia that could help management and research decisions., Competing Interests: Declaration of competing interest Khaled M. Musallam has been or is a consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Agios Pharmaceuticals, CRISPR Therapeutics and Vifor Pharma. Efthymia Vlachaki received hononaria from DEMO S.A. Pharmaceutical Industry and Novartis. Alessia Pepe is the principal investigator of the MIOT project that receives ‘non-profit support’ from industrial sponsorships (Chiesi Farmaceutici S.p.A. and Bayer) and she received speakers' honoraria from Chiesi Farmaceutici S.p.A. Ali T. Taher has been or is consultant for Novartis, Celgene Corp (Bristol Myers Squibb), Vifor Pharma, Silence Therapeutics and Ionis Pharmaceuticals; and received research funding from Novartis, Celgene Corp (Bristol Myers Squibb), La Jolla Pharmaceutical Company, Roche, Protagonist Therapeutics and Agios Pharmaceuticals. Vijay G Sankaran serves as an advisor to and/or has equity in Novartis, Forma, Cellarity, Ensoma, and Branch Biosciences. Aurelio Maggio has been or is a member of advisory boards for Novartis, Celgene Corp (Bristol Meyers Squibb) and Bluebird Bio. The remaining authors have no conflicts of interest to disclose., (Copyright © 2022 Elsevier Inc. All rights reserved.)

In β-thalassaemia, the severity of inherited β-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 β-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β 0 /β 0 , β 0 /β + , β + /β + , β 0 /β ++ , β + /β ++ , and β ++ /β ++ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β 0 and β + mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β 0 /β 0 , β 0 /β + , or β + /β + had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β-thalassaemia and suggests inclusion of both β + and β 0 mutations in strata of greatest severity., (© 2021 British Society for Haematology and John Wiley & Sons Ltd.)

The thalassaemia syndromes (TS) show different phenotype severity. Developing a reliable, practical and global tool to determine disease severity and tailor treatment would be of great value. Overall, 7910 patients were analysed with the aim of constructing a complication risk score (CoRS) to evaluate the probability of developing one or more complications. Nine independent variables were included in the investigation as predictors. Logistic regression models were used for Group A [transfusion-dependent thalassaemia (TDT)], Group B [transfused non-TDT (NTDT)] and Group C (non-transfused NTDT). Statistically significant predictors included age (years), haemoglobin levels, hepatic transaminases [alanine aminotransferase (ALT) and aspartate aminotransferase] and left-ventricular ejection fraction (LVEF) for Group A; age (years), age at first chelation (months), ALT and LVEF for Group B; and age (years), mean serum ferritin (SF) levels and LVEF for Group C. The area under the receiver operating characteristic curve was 84·5%, 82·1% and 80·0% for Groups A, Group B and Group C respectively, suggesting the models had good discrimination. Finally, the CoRS for each group was categorised into four risk classes (low, intermediate, high, and very high) using the centiles of its distribution. In conclusion, we have developed a CoRS for TS that can assist physicians in prospectively tailoring patients' treatment., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

In the Eastern province of Saudi Arabia, thalassemia is highly common. Data on the effect of alpha globin gene variation on the concentration of iron on transfusion dependent Saudis are scanty. A total of 166 transfusions dependent β-thalassemia were included in this study to understand association between the alpha globin gene variation and concentration of iron. Using multiplex PCR, the alpha globin gene deletions were identified. Also, HBA1 and HBA2 genes were sequenced by Sanger sequencing. Saudi transfusion dependent female β-thalassemia patients with wild alpha globin genotype (αα/αα) were observed with iron level beyond the normal range. However, normal range of iron was observed in transfusion dependent Saudi female beta thalassemia patients co-inherited with double (-α 3.7 /-α 3.7 , or -- Fil /αα or -- MED /αα or - (α) 20.5 /αα) or double heterozygosity (- -/-α 3.7 ) alpha globin gene deletions, which is significantly (p < 0.0001) less compared to the Saudi transfused female with wild alpha globin genotype (αα/αα). The co-inheritance alpha globin gene deletions in female beta thalassemia patients were significantly lowering serum iron. Detailed studies can be taken forward to identify the molecular pathways involved in globin gene deletion as modulator.

