title: Hb A2Episkopi - a novel δ-globin chain variant [HBD:c.428C>T] in a family of mixed Cypriot-Lebanese descent.
abstract: OBJECTIVE
  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 A2Episkopi, 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 A2Episkopi.
  
  
  RESULTS
  The GCT > GTT missense mutation, underlying Hb A2Episkopi, HBD:c.428C > T, introduces a cd142 codon change in the mature protein, resulting in reduced normal Hb A2amounts and a novel, less abundant Hb A2variant (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.
  
  
  CONCLUSIONS
  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 A2Episkopi in both the Cypriot and the Lebanese populations.
authors.affiliation: a Department of Molecular Genetics Thalassaemia , The Cyprus Institute of Neurology and Genetics, Cyprus & Cyprus School of Molecular Medicine , Nicosia , Cyprus.
authors.forename: Carsten W
authors.initials: CW
authors.lastname: Lederer
authors.affiliation: a Department of Molecular Genetics Thalassaemia , The Cyprus Institute of Neurology and Genetics, Cyprus & Cyprus School of Molecular Medicine , Nicosia , Cyprus.
authors.forename: Eleni
authors.initials: E
authors.lastname: Pavlou
authors.affiliation: b Clinical Genetics Department , The Cyprus Institute of Neurology and Genetics , Nicosia , Cyprus.
authors.forename: George A
authors.initials: GA
authors.lastname: Tanteles
authors.affiliation: c Department of Cytogenetics and Genomics , The Cyprus Institute of Neurology and Genetics, Cyprus & Cyprus School of Molecular Medicine , Nicosia , Cyprus.
authors.forename: Paola
authors.initials: P
authors.lastname: Evangelidou
authors.affiliation: c Department of Cytogenetics and Genomics , The Cyprus Institute of Neurology and Genetics, Cyprus & Cyprus School of Molecular Medicine , Nicosia , Cyprus.
authors.forename: Carolina
authors.initials: C
authors.lastname: Sismani
authors.affiliation: d Thalassaemia Centre, Ministry of Health , Cyprus.
authors.forename: Annita
authors.initials: A
authors.lastname: Kolnagou
authors.affiliation: d Thalassaemia Centre, Ministry of Health , Cyprus.
authors.forename: Maria
authors.initials: M
authors.lastname: Sitarou
authors.affiliation: d Thalassaemia Centre, Ministry of Health , Cyprus.
authors.forename: Soteroulla
authors.initials: S
authors.lastname: Christou
authors.affiliation: d Thalassaemia Centre, Ministry of Health , Cyprus.
authors.forename: Michael
authors.initials: M
authors.lastname: Hadjigavriel
authors.affiliation: a Department of Molecular Genetics Thalassaemia , The Cyprus Institute of Neurology and Genetics, Cyprus & Cyprus School of Molecular Medicine , Nicosia , Cyprus.
authors.forename: Marina
authors.initials: M
authors.lastname: Kleanthous
mesh_terms: D000328:Adult; D019943:Amino Acid Substitution; D000747:Anemia, Hypochromic / Q000235:genetics*; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D003535:Cyprus; D005190:Family; D005260:Female; D006455:Hemoglobins, Abnormal / Q000235:genetics*; D006801:Humans; D007861:Lebanon; D008297:Male; D020125:Mutation, Missense; D055546:delta-Globins / Q000235:genetics*
chemical_list: D006455:Hemoglobins, Abnormal; D055546:delta-Globins
keywords: Haemoglobin A2; cation-exchange HPLC; cellulose acetate electrophoresis; globin variant; thalassaemia