δ-Thalassemia (OMIM No. 142000) resulting from mutations on the HBD gene usually has no clinical consequences, but it may cause a reduced rate of hemoglobin A2 (HbA2) [1,2]. Human HbA2 (α2δ2), which contains δ-globin, represents a minor fraction of the Hb found in human adults. In normal individuals, it constitutes between 2.5 and 3.3% of the total adult Hb content as measured by high-performance liquid chromatography [3].

Although genetic defects (δ-thalassemia o HbA2 variants) that decrease HbA2 levels (2% in heterozygote or ≤0.6% in homozygote subjects) do not affect health, they can hinder the diagnosis of the β-thalassemia trait [4]. Values of HbA2 >3.2% associated with microcytosis characterize the β-thalassemia trait [3]. However, the coinheritance of β-globin and δ-globin gene mutations can decrease HbA2 values to normal or lower levels due to a decreased δ-chain production. As iron deficiency anemia is also characterized by low HbA2 levels, this disease must firstly be ruled out by evaluating iron parameters. Subsequently, a δ-globin mutation screening should be performed, especially in subjects from geographic areas with a high incidence of β-thalassemia carriers.

Here, we report a novel mutation of the δ-globin gene which was found in an asymptomatic 30-year-old female from Messina (Sicily, Italy) during a routine screening for thalassemia. We performed biochemical and genetic tests after informed consent was provided by the patient. Hematological parameters and serum ferritin were normal. We found low HbA2 levels on high-performance liquid chromatography screening (HbA2 1.4%). However, as the patient was from a geographic area with a high prevalence of β-thalassemia, we performed automatic sequencing of the β-globin gene (ABI 3130 analyzer, Applied Biosystems, Foster City, CA, USA). DNA extraction was performed according to standard methods. No mutations of the β-globin gene were found.

Therefore, we amplified DNA samples by polymerase chain reaction to analyze the entire δ-globin gene (promoter region, all exons, and exon-intron junctions) [5]. The amplified samples were subjected to automatic sequencing (ABI 3130 analyzer; Applied Biosystems, Foster City, CA, USA) utilizing the BigDye Terminator Cycle Sequencing kit v3.1 (Applied Biosystems).

We found a novel TGA>CGA (stop to Arg) mutation at cd147 of the δ-globin gene in a heterozygous state (Fig. 1). Previously, Alkindi et al. [6] described for the first time a TGA>TTA (stop to Leu) mutation at cd147 in a heterozygous state in a subject who was also homozygous for -α3.7 allele. The subject was also asymptomatic and was identified during a screening for β-thalassemia screening.

Fig. 1
Fig. 1. Electropherogram showing the novel δ-globin gene mutation: cd147 T>C.
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Electropherogram showing the novel δ-globin gene mutation: cd147 T>C.

Fig. 1
Fig. 1. Electropherogram showing the novel δ-globin gene mutation: cd147 T>C.
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Electropherogram showing the novel δ-globin gene mutation: cd147 T>C.

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Thus, to the best of our knowledge, only 2 mutations have been found in cd147: TGA>CGA (stop to Arg) and TGA>TTA (stop to Leu). Both mutations cause an elongation of 15 amino acids in the protein carboxy terminal. We hypothesize that this elongated δ-globin, similarly to the elongated polypeptides α-globin and β-globin, would be unstable [6]. Certainly, the number of mutations on the δ-gene has increased greatly and about 117 δ-globin gene mutations have been reported so far (http://globin.cse.psu.edu/hbvar/menu.html) [7].

The presence of HBD mutations could compromise the diagnosis of β-thalassemia carriers as it produces a lower HbA2. Therefore, the molecular screening of δ-globin gene mutations could be useful for the genetic counseling of at-risk couples from geographic areas in which thalassemia is common.

1.
Jain S, Edison ES, Mathews V, Shaji RV: A novel δ-globin gene mutation (HBD: c.323G>A) masking the diagnosis of β-thalassemia: a first report from India. Int J Hematol 2012;95:570-572.
2.
Hariharan P, Colaco S, Colah R, Ghosh K, Nadkarni A: Delta globin gene variations leading to reduction in HbA2 levels. Int J Lab Hematol 2016;38:610-615.
3.
Mosca A, Paleari R, Ivaldi G, Galanello R, Giordano PC: The role of haemoglobin A2 testing in the diagnosis of thalassaemias and related haemoglobinopathies. J Clin Pathol 2009;62:13-17.
4.
Giambona A, Passarello C, Ruggeri G, Renda D, Teresi P, Anzà M, Maggio A: Analysis of delta-globin gene alleles in the Sicilian population: identification of five new mutations. Haematologica 2006;91:1681-1684.
5.
Bouva MJ, Harteveld CL, van Delft P, Giordano PC: Known and new δ-globin gene mutations and their diagnostic significance. Haematologica 2006;91:129-132.
6.
Alkindi S, Alzadjali S, Daar S, Ambusaidi R, Gravell D, Al Haddabi H, Krishnamoorthy R, Pathara A: First report of the spectrum of δ-globin gene mutations in Omani subjects - identification of novel mutations. Int J Lab Hematol 2015;37:238-243.
7.
Patrinos GP, Giardine B, Riemer C, Miller W, Chui DH, Anagnou NP, Wajcman H, Hardison RC: Improvements in the HbVar database of human hemoglobin variants and talassemia mutations for population and variation studies. Nucleic Acids Res 2004;1:32:D537-D541.
© 2016 S. Karger AG, Basel
2018
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