Hb A2 Episkopi – a novel δ-globin chain variant [HBD:c.428C>T] in a family of mixed Cypriot–Lebanese descent
Carsten W. Lederer, Eleni Pavlou, George A. Tanteles, Paola Evangelidou, Carolina Sismani, Annita Kolnagou, Maria Sitarou, Soteroulla Christou, Michael Hadjigavriel, Marina Kleanthous
Marina Kleanthous (2016) : Hb A 2 Episkopi -a novel δ-globin chain variant [HBD:c.428C>T] in a family of mixed Cypriot-Lebanese descent, Hematology, ABSTRACT Objectives: Thalassaemia is a potentially lethal inherited anaemia, caused by reduced or absent synthesis of globin chains. Measurement of the minor adult haemoglobin Hb A 2 , combining αwith δ-globin, is critical for the routine diagnosis of carrier status for αor β-thalassaemia. Here, we aim to characterize a novel δ-globin variant, Hb A
... 2 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. Methods: Analyses included comprehensive haematological analyses, cation-exchange highperformance liquid chromatography (CE-HPLC), cellulose acetate electrophoresis (CAE), Sanger sequencing and structure-based stability predictions for Hb A 2 Episkopi. Results: The GCT > GTT missense mutation, underlying Hb A 2 Episkopi, HBD:c.428C > T, introduces a cd142 codon change in the mature protein, resulting in reduced normal Hb A 2 amounts and a novel, less abundant Hb A 2 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. Discussion: 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 A 2 Episkopi in both the Cypriot and the Lebanese populations.