THE Hb S/β⁺-Thalassemia Phenotype Demonstrates that the IVS-I (−2) (A>C) Mutation is a Mild β-Thalassemia Allele

Abstract

We report a family in which two siblings are compound heterozygotes for Hb S [beta6(A3)GluVal] and a rare beta-globin mutation [IVS-I (-2) (A>C)]. Both patients had significant levels of Hb A, indicating that the IVS-I (-2) mutation is a relatively mild beta(+)-thalassemia (beta(+)-thal) allele. This mutation, in compound heterozygosity with Hb S, does not necessarily lead to a mild clinical course.

The compound state: Hb S/beta-thalassemia

“…Many different β-Thal mutations have been associated with Hb S, and the molecular basis of the thalassemia in Hb S/β-Thal individuals reflects the spectrum of β-Thal mutations observed in a particular population. 5,7–12 The heterogeneity of the β-Thal mutations leads to quantitatively different β-globin synthesis and consequently to different amounts of Hb A. This fact results in variable clinical manifestations, ranging from nearly asymptomatic to a severe condition similar to sickle cell anemia (homozygous Hb S).…”

“…The Hb A levels vary from <5% to 45% of the hemolysate and higher levels of Hb A are usually associated with a milder phenotype. 5,8,12–15 However, because of the confounding influences of other genetic modifiers, such as γ-globin gene expression and α-thalassemia, a rigid genotype–phenotype correlation is difficult to establish. 5 …”

Computational and drug target analysis of functional single nucleotide polymorphisms associated with Haemoglobin Subunit Beta (HBB) gene

“…Arginine is substituted by Glycine at position 31 of the beta subunit of HBB [54]. This substitution was believed to be a β 0 -thal allele since heterozygous individuals show elevated Hb A2 β 0 -thal trait [55]. Individuals with mutations in both HBB alleles that significantly reduce the HBB protein production suffer from severe anaemia and skeletal abnormalities [7].…”

Sickle cell/β-thalassemia: Comparison of Sβ0 and Sβ+ Brazilian patients followed at a single institution

“…9 Furthermore, mutations described as associated to a milder profile of complications did not necessarily lead to favorable clinical presentation when in compound heterozygosity with HbS. 34 This study aimed to draw a profile of hematological parameters and end organ damage in patients with sickle cell/β-thalassemia followed in a single Brazilian institution. We were able to demonstrate that Sβ 0 patients have a higher degree of hematological involvement when compared with Sβ + patients, with significantly lower baseline hemoglobin levels, and higher levels of HbF and HbS.…”