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Hemoglobin H (Hb H) disease is the most significant health problem of the α-thalassemia syndromes. The Hb disease patients are categorized based on their genotype to deletional and nondeletional, with the latter genotype presents the more severe clinical symptoms. Since telomere length is an indicator of biological aging and health, we hypothesized that telomere length could reflect Hb H disease's severity. In this study, we recruited 48 deletional and 47 nondeletional Hb H disease patients, along with 109 normal controls, for telomere length assessment. The leukocyte telomere length was assessed by monochromatic multiplex real-time PCR and reported as the telomere to single-copy gene (T/S) ratio. When telomere length was adjusted for age, the analysis of covariance between the control and the two Hb H disease groups revealed no significant difference. However, the telomere shortening rate was more rapid in the nondeletional Hb H disease group than those of the control and deletional Hb H disease groups. Gender analysis found that male patients have a significantly lower T/S ratio than females in the nondeletional group but not in the control and deletional groups. In the two disease groups, the T/S ratio was not influenced by ferritin level or transfusion burden but was positively correlated with the absolute reticulocyte count., (Copyright © 2021 Elsevier Inc. All rights reserved.)

HbH disease had been introduced as a mild anemia disease. It recently has become the most challenging hemoglobinopathy due to the increasingly described genotype patterns and very variable phenotypic presentations in different ethnics. Phenotypic severity of HbH syndrome is not simply related to the degree of α-globin deficiency and being influenced by several environmental and/or genetic factors. Hence, more investigation needs to identify factors like other genetic loci linked and/or unlinked to the α-globin genes affecting molecular mechanisms that influence clinical expression of HbH disease. Altogether, the complicated pathophysiology of HbH disease makes it to be known as a poorly understood syndrome. It may offer the hypothesis that it is a multifactorial disease, which needs to be investigated by more comprehensive genetic approach like genome wide association studies (GWAS) looking for genetic variants. Moreover, extended haplotype analysis to find out probable specific association between haplotypes of modifier genes and disease severity in patients with a specific HbH genotype may be a key point. In this review, we aim to provide important information regarding phenotypic presentation of different genotypes that have been described worldwide. It may help geneticists regarding challenging health care aspects of HbH disease in a specific ethnic., (Copyright © 2015 Elsevier Inc. All rights reserved.)

AEBart's disease is a thalassemia intermedia usually characterized by the interaction of α(0)-thalassemia with either deletional or non-deletional α(+)-thalassemia in Hb E heterozygote. Genotypic and phenotypic features are heterogeneous. We studied the hematologic and molecular characteristics of this disease in a cohort of 173 Thai patients encountered at our center in northeast Thailand. Hemoglobin and DNA analyses identified patients with deletional AEBart's disease (n=84), Hb Constant Spring AEBart's disease (n=81), Hb Paksé-AEBart's disease (n=5), AEBart's disease with codon 30 mutation (n=1) and two hitherto un-described forms of AEBart's disease due to interaction of Hb E heterozygote and α(0)-thalassemia with the -α(16.6)kb deletional α(+)-thalassemia (n=1) and Hb Q-Thailand (n=1). Different phenotypic expression of these AEBart's diseases with low Hb, Hct and MCV and increased RDW values with marked reduction in Hb E levels were observed. It was found that all these forms of AEBart's disease showed similar thalassemia intermedia phenotypes but those with non-deletional forms were relatively more anemic. Our data confirm that in such area with high prevalence of hemoglobinopathies such as Southeast Asia, identification of rare thalassemia alleles in a thalassemia intermedia patient should not be ignored. Careful consideration of different phenotypic expression may help in providing presumptive diagnosis of this disease where access to molecular testing is limited. However, molecular diagnostic is useful for predicting the clinical outcome and improving genetic counseling of these complex hemoglobinopathies., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Genetic recombination has been implicated as a mechanism that drives mutagenesis in the human globin gene clusters, either as a result of unequal crossover or gene conversion. In this paper, a novel fusion gene was identified in a Chinese girl with hemoglobin H disease. The proband's father was a compound heterozygote for the common -α(4.2) deletion and this fusion gene, and her mother was heterozygous for the common --(SEA) deletion (--(SEA)/αα). Both her parents had a hypochromic and microcytic red cell phenotype and a normal hemoglobin level. Molecular studies revealed a compound heterozygote for the --(SEA) deletion and this novel fusion gene and the patient had the clinical features of classic hemoglobin H disease. Sequence analysis revealed that the mutant gene was the result of a fusion between the α2 and ψα1 genes. The recombination began at exon 3 of α2 gene, crossing with exon 3 of the ψα1 gene. With this recombination, the conservative 3'UTR of the α2 gene was changed, and an extensive transcript with a new signal 1048bp 3' to the terminating codon was found. The abnormal transcripts of the fusion gene read through the intergenic sequence., (Copyright © 2013 Elsevier Inc. All rights reserved.)

