Hb S/ β-Thalassemia in the REDS-III Brazil Sickle Cell Disease Cohort: Clinical, Laboratory and Molecular Characteristics

Abstract

We described the clinical, laboratory and molecular characteristics of individuals with Hb S (HBB: c.20A>T)/β-thalassemia (Hb S/β-thal) participating in the Recipient Epidemiology and Donor Evaluation Study (REDS-III) Brazil Sickle Cell Disease cohort. HBB gene sequencing was performed to genotype each β-thal mutation. Patients were classified as Hb S/β⁰-thal, Hb S/β⁺-thal-severe or Hb S/β⁺-thal based on prior literature and databases of hemoglobin (Hb) variants. Characteristics of patients with each β-thal mutation were described and the clinical profile of patients grouped into Hb S/β⁰-thal, Hb S/β⁺-thal and Hb S/β⁺-thal-severe were compared. Of the 2793 patients enrolled, 84 (3.0%) had Hb S/β⁰-thal and 83 (3.0%) had Hb S/β⁺-thal; 40/83 (48.2%) patients with Hb S/β⁺-thal had mutations defined as severe. We identified 19 different β-thal mutations, eight Hb S/β⁰-thal, three Hb S/β⁺-thal-severe and eight Hb S/β⁺-thal. The most frequent β⁰ and β⁺ mutations were codon 39 (HBB: c.118C>T) and IVS-I-6 (T>C) (HBB: c.92+6T>C), respectively. Individuals with Hb S/β⁰-thal had a similar clinical and laboratory phenotype when compared to those with Hb S/β⁺-thal-severe. Individuals with Hb S/β⁺-thal-severe had significantly lower total Hb and Hb A levels and higher Hb S, white blood cell (WBC) count, platelets and hemolysis markers when compared to those with Hb S/β⁺-thal. Likewise, individuals with Hb S/β⁺-thal-severe showed a significantly higher occurrence of hospitalizations, vaso-occlusive events (VOE), acute chest syndrome (ACS), splenic sequestration, blood utilization, and hydroxyurea (HU) therapy.

Keywords: Clinical events; Hb S/β+-thalassemia (Hb S/β+-thal); Hb S/β0-thalassemia (Hb S/β0-thal); sickle cell disease; thalassemia mutation.

Figure 1.

Mutations causing β-thal observed in this study. The HBB is depicted with the three exons (1, 2 and 3), two introns (IVS-I and IVS-II), conserved sequences in the 5' and 3' untranslated regions (5'UTR and 3'UTR), and the invariant dinucleotides at the exon-intron junctions of the gene. The vertical lines above or below HBB represent the sites of the different point mutations. The mutations found in the study can be classified into four groups according to their effect on gene function and Hb A production: (A) transcriptional, (B) consensus splice site, (C) cryptic splice site, (D) polyA signal mutations, (E) Splice junction, (F) frameshift and (G) nonsense codon.