Genotype of subjects with borderline hemoglobin A2 levels: Implication for, β‐thalassemia carrier screening

Abstract

In this study, we have defined by molecular analysis, the alpha, beta, and delta globin genotype in a group of individuals with normal or thal-like red cell indices but borderline hemoglobin (Hb)A2 levels, who were identified in a program for beta-thal carrier screening. In 37 of 125 individuals with borderline HbA2 levels, we detected a molecular defect in the beta, in both the delta and the beta, or in the alpha globin gene. Specifically seven of these subjects were carriers of the -101 C T mutation, ten of the IVSI nt6 T C mutation, 16 were double heterozygotes for delta and beta thal, and two had the triple alpha globin gene and two the single alpha globin gene deletion. From these results, we may conclude that subjects with borderline HbA2, particularly when they marry a typical beta-thal carrier, should be extensively investigated in order not to miss heterozygous beta-thalassemia.

Significance of borderline hemoglobin A2 values in an Italian population with a high prevalence of -thalassemia

“…In Group A, α + thalassemia showed classical hematologic findings associated with an anomalous slight increase in HbA2 level (Table 1A). Similar results were reported by Galanello 19 during screening programs in Sardinia. Regulation factors may play a role in the increase in HbA2 levels, although so far there is no plausible explanation.…”

Beta-thalassemia

“…100 In the presence of normal MCV and borderline HbA 2 levels, we are inclined to suspect the presence of a silent mutation or the triple or quadruple alpha globin gene arrangement and, therefore, proceed directly to alpha-and beta globin gene analysis, because the alpha/beta globin chain synthesis ratio could also be normal. 101 Definition of the type of thalassemias in these carriers is solely recommended when they mate with a carrier of a typically high HbA 2 beta-thalassemia or an undetermined type of thalassemia. In those rare cases showing normal or low MCV-MCH, normal or reduced HbA 2 levels, and high HbF, we suspect the presence of deltabeta-thalassemia, which should be differentiated from HPFH.…”

“…However, identification of delta and beta double heterozygotes may be accomplished by globin chain synthesis analysis and/or alpha, beta, and delta globin gene analysis. 101,102 Definition of the delta-thalassemia mutation may be carried out using one of the previously mentioned PCR-based methods. As in beta-thalassemia, also in delta-thalassemia, each population at risk has its own spectrum of common delta-thalassemia mutations that may be defined through a limited number of specific primers/probes.…”

The Prevention of Thalassemia

“…Silent b-thalassemia (normal HbA 2 b-thalassemia type 1) shows normal hematological features and HbA 2 level and may be identified solely by globin chain synthesis analysis or b-globin gene analysis (Kattamis et al 1979;Gonzalez-Redondo et al 1989;Galanello et al 1994). The triple or quadruple aglobin gene arrangement, which also displays the phenotype of normal HbA 2 b-thalassemia type 1, may show a slight unbalance of a/b þ gglobin chain synthesis but may also have a balanced synthesis (Harteveld et al 2008;Faa et al 2010).…”

“…Known determinants causing this phenotype are the triple a-globin gene arrangement, some b-promoter mutation (HBB c. 151 C ! T), and rare HBB or HBD gene variant (Table 1) (Galanello et al , 1994Gasperini et al 1993). Recently, we performed in the Sardinian population molecular analysis of the KLF1 gene (which codes fora zincfinger transcriptional factor) in a large group of individuals with borderline HbA 2 .…”