We describe the molecular and hematological profiles of thalassemia syndromes caused by interactions of hemoglobin (Hb) Q-Thailand [α74(EF3) Asp-His] and various hemoglobinopathies found in 52 unrelated adult Thai subjects. Ten genotypes including several previously undescribed conditions were observed, which were classified into 4 groups. Group I included 26 Hb Q-Thailand heterozygotes and a homozygotous subject. Group II included subjects with Hb Q-Thailand and other α-thalassemia alleles in trans including 1 compound Hb Q-Thailand/α(+)-thalassemia (-α(3.7)), 2 Hb Q-Thailand/Hb Constant Spring disease and 6 Hb H/Q-Thailand disease. The average levels of Hb Q-Thailand were found to be 29.8%, 82.3%, 34.7%, 49.2-49.3% and 79.4%, respectively. Both Hbs Bart's and H were observed in addition to Hb Q-Thailand in all 6 cases with Hb Q-H disease but not in a homozygous Hb Q-Thailand. Group III included 7 double heterozygotes for Hb Q-Thailand/Hb E, 3 Hb Q-Thailand/Hb E/α(+)-thalassemia (-α(3.7)), 3 heterozygous Hb Q-Thailand/homozygous Hb E and 1 triple heterozygote for Hb Q-Thailand/Hb Constant Spring/Hb E. In this group, Hbs E (α(A)(2)β(E)(2)), Q-Thailand (α(QT)(2)β(A)(2)) and QE (α(QT)(2)β(E)(2)) were observed on both HPLC and capillary electrophoresis. The Hb QE, rather than Hb Q-Thailand, was detected in all 3 cases with heterozygous Hb Q-Thailand and homozygous Hb E. The remaining two cases in group 4 were double heterozygotes for Hb Q-Thailand and β(0)-thalassemia in which Hb Q-Thailand, elevated Hb A(2) (α(A)(2)δ(2)), and Hb QA(2) (α(QT)(2)δ(2)) were detected. DNA analysis identified the Hb Q-Thailand mutation (α74: GAC-CAC) and the linked (-α(4.2)) in all cases. Analysis of α-globin gene haplotype provided the first evidence of a single origin of this Hb variant in Thai population., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Globin genes, which encode the protein subunits of hemoglobin (Hb), are organized in two different gene clusters and present a coordinated and differential pattern of expression during development. Concerning the human alpha-globin gene cluster (located at chromosome region 16p13.3), four upstream highly conserved elements known as multispecies conserved sequences (MCS-R1-4) or DNase I hypersensitive sites (HSs) are implicated in the long-range regulation of downstream gene expression. However, only the absence of the MCS-R2 site (HS-40) has proven to drastically downregulate the expression of those genes, and consequently, it has been regarded as the major and crucial distal regulatory element. In this study, Multiplex Ligation-dependent Probe Amplification was used to screen for deletions in the telomeric region of the short arm of chromosome 16, in an attempt to explain the alpha-thalassemia or the HbH disease present in a group of Portuguese patients. We report four novel and five uncommon deletions that remove the alpha-globin distal regulatory elements and/or the complete alpha-globin gene cluster. Interestingly, one of them occurred de novo and removes all HSs except HS-10, while other eliminates only the HS-40 site, the latter being replaced by the insertion of a 39 nucleotide orphan sequence. Our results demonstrate that HS-10 alone does not significantly enhance the alpha-globin gene expression. The absence of HS-40 in homozygosity, found in a patient with Hb H disease, strongly downregulates the expression of alpha-globin genes but it is not associated with a complete absence of alpha-globin chain production. The study of naturally occurring deletions in this region is of great interest to understand the role of each upstream regulatory element in the native human erythroid environment., (2010 Elsevier Inc. All rights reserved.)

We describe the screening of newborns for thalassemia and Hb variants by using isoelectric focusing (IEF) in a population from northern Thailand where hemoglobinopathies are highly prevalent. The report focuses on findings of alpha-thalassemia, Hb E, and other hemoglobin variants, and their correlation with genotypes and hematologic parameters. Two-hundred and seven out of 566 newborns (36.6%) had thalassemia genes or Hb variants. Seventeen different genotypes were found. Nine cases (1.6%) of Hb H disease (five deletional Hb H diseases, two Hb H/Constant Spring diseases, one deletional Hb H disease/Hb E, carrier and one Hb H/Constant Spring disease/Hb E carrier) and one Hb E-beta-thalassemia were identified. IEF could clearly distinguish Hb H diseases and carriers of two alpha-globin gene defects from normal individuals according to the presence of Hb Bart's and its percentage. For carriers of a single alpha-globin gene defect, Hb Bart's was either absent or present in a small amount and was therefore not reliable for screening. The presence of an additional band at the Hb A(2) position in the newborns signified an Hb E carrier. One case of an absent Hb A and a presence of Hb E was identified as Hb E-beta-thalassemia. Two Hb Q-Thailand carriers were seen with two additional Hb fractions, presumably combinations of gamma-globin and beta-globin with the alpha-globin variant. Newborns with Hb H disease had lower Hb, MCV, and MCH levels than normal. MCV and MCH were also useful for differentiation of carriers of two alpha-globin gene defects, but not for carriers of Hb E or single alpha-globin gene defect. IEF was a reliable method for neonatal cord blood screening for alpha-thalassemia and Hb variants., (Copyright 2010 Elsevier Inc. All rights reserved.)