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Hb A Episkopi - a novel δ-globin chain variant [HBD:c.428C>T] in a family of mixed Cypriot-Lebanese descent.

TitleHb A Episkopi - a novel δ-globin chain variant [HBD:c.428C>T] in a family of mixed Cypriot-Lebanese descent.
Publication TypeJournal Article
Year of Publication2017
AuthorsLederer, C. W., Pavlou E., Tanteles G. A., Evangelidou P., Sismani C., Kolnagou A., Sitarou M., Christou S., Hadjigavriel M., & Kleanthous M.
Date Published2017 Jun
KeywordsAdult, Amino Acid Substitution, Anemia, Hypochromic, Chromosomes, Human, Pair 1, Cyprus, delta-Globins, Family, Female, Hemoglobins, Abnormal, Humans, Lebanon, Male, Mutation, Missense

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, 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 A 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 high-performance liquid chromatography (CE-HPLC), cellulose acetate electrophoresis (CAE), Sanger sequencing and structure-based stability predictions for Hb A Episkopi.RESULTS: The GCT > GTT missense mutation, underlying Hb A Episkopi, HBD:c.428C > T, introduces a cd142 codon change in the mature protein, resulting in reduced normal Hb A amounts and a novel, less abundant Hb A 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 Episkopi in both the Cypriot and the Lebanese populations.

Alternate JournalHematology
PubMed ID28007020


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