HbH Disease in Sardinia: Molecular, Hematological and Clinical Aspects

Abstract

In this study we have defined the molecular basis and correlated the clinical phenotype with the α-globin genotype in a large series of patients of Sardinian descent with HbH disease. The most prevalent molecular defect was the deletion of 3 α-globin structural genes most commonly the (– –/–α^3.7) genotype (83.6%) and rarely the (– –/– α^4.2) genotype (1.4%), followed in decreasing order of incidence by the combination of deletion α°-thalassemia and initiation codon mutation of the α₂-gene (– –/α^NcoIα = 9.8%), deletion α°-thalassemia and pentanucleotide deletion of IVS-I of the α₂-globin gene, (– –/α^HphIα = 3.3%) deletion α°-thalassemia and initiation codon mutation of the α₁-gene (– –/αα^NcoI = 1.3%), a homozygous state for initiation codon mutation of the α₂-gene (α^Ncoα/α^NcoIα = 0.7%). Patients with the (– –/α^thalα) genotypes showed severer clinical and hematological features as compared to those with the (– –/–α) or those with the (– –/αα^thal) genotypes. The single patient with the (α^Ncoα/α^Ncoα) genotype had a clinical phenotype intermediate between HbH disease and the α-thalassemia carrier status. This heterogeneity depends on the fact that the α₂-globin gene produces 2-3 times α-globin chains than the α₁-gene and the single remaining α₁-like globin gene in the -α^{3 7} chromosome has a compensatory increase in the α-globin chain output. α-Globin gene mapping of HbH disease patients may be useful for predicting the clinical outcome and to improve genetic counselling.

The Diverse Molecular Basis and Hematological Features of Hb H and AEBart’s Diseases in Northeast Thailand

“…Unlike other populations in which the Hb H disease is much more frequently due to deletions than nondeletion mutations [18, 19, 20, 21, 22, 23, 24], as shown in table 1, the Hb H disease in this group of the Thai population most commonly (35 of 52 cases, 67.3%) results from the combination of α-thalassemia 1 (SEA) and Hb CS (–– SEA /α CS α) and less commonly (14 of 52 cases, 26.9%) from the interaction of α-thalassemia 1 (SEA) and deletional α-thalassemia 2 (–– SEA /–α). Interaction of α-thalassemia 1 (SEA) with other nondeletional forms of α-thalassemia 2, the Hb Paksé (–– SEA /α PS α), was observed in 3 remaining cases (5.8%).…”

Hemoglobin H (Hb H) disease in Canada: Molecular diagnosis and review of 116 cases

“…The most common complications associated with Hb H disease are hepatomegaly, severe splenomegaly with hypersplenism, and jaundice [9]. Other complications include infection, leg ulcers, gallstones, folic acid deficiency, and acute hemolytic episodes in response to drugs and infection.…”

“…There have been several mutational surveys of Hb H disease patients in various regions of the Mediterranean basin [7,[9][10][11][12][13] and southeast Asia [16][17][18]. As is the case for ␤-thalassemia, each population group is characterized by a relatively small number of ␣-thalassemia determinants and Hb H disease genotypes.…”

Two atypical forms of HbH disease in Sardinia

“…2 The different size of alpha 0 deletions and the loss of genes located in the deleted region in Family B do not seem to interfere in the determination of specific phenotype. Several large deletions involving the a-globin gene cluster have been recently described.…”

“…2,3 HbH disease due to deletions including the major upstream regulatory element (MCS-R2) and leaving intact both a-globin genes have also been described. 4,5 We report here two new a 0 deletions, both located on the short arm of chromosome 16, responsible for HbH disease in two different Sardinian families.…”