Introduction: Detection of β-thalassemia trait or carriers (β-TT) depends significantly on an increase in Hemoglobin A 2 (HbA 2 ) levels, which is found at low levels (<3%) in normal healthy individuals and elevated levels (≥3.5%) in β-TT individuals. The study was designed to evaluate the reliability of the diagnostic parameter HbA 2 in the differentiation of β-TT and non-β-TT in Saudis., Methods: The widely used high performance liquid chromatography (Variant II Bio-Rad) was used to measure HbA 2 levels in blood. Sanger sequencing was used to screen the variation in globin genes (HBB, HBD, HBA1, and HBA2). All the study subjects were divided into βTT and non-βTT (wild) categories based on the presence or absence of HBB variations and further sub-divided into false positive, true positive, false negative, and true negative, based on HbA 2 values., Results: Out of 288 samples, 96 had HBB gene mutations. Of the 96 β-TT samples, sickle cell trait (SCT) samples (n = 58) were excluded, while the remaining (38 β-TT) were included in the detailed analysis: seven subjects with the HBB mutation had normal HbA 2 (<3%), and three were borderline (3.1-3.9%). The remainder (n = 28) had an elevated HbA 2 level (>4%). Based on HbA 2 analysis alone, both these groups would be incorrectly diagnosed as normal. Similarly, of the 189 non-β-TT samples, 179 had normal HbA 2 , eight had borderline HbA 2 , and two had a HbA 2 level above 4%. Based on HbA 2 analysis alone, borderline and >4% HbA 2 individuals, negative for β-TT, can be incorrectly diagnosed as carriers., Conclusion: Given the percentage of samples falling in the HbA 2 "borderline" and "normal" categories, it can be concluded that HbA 2 has a measure of unreliability in the diagnosis of β-thalassemia carriers.

The regions of Al‑Qatif and Al‑Ahssa in the Eastern Province of Saudi Arabia are known for their high prevalence of hemoglobinopathies, including β‑thalassemia and sickle cell anemia. Previously, the α‑gene deletion has been demonstrated as highly prevalent among populations residing in these two regions. The present study was conducted in order to investigate the implications of the α‑globin gene deletion on fetal hemoglobin (HbF) and hemoglobin α2 (HbA2) concentrations in patients with transfusion‑dependent β‑thalassemia. A total of 166 Saudi patients with transfusion‑dependent β‑thalassemia and 337 healthy Saudi patients were included in the study. The ‑α3.7, ‑α4.2, -‑FIL, -‑SEA, -‑MED and -‑(20.5) gene deletions were identified using multiplex α‑globin deletion polymerase chain reaction. The present study revealed that the ‑α3.7 gene deletion is the most prevalent (43.5%) in the Saudi populations that were analyzed and is characterized by the deletion of 3,804 base pairs. Numerous genotypes, namely ‑3.7α2/α1α2, ‑3.7α2/α1α12, ‑3.7α2/‑3.7α2, ‑3.7α2HphI/α1α2HphI, ‑3.7α2/α1‑4.2, ‑3.7α2/α1polyA‑1α2, ‑3.7α12/α1α12, ‑‑FIL/‑3.7α2 and ‑3.7α2/‑3.7α2Hb Villiers le Bel were also identified in the investigated population. Furthermore, a gradual increase in the concentration of HbF and HbA2 in patients with β‑thalassemia and the number of α‑gene deletions was demonstrated; whereas in healthy patients the level of HbA2 was demonstrated to decrease as the number of α‑gene deletions increased. Therefore, it can be concluded that the high HbF concentration in the present study is predominantly associated with other mutations associated with β‑thalassemia rather than α‑globin deletions. Furthermore, the results of the present study also revealed novel α‑gene deletion genotypes prevalent in the population studied, namely α1α2/α1α2HphI, α1α2HphI/α1α2HphI, α1α2/α1α2Hb Handsworth, ‑3.7α2HphI/α1α2HphI, ‑3.7α2/‑3.7α2Hb Villiers le Bel and ‑-MED/α1α2HphI.

