title: The genetic basis of asymptomatic codon 8 frame-shift (HBB:c25_26delAA) β(0) -thalassaemia homozygotes.
abstract: Two 21-year old dizygotic twin men of Iraqi descent were homozygous for HBB codon 8, deletion of two nucleotides (-AA) frame-shift β(0) -thalassaemia mutation (FSC8; HBB:c25_26delAA). Both were clinically well, had splenomegaly, and were never transfused. They had mild microcytic anaemia (Hb 120-130 g/l) and 98% of their haemoglobin was fetal haemoglobin (HbF). Both were carriers of Hph α-thalassaemia mutation. On the three major HbF quantitative trait loci (QTL), the twins were homozygous for G>A HBG2 Xmn1 site at single nucleotide polymorphism (SNP) rs7482144, homozygous for 3-bp deletion HBS1L-MYB intergenic polymorphism (HMIP) at rs66650371, and heterozygous for the A>C BCL11A intron 2 polymorphism at rs766432. These findings were compared with those found in 22 other FSC8 homozygote patients: four presented with thalassaemia intermedia phenotype, and 18 were transfusion dependent. The inheritance of homozygosity for HMIP 3-bp deletion at rs66650371 and heterozygosity for Hph α-thalassaemia mutation was found in the twins and not found in any of the other 22 patients. Further studies are needed to uncover likely additional genetic variants that could contribute to the exceptionally high HbF levels and mild phenotype in these twins.
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Jiang
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Hong-Yuan
authors.initials: HY
authors.lastname: Luo
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Shengwen
authors.initials: S
authors.lastname: Huang
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: Farrell
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Lance
authors.initials: L
authors.lastname: Davis
authors.affiliation: Center for Biomedical Mass Spectrometry, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Théberge
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Benson
authors.affiliation: Department of Paediatrics and Thalassaemia Centre, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Suchada
authors.initials: S
authors.lastname: Riolueang
authors.affiliation: Department of Paediatrics and Thalassaemia Centre, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
authors.forename: Vip
authors.initials: V
authors.lastname: Viprakasit
authors.affiliation: Faculty of Medical Sciences, Scientific Research Centre, University of Duhok, Duhok, Iraq.
authors.forename: Nasir A S
authors.initials: NA
authors.lastname: Al-Allawi
authors.affiliation: Division of Paediatric Haematology, Department of Paediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Sule
authors.initials: S
authors.lastname: Ünal
authors.affiliation: Division of Paediatric Haematology, Department of Paediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Fatma
authors.initials: F
authors.lastname: Gümrük
authors.affiliation: Department of Paediatric Molecular Genetics, Medical School, Ankara University, Ankara, Turkey.
authors.forename: Nejat
authors.initials: N
authors.lastname: Akar
authors.affiliation: Department of Molecular Biology and Genetics, Neurodegeneration Research Laboratory, Boğaziçi University, Istanbul, Turkey.
authors.forename: A Nazli
authors.initials: AN
authors.lastname: Başak
authors.affiliation: Laboratório de Genética Molecular, Faculdade de Ciências e Tecnologia, Universidade Nova de Lisboa, Caparica, Portugal.
authors.forename: Leonor
authors.initials: L
authors.lastname: Osorio
authors.affiliation: Laboratoire de génétique moléculaire, Centre de référence Thalassémies, APHM, Hôpital d'enfants de la Timone, Marseille, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Badens
authors.affiliation: Departement de genetique, GHU Henri Mondor, Créteil, France.
authors.forename: Serge
authors.initials: S
authors.lastname: Pissard
authors.affiliation: Laboratoire de Biochimie et de Biologie Moléculaire, Hôpital Edouard Herriot, Unité de Pathologie Moléculaire du Globule Rouge, Hospices Civils & Université Claude Bernard-Lyon 1, Lyon, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Joly
authors.affiliation: Department of Pediatrics, University of Michigan School of Medicine, Ann Arbor, MI, USA.
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Campbell
authors.affiliation: Departments of Pediatrics, Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Gallagher
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: Martin H
authors.initials: MH
authors.lastname: Steinberg
authors.affiliation: Departments of Medicine, Genetics, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Bernard G
authors.initials: BG
authors.lastname: Forget
authors.affiliation: Departments of Medicine, Pathology and Laboratory Medicine, Boston University School of Medicine, Boston, MA, USA.
authors.forename: David H K
authors.initials: DH
authors.lastname: Chui
mesh_terms: D002352:Carrier Proteins / Q000235:genetics; D004200:Diseases in Twins / Q000235:genetics*; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis / Q000235:genetics; D016368:Frameshift Mutation; D020570:Genes, myb; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012097:Repressor Proteins; D014429:Twins, Dizygotic / Q000235:genetics; D055815:Young Adult; D017086:beta-Thalassemia / Q000235:genetics*
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D005319:Fetal Hemoglobin
keywords: HBS1L-MYB intergenic polymorphism; HbF quantitative trait loci; fetal haemoglobin; α-Thalassaemia; β0-Thalassaemia