A Study of δ-Globin Gene Mutations in the UK Population: Identification of Three Novel Variants and Development of a Novel DNA Test for Hb A′₂

Abstract

We report here the spectrum of δ-globin gene mutations found in the UK population. Nine different δ chain variants and two δ-thalassemia (δ-thal) mutations were characterized in a study of 127 alleles in patients with either a low Hb A2 value or a split Hb A2 peak on high performance liquid chromatography (HPLC). The most common δ chain variant was Hb [Formula: see text] (or Hb B2) [δ16(A13)Gly → Arg; HBD: c.49G > C] (77.0%), followed by Hb A2-Yialousa [δ27(B9)Ala → Ser; HBD: c.82G > T] (12.0%), Hb A2-Babinga [δ136(H14)Gly → Asp; HBD: c.410G > A] (3.0%), Hb A2-Troodos [δ116(G18)Arg → Cys; HBD: c.349C > T] (1.0%), Hb A2-Coburg [δ116(G18)Arg → His; HBD: c.350G > A] (2.0%) and Hb A2-Indonesia [δ69(E13)Gly → Arg; HBD: c.208G > C] (1.0%). Three novel variants were identified: Hb A2-Calderdale [codon 2 (CAT > AAT), His → Asn; HBD: c.7C > A], Hb A2-Walsgrave [codon 52 (GAT > CAT), Asp → His; HBD: c.157G > C] and Hb A2-St. George's [codon 81 (CTC > TTC), Leu → Phe; HBD: c.244C > T]. In addition, two known δ-thal mutations were observed: -68 (C > T); HBD: c.-118C > T and codon 4 (ACT > ATT); HBD: c.14C > T. Amplification refractory mutation system (ARMS) primers were developed to provide a simple molecular diagnostic test for the most common variant, Hb [Formula: see text]. Three of the variants had a characteristic HPLC retention time that can be used for a presumptive diagnosis.

Delta globin gene variations leading to reduction in HbA2 levels

“…Mutations in the δ‐globin gene can affect the structure or expression of the δ‐globin. The stable structural defects will produce a second and usually a visible HbA 2 fraction as seen in HbA 2 St. George and a small shoulder in the HbA 2 peak in case of HbA 2 Saurashtra . Hence, we suggest careful evaluation of HPLC chromatograms, so that such variants are not missed out during routine preliminary screening.…”

“…A study carried out by Khalil et al . 2014 identified the HbA 2 St. George in 3 patients of Asian descent, with a split HbA 2 peak and low HbA 2 level. One of the 3 patients showed extremely low HbA 2 value of 0.5% with other two cases showing HbA2 of 1.4% and 1.5%.…”

“…Here, we highlight two individuals with extremely low HbA 2 levels (HbA 2 <1%) probably due to the presence of a δ−chain variant. There are hardly any studies in world literature, where in the HbA 2 value mentioned is substantially low .…”

The phenotypic and molecular diversity of hemoglobinopathies in India: A review of 15 years at a referral center

“…Associated δ gene mutations are now increasingly being reported in such heterozygotes leading to lowering of HbA 2 levels . In the UK population, investigating 127 δ alleles in patients with either low HbA 2 levels or a split HbA 2 peak picked up nine δ chain variants and two δ thalassemia mutations which included three novel variants . Thus delta genotyping is important particularly in couples where one of the partners is a classical β thalassemia carrier and the other has normal/borderline HbA 2 levels and they have come for testing during an ongoing pregnancy.…”

Haemoglobinopathies that occur with decreased HbA2levels: a gene mutation set involving the δ gene at a Spanish centre

“…HbB 2 is the most common δ chain variant and is observed in approximately 1% of African-Americans, but it has also been described in various African and Asian populations 17 18. Two cases were identified in this study: one of Indian origin and the other from Equatorial Guinea.…”