Occurrence of common and rare delta-globin gene defects in two multiethnic populations: thirteen new mutations and the significance of delta-globin gene defects in beta-thalassemia diagnostics

Genetics of disease, diagnosis and treatmen

Two New alpha 1-Globin Gene Point Mutations: Hb Nedlands (HBA1:c.86C > T) [alpha 28(B9)Ala -> Val] and Hb Queens Park (HBA1:c.98T > A) [alpha 32(B13)Met -> Lys]

We report two new point mutations of the alpha 1-globin gene found in a Greek and a Burmese patient, both living in Western Australia. The patients were initially selected for their microcytic hypochromic parameters as belonging to a group suspected for uncommon (deletion) defects. Gap-polymerase chain reaction (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA) technologies were applied, and in those cases not showing deletions, direct sequencing was performed. We have found 1) HBA1:c.86C > T, Hb Nedlands [alpha 28(B9)Ala -> Val] which, based on the red cell indices and phenotype prediction scores, is presumed to be clinically silent, and 2) HBA1:c.98T > A, Hb Queens Park [alpha 32(B13)Met -> Lys] which seems to be associated with a mild alpha-thalassemia (alpha-thal) phenotype. The phenotype/genotype correlation is briefly described

NEW AND KNOWN beta-THALASSEMIA DETERMINANTS MASKED BY KNOWN AND NEW delta GENE DEFECTS [Hb A(2)-Ramallah OR delta 6(A3)Glu -> Gln, GAG >> CAG]

We report a novel thalassemia determinant found in a Nigerian woman living in the Netherlands, resulting from a 2 bp insertion at codons 9/10 of the beta-globin gene (HBBc.28_29ins TA p. Ser10LeufsX11). The novel defect causes a frameshift with a consequent premature TGA stop codon, located at 11 positions downstream from the mutated codon. The phenotype was typical of a beta-thalassemia (beta-thal), trait with high RBC counts and compensated mild microcytic anemia. However, the Hb A(2) level was reported to be normal due to the presence of the common Hb A(2)' or Hb B2 [delta 16(A13)Gly-->Arg, GGC>CGC] variant that was not taken into account. We also present the opposite but comparable situation found in an a Palestinian man living in the USA. He was a carrier of a common beta-globin gene defect [codon 6 (-A), HBB:c.20delA] in combination with a novel delta-globin gene defect at codon 6 [HBD.c.19G>C, Glu6Gln] that we have named Hb A(2)-Ramallah. In both cases, the provisional diagnosis could have been compromised when based on the measurement of the normal Hb A(2) fraction only.Genetics of disease, diagnosis and treatmen

Hb Den Haag [beta 45(CD4)Phe -> Tyr]. A New Hemoglobin Variant Observed During Early Pregnancy Diagnostics

During a second pilot study, intended to explore the possibility of a country wide implementation of carrier diagnostics for hemoglobinopathies in The Netherlands, we observed a new abnormal hemoglobin (Hb) variant in three members of a family of Scandinavian origin living in the Dutch city of The Hague (Den Haag). The proband, a 34-year-old female presented with low Hb, packed cell volume (PCV) and red blood cell (RBC) values but was normocytic and normochromic. High performance liquid chromatography (HPLC) analysis revealed a partially separated fraction following Hb A. Molecular diagnostics disclosed a TTT > TAT transversion at HBB:c.137 causing a Phe -> Tyr single amino acid substitution at position 45 of the beta-globin gene. Previously described heterozygous mutations at the same position [Hb Cheverly (Phe -> Ser) and Hb Arta (Phe -> Cys)] were reported to be associated with mild chronic hemolysis similar to this case. We describe the hematological features of the six family members, the biochemical and molecular data and we discuss the possible consequences in combination with the common beta-thalassemia (beta-thal) trait.Genetics of disease, diagnosis and treatmen

Hb Den Haag [beta 45(CD4)Phe -> Tyr]. A New Hemoglobin Variant Observed During Early Pregnancy Diagnostics

During a second pilot study, intended to explore the possibility of a country wide implementation of carrier diagnostics for hemoglobinopathies in The Netherlands, we observed a new abnormal hemoglobin (Hb) variant in three members of a family of Scandinavian origin living in the Dutch city of The Hague (Den Haag). The proband, a 34-year-old female presented with low Hb, packed cell volume (PCV) and red blood cell (RBC) values but was normocytic and normochromic. High performance liquid chromatography (HPLC) analysis revealed a partially separated fraction following Hb A. Molecular diagnostics disclosed a TTT > TAT transversion at HBB:c.137 causing a Phe -> Tyr single amino acid substitution at position 45 of the beta-globin gene. Previously described heterozygous mutations at the same position [Hb Cheverly (Phe -> Ser) and Hb Arta (Phe -> Cys)] were reported to be associated with mild chronic hemolysis similar to this case. We describe the hematological features of the six family members, the biochemical and molecular data and we discuss the possible consequences in combination with the common beta-thalassemia (beta-thal) trait

Hb St. TRUIDEN [alpha 68(E17)Asn -> His] AND Hb WESTEINDE [alpha 125(H8)Leu -> Gln]: TWO NEW ABNORMALITIES OF THE alpha 2-GLOBIN GENE

We report two new abnormal hemoglobins (Hbs) caused by mutations on the alpha 2 gene. One resulted into an Asn-->His substitution at position 68, the other in a Leu-->Gln substitution at position 125. The first mutation was observed in a 61-year-old North European Belgian male during Hb A(1c) analysis and subsequently in other members of his family. The variant was expressed at a normal level and caused no hematological abnormalities in the carriers. The second was found in a 27-year-old Turkish male living in The Hague, The Netherlands, who presented with microcytic hypochromic parameters without iron deficiency and was also carrier of the common alpha 2 IVS-I (-5 nt) deletion.Genetics of disease, diagnosis and treatmen

alpha-thalassaemia masked by beta gene defects and a new polyadenylation site mutation on the alpha 2-globin gene

We report three examples of chronic anaemia involving complex combinations of alpha- and beta-globin gene defects. The first case had a potential Hb H disease caused by the classic SEA/RW deletions masked by Hb E [beta 26(B8)Glu -> 4Lys] in the homozygous state. The second had an unusual Hb H disease caused by compound heterozygosity for two different alpha 2 polyadenylation site mutations masked by a beta-thalassaemia heterozygosity. The third had an intermediate alpha-thalassaemia with considerable anaemia caused by an as yet unknown polyadenylation site (AATAAA>AATAAC) mutation in combination with a common RW deletion masked by a common Hb C [beta 6(A3)Glu -> Lys] heterozygosity. Diagnostic methods, genotype/phenotype correlations and the chance of overlooking these combinations during risk assessment in a multiethnic society are discussed.Genetics of disease, diagnosis and treatmen

Adult-onset beta-thalassaemia intermedia caused by a 5-Mb somatic clonal segmental deletion in haemopoietic stem cells involving the beta-globin locus

Genetics of disease, diagnosis and treatmen

Hb BOSKOOP [HBA2c.112C > T p.Pro38Ser]: A NEW alpha 2 CHAIN VARIANT OBSERVED IN A MORROCAN FAMILY

Genetics of disease, diagnosis and treatmen