Hb A₂ Episkopi – a novel <i>δ</i>-globin chain variant [HBD:c.428C&gt;T] in a family of mixed Cypriot–Lebanese descent

<b>Objectives:</b> Thalassaemia is a potentially lethal inherited anaemia, caused by reduced or absent synthesis of globin chains. Measurement of the minor adult haemoglobin Hb A₂, combining α- with δ-globin, is critical for the routine diagnosis of carrier status for α- or β-thalassaemia. Here, we aim to characterize a novel δ-globin variant, Hb A₂ Episkopi, in a single family of mixed Lebanese and Cypriot ancestry with mild hypochromic anaemia and otherwise normal globin genotype, which also presents with a coincidental 0.78-Mb sequence duplication on chromosome 1 (1q44) and developmental abnormalities. <b>Methods</b>: Analyses included comprehensive haematological analyses, cation-exchange high-performance liquid chromatography (CE-HPLC), cellulose acetate electrophoresis (CAE), Sanger sequencing and structure-based stability predictions for Hb A₂ Episkopi. <b>Results</b>: The GCT &gt; GTT missense mutation, underlying Hb A₂ Episkopi, HBD:c.428C &gt; T, introduces a cd142 codon change in the mature protein, resulting in reduced normal Hb A₂ amounts and a novel, less abundant Hb A₂ variant (HGVS: HBD:p.A143V), detectable as a delayed peak by CE-HPLC. The latter was in line with structure-based stability predictions, which indicated that the substitution of a marginal, non-helical and non-interface residue, five amino acids from the δ-globin chain carboxy-terminus, was moderately destabilizing. <b>Discussion</b>: Detection of the new variant depends on the diagnostic set-up and had failed by CAE and on an independent CE-HPLC system, which, in unfavourable circumstances, may lead to misdiagnoses of β-thalassaemia as α-thalassaemia. Given the mixed background of the affected family, the ethnic origin of the mutation is unclear, and this study thus suggests awareness for possible detection of Hb A₂ Episkopi in both the Cypriot and the Lebanese populations.