Hannes Frischknecht

Neonatal cyanosis due to a new (G)γ-globin variant causing low oxygen affinity: Hb F-Sarajevo [(G)γ102(G4)Asn→Thr, AAC>ACC].

A baby girl, born at term, presented with severe cyanosis and received oxygen supplementation. Consecutive arterial blood gas analysis showed a pronounced right shift of the saturation curve, suggesting the presence of a hemoglobin (Hb) variant. A new Gγ-globin variant was detected, namely HBG2:c.308G, which we have named Hb F-Sarajevo, the city from where the baby’s parents originate. This A to C transversion exists in cis to the common AγT and the resulting mutant Hb molecule exhibits very low oxygen affinity and cooperativity. Its analogue in the β-globin gene is Hb Kansas [β102(G4)Asn→Thr, AAC>ACC].

Two New δ-Globin Mutations: Hb A2-Ninive [δ133(H11)Val → Ala] and A δ+-Thalassemia Mutation [− 31 (A → G)] in the Tata Box of the δ-Globin Gene

Two new δ-globin gene mutations have been detected: one leads to a fairly stable Hb A2 variant differing electrophoretically only minimally from normal Hb A2, and the second causes a δ+-thalassemia (thal) phenotype.

A New Highly Unstable α Chain Variant Causing α+‐Thalassemia: Hb Zurich Albisrieden [α59(E8)Gly→Arg (α2)]

A new α‐globin mutation causing persistent mild hypochromic microcytosis and erythrocytosis is described. Hb Zurich Albisrieden [α59(E8)Gly→Arg (α2)] is not detected at the protein level and leads to α+‐thalassemia (thal).

α-Thalassemia Caused by Two Novel Splice Mutations of the α2-Globin Gene: IVS-I-1 (G>A and G>T)

We report the identification of two different mutations involving the first nucleotide of intron 1 of the α2-globin gene: IVS-I-1 G→A and G→T. The available data indicated that both mutations reduce the efficiency of proper mRNA splicing, resulting in α+-thalassemia (α+-thal).

Comparison of two known chromosomal rearrangements in the δβ-globin complex with identical DNA breakpoints but causing different Hb A(2) levels.

We report three cases with very heterogeneous Hb A2 levels caused by known chromosomal rearrangements in the β-globin locus. These rearrangements had their breakpoints at the same region in the δ gene, leading either to the Senegalese δ0β+-thalassemia (δ0β+-thal) deletion or to an insertion of a δ gene, known as Anti-Lepore. One patient showed, apart from drastically increased Hb A2 values of 17.0%, inconspicuous hematological values. He had an Anti-Lepore mutation with three copies of the δ gene, thus explaining the high Hb A2 level. Two other patients had Hb A2 levels in the lower borderline range and increased Hb F levels. Molecular analysis showed the Senegalese δ0β+-thal deletion. One of them presented with an additional mild β-thal mutation leading to β-thal intermedia. These cases illustrate that different gene rearrangements with the same breakpoints in the δ gene can lead to different levels of Hb A2 depending on the remaining number of δ genes.

A New Electrophoretically Silent β-Globin Variant in a Portuguese Family: Hb Viseu [β57(E1)Asn→Thr]

A new electrophoretically and clinically silent β-globin variant has been detected by DNA analysis. The mutation was demonstrated at the protein level by reversed phase high performance liquid chromatography (HPLC) and electrospray ionization-mass spectrometry (ESI-MS).

Characterization of three novel delta chain hemoglobin variants and two delta-thalassemia alleles.

We report the characterization of five novel δ-globin gene mutations detected during routine screening for thalassemia. Three missense mutations were identified, resulting in the following δ chain hemoglobin (Hb) variants: Hb A2-Acacias [δ4 (ACT>AGT), Thr→Ser, HBD c.14C>G], Hb A2-Toronto [δ74 (GGC>GAC), Gly→Asp, HBD c.224G>A], and Hb A2-Calgary [δ99 (GAT>GGT), Asp→Gly, HBD c.299A>G]. Two other mutations most likely result in δ0-thalassemia (δ0-thal). One mutation altered the translation initiation codon from ATG to ATA (HBD c.3G>A), and another changed the canonical splice donor sequence of IVS-II from GT to AT (HBD C.315+1G>A).

Three New β-Thalassemia Mutations with Varying Degrees of Severity

We report the identification of three, new β-thalassemia (β-thal) mutations with varying degrees of severity. The most severe mutation, a frameshift mutation in exon 3 of the β-globin gene [codon 120 (−A)], was associated with a dominant β-thal phenotype. A second frameshift mutation, codon 50 (−T), resulted in a phenotype of typical high Hb A2 β-thal trait. The mildest mutation was IVS-II-2 (T > C), which changes the splice donor sequence of IVS-II from GT to GC. This transition mutation resulted in a slight reduction in β-globin gene expression and could be considered a mild β+-thal allele.

THE Hb S/beta+ -thalassemia phenotype demonstrates that the IVS-I (-2) (A>C) mutation is a mild beta-thalassemia allele

We report a family in which two siblings are compound heterozygotes for Hb S [β6(A3)Glu→Val] and a rare β-globin mutation [IVS-I (−2) (A>C)]. Both patients had significant levels of Hb A, indicating that the IVS-I (−2) mutation is a relatively mild β+-thalassemia (β+-thal) allele. This mutation, in compound heterozygosity with Hb S, does not necessarily lead to a mild clinical course.

Compound Heterozygosity for Hb S [β6(A3)Glu→Val, GAG→GTG] and a New Thalassemic Mutation [β132(H10)Lys→Term, AAA→TAA] Detected in a Family from West Africa

We describe a Hb S/β-thalassemia (β-thal) mutation involving an A→T transition at codon 132 of the β-globin gene. The mutation, in the heterozygous state, unlike several other mutations in exon 3, shows no signs of dominant thalassemia but those of a typical β0 carrier. Compound heterozygosity with Hb S [β6(A3)Glu→Val, GAG→GTG] showed a severe clinical picture.