title: Ten Years of Routine α- and β-Globin Gene Sequencing in UK Hemoglobinopathy Referrals Reveals 60 Novel Mutations.
abstract: We review and report here the genotypes and phenotypes of 60 novel thalassemia and abnormal hemoglobin (Hb) mutations discovered following the adoption of routine DNA sequencing of both α- and β-globin genes for all UK hemoglobinopathy samples referred for molecular investigation. This screening strategy over the last 10 years has revealed a total of 11 new β chain variants, 15 α chain variants, 19 β-thalassemia (β-thal) mutations and 15 α(+)-thalassemia (α(+)-thal) mutations. The large number of new thalassemia alleles confirms the wide racial heterogeneity of mutations in the UK immigrant population. Eleven of the new variants ran with Hb A on high performance liquid chromatography (HPLC), demonstrating the value of routine sequencing of both α- and β-globin genes for all hemoglobinopathy investigations. The new β chain variants are: Hb Bury [β22(B4)Glu  →  Asp (HBB: c.69A > T)], Hb Fulwood [β35(C1)Tyr → His (HBB: c.106T > C)], Hb Little Venice [β42(CD1)Phe → Cys (HBB: c.128T > G)], Hb Cork [β57(E1)Asn → Ser (HBB: c.173A > G), Hb Basingstoke [β118(GH1)Phe → Ser (HBB: c.356T > C)], Hb Howden [β20(B2)Val → Ala (HBB: c.62T > C)], Hb Wilton [β41(C7)Phe → Leu (HBB: c.126C > A)], Hb Belsize Park [β120(GH3)Lys → Asn (HBB: c.363A > T)], Hb Hampstead Heath [β2(NA2)His → Gln;β26(B8)Glu → Lys (HBB: c.[6C > G;79G > A])], Hb Grantham [β85(F1)Phe → Cys (HBB: c.257T > G)] and Hb Calgary [β64(E8)Gly → Val (HBB: c.194G > T). The new α chain variants are: Hb Edinburgh [α70(E19)Val → Gly (HBA2: c.212T > G)], Hb Walsgrave [α116(GH4)Glu → Val (HBA2: c.350A > T)], Hb Wexham [α117(GH5) and 118(H1) insertion Ser (HBA1: c.354-355insTCA)], Hb Coombe Park [α127(H10)Lys → Glu (HBA2: c.382A > G)], Hb Oxford [α17(A15)Val → Asp (HBA2: c.53T > A)], Hb Bridlington [α32(B13)Met → Thr (HBA1: c.98T > C), Hb Wolverhampton [α81(F2)Ser → Tyr (HBA2: c.9245C > A)], Hb Little Waltham [α13(A11)Ala → Asp (HBA2: c.41C > A)], Hb Derby [α61(E10)Lys → Arg (HBA1: c.185A > G)], Hb Uttoxter [α74(EF3)Tyr → Asp (HBA2: c.223G > T)], Hb Harehills [α124(H7)Ser → Cys (HBA1: c.374C > G)], Hb Hekinan II [α27(B8)Glu → Asp (HBA1: c.84G > T)], Hb Manitoba IV [α102(G9)Ser → Arg (HBA1: c.307A > C), Hb Witham [α139(HC1)Lys → Arg (HBA2: c.419A > G) and Hb Farnborough [α9(A7)Asn → Asp (HBA1: c.28A > G). In addition, 10 more paralogous α-globin chain variants have been discovered. The novel β-thal alleles are: HBB: c.-138C > G, HBB: c.-121C > T, HBB: c.-80T > G, HBB: c.18_19delTG, HBB: c.219_220insT, HBB: c.315 + 2_315 + 13delTGAGTCTATGGG, HBB: c.316-70C > G, HBB: c.345_346insTGTGCTG, HBB: c.354delC, HBB: c.376-381delCCAGTG, HBB: c.393T > A, HBB: c.394_395insA, HBB: c.375_376insA, HBB: c.*+95_*+107delTGGATTCTinsC, HBB: c.* + 111_*+112delAA, HBB: c.*+112A > T, HBB: c.394C > T, HBB: c.271delG and HBB: c.316-3C > T. The novel α (+ )-thal alleles are: HBA1: c.95+1G > C, HBA1: c.315C > G [Hb Donnington, α104(G11)Cys → Trp], HBA1: c.327delC, HBA1: c.333_345del, HBA1: c.*+96G > A, HBA2: c.2T > G, HBA2: c.112delC, HBA2: c.143delA, HBA2: c.143_146delACCT, HBA2: c.156_157insG, HBA2: c.220_223delGTGG, HBA2: c.305T > C [Hb Bishopstown, α101(G8)Leu → His], HBA2: c.169_170delAA, HBA2: c.1A > T and HBA2: c.-3delA.
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Shirley J
authors.initials: SJ
authors.lastname: Henderson
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Adele T
authors.initials: AT
authors.lastname: Timbs
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Janice
authors.initials: J
authors.lastname: McCarthy
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Gallienne
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Melanie
authors.initials: M
authors.lastname: Proven
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Rugless
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Herminio
authors.initials: H
authors.lastname: Lopez
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Eglinton
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Dariusz
authors.initials: D
authors.lastname: Dziedzic
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Beardsall
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: Mohamed S M
authors.initials: MS
authors.lastname: Khalil
authors.affiliation: a National Haemoglobinopathy Reference Laboratory, Biomedical Research Centre Molecular Diagnostic Laboratory, Haematology Department, John Radcliffe Hospital , Oxford , Oxfordshire , UK.
authors.forename: John M
authors.initials: JM
authors.lastname: Old
mesh_terms: D000483:Alleles; D019943:Amino Acid Substitution; D056726:Genetic Association Studies; D005838:Genotype; D006453:Hemoglobinopathies / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D009154:Mutation; D010641:Phenotype; D012017:Referral and Consultation; D017422:Sequence Analysis, DNA; D006113:United Kingdom / Q000453:epidemiology; D055542:alpha-Globins / Q000235:genetics*; D017085:alpha-Thalassemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D055544:beta-Globins / Q000235:genetics*; D017086:beta-Thalassemia / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics
chemical_list: D055542:alpha-Globins; D055544:beta-Globins
keywords: hemoglobin (Hb) variants; novel mutations; sequencing; α-Thalassemia (α-thal); β-thalassemia (β-thal)