Introduction: Elevated HbA 2 (hemoglobin A 2 ) level is considered the most reliable hematological parameter for the detection of β-thalassemia carriers. However, some carriers are difficult to recognize because the level of HbA 2 is not in the distinctive carrier range, i.e. 4.0-6.0%; instead, some carriers have HbA 2 levels between normal and carrier levels, i.e. borderline HbA 2 (HbA 2 = 3.1-3.9%). Studies have shown that variations in the erythroid Krüppel-like factor ( KLF1 ) gene lead to borderline HbA 2 in β-thalassemia carriers from various populations. The incidence of borderline HbA 2 in Saudis is high., Material and Methods: To confirm the influence of variations in KLF1 , HBA1 , HBA2 and HBB genes for the reduction of the level of HbA 2 in Saudi β-thalassemia carriers, we performed a direct sequence analysis of KLF1 , HBA1 , HBA2 and HBB genes from 212 healthy Saudis (88 subjects: HbA 2 < 3; 72 subjects: HbA 2 = 3.1 to 3.9; 52 subjects HbA 2 > 4.3)., Results: The presence of the borderline HbA 2 level is not specific to any type of β-thalassemia variation or β + -thalassemia variations in Saudis. Two exonic (c.304T>C and c.544T>C) and two 3' untranslated region (3'UTR) (c.*296G>A and c.*277C>G) variations have been identified in the KLF1 gene for the first time from an Arab population. None of these four variations in KLF1 genes are significantly associated with the Saudis with borderline HbA 2 . α Globin genotype, -α 2 3.7 /α 1 α 2 , is found to be the most frequent (55.55%) among healthy Saudis with borderline HbA 2 compared with the other groups (HbA 2 < 3 = 20.45%; HbA 2 > 4.3 = 13.51%)., Conclusions: Further studies are necessary to determine the influence of other factors on the presence of borderline HbA 2 in 41.67% of Saudis., Competing Interests: The authors declare no conflict of interest.

α-Thalassemia X-linked mental retardation syndrome is a rare inherited intellectual disability disorder due to mutations in the ATRX gene. In our previous study of the prevalence of β-thalassemia mutations in the Eastern Province of Saudi Arabia, we confirmed the widespread coinheritance of α-thalassemia mutation. Some of these subjects have a family history of mental retardation, the cause of which is unknown. Therefore, we investigated the presence or absence of mutations in the ATRX gene in these patients. Three exons of the ATRX gene and their flanking regions were directly sequenced. Only four female transfusion dependent β-thalassemia patients were found to be carriers of a novel mutation in the ATRX gene. Two of the ATRX gene mutations, c.623delA and c.848T>C were present in patients homozygous for IVS I-5(G→C) and homozygous for Cd39(C → T) β-thalassemia mutation, respectively. While the other two that were located in the intronic region (flanking regions), were present in patients homozygous for Cd39(C → T) β-thalassemia mutation. The two subjects with the mutations in the coding region had family members with mental retardation, which suggests that the novel frame shift mutation and the missense mutation at coding region of ATRX gene are involved in ATRX syndrome., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Thalassemia and sickle cell disease are the most prevalent hemoglobin disorders in the populations of Dammam, Al-Qatif and Al-Ahsa regions in the Eastern Province of Saudi Arabia where our study cases originated. Increased HbF can modify these disorders. Direct sequencing of the HBA2 and HBA1 genes from 157 Saudi subjects revealed a new HBA2 gene conversion in cis or trans in 5.7% of the total. We refer to this new HBA2 gene convert as an α12 (HBA12) allele due to its combination of α1 (HBA1) and α2 (HBA2) sequences. Three genotypes, homozygous (-α12(3.7)/α1α12), heterozygous (α1α2/α1α12) and hemizygous (α1- (4.2)/α1α12) for the α12 allele were observed. The majority of individuals who were positive for the α12 allele had a reduction in the percentage of HbA2. Further studies are necessary to evaluate the possible effect of these changes on globin gene expression., (Copyright © 2014 Elsevier Inc. All rights reserved.)