NOVEL β-THALASSEMIA MUTATION IN A β-THALASSEMIA INTERMEDIA PATIENT [POLY A (AATAAA →GATAAA)]

Hb H disease is rarely seen in individuals of African descent although α-thalassemia (α-thal) is common in this population. Usually α-thal is due either to heterozygosity or homozygosity for the ?α^3.7 deletion in this population. We report Hb H disease that is caused by a frameshift mutation on one ?α^3.7 allele in two unrelated individuals homozygous for the ?α^3.7 deletion. These two cases highlight the importance of further investigation by direct sequencing of the –α^3.7 allele when the thalassemic phenotype does not correlate with the genotype obtained by initial molecular testing.     

IDENTIFICATION OF TWO NEW β-THALASSEMIA SPLICE MUTATIONS: IVS-I-1 (G → C) AND IVS-I (−2) (A → C)

Hb Constant Spring [Hb CS; α142, Term→Gln (TAA>CAA in α2)] is a nondeletional α-thalassemia (α-thal) defect difficult to detect on conventional electrophoresis because of its small amount in heterozygotes. We have found that individuals with an Hb CS trait could efficiently be detected using the Sebia capillarys 2 system. In the present study, we have confirmed this method in a cohort of 23,842 individuals from Guangdong Province (South China). Hb CS was detected in 71 (0.3%) of the cases. The levels of Hb CS in heterozygotes ranged from 0.1–1.0% with an average of 0.6%. We propose the reported 0.3% as a realistic figure for the prevalence of Hb CS in South China.     

A novel compound heterozygosity in Southern China: IVS-II-5 (G > C) and IVS-II-672 (A > C)

β-Thalassemia (β-thal) is a common hereditary anemia due to decreased or absent synthesis of the β-globin chains. Here, we report a patient found to be a novel compound heterozygote for the rare IVS-II-5 (G?>?C) (NG_000007.3: g.71044G?>?C) and IVS-II-672 (A?>?C) (NG_000007.3: g.71711A?>?C) mutations, which may be silent mutations that are associated with consistent residual output of β chains, normal red blood cell (RBC) indices and normal or borderline Hb A₂ levels.     

The IVS-II-1 (G → A) β0-Thalassemia Mutation in CIS with Hb A2-Troodos [δ116(G18)Arg → Cys (CGC → TGC)] Causes a Complex Prenatal Diagnosis in an Iranian Family

The β-thalassemia (thal) minor phenotypes with normal Hb A₂ levels and decreased MCV and MCH values are relatively rare β-thal traits. Here, we describe a family with normal Hb A₂ and decreased MCV and MCH levels. Amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) revealed the IVS-II-1 (G→A) mutation in the β-globin gene of the proband and her father. Direct sequencing of the δ-globin gene of the proband and her father also revealed a previously reported variant called Hb A₂-Troodos [δ116(G18)Arg→Cys] [in cis with the IVS-II-1 (G→A) β⁰-thal mutation]. This is the first case report of Hb A₂-Troodos in association with the β⁰ IVS-II-1 mutation. Reduced Hb A₂ expression by a concomitant Hb A₂ β-thal in cis or trans, may cause problems in carrier diagnostics, and eventually in genetic counseling and prenatal diagnosis when insufficient molecular analyses are performed.     

Hb G-MAKASSAR [β6(A3)Glu→Ala; CODON 6 (G A G→G C G)]: MOLECULAR CHARACTERIZATION,CLINICAL, AND HEMATOLOGICAL EFFECTS

We report a Thai family in which five members are Hb G-Makassar heterozygotes and one member is, in addition, a heterozygote for β⁰-thalassemia (IVS-I-1, G→T). We confirm that the previously presumed mutation at codon 6 of the β-globin gene is G A G→G C G. Hb G-Makassar heterozygotes are asymptomatic and hematologically normal. The Hb G-Makassar/β⁰-thalassemia compound heterozygote has features of thalassemia minor. A simple and rapid polymerase chain reaction-restriction fragment length polymorphism for the detection of Hb G-Makassar is described.     

THE β+-IVS-I-6 (T → C) MUTATION ACCOUNTS FOR HALF OF THE THALASSEMIA CHROMOSOMES IN THE PALESTINIAN POPULATIONS OF THE MOUNTAIN REGIONS

A study of the spectrum of β-thalassemia mutations in the southern part of the West Bank of the Palestinian Authority revealed the presence of 10 different β-globin mutations. The study included 41 patients and 54 carriers of β-thalassemia and sickle cell anemia. The spectrum of mutations observed was typically Mediterranean. However, their relative frequencies was unique. The predominant allele was IVS-I-6 (T → C), with an exceptionally high frequency of 48.5% for this mutation. The homozygous IVS-I-6 patients had widely variable clinical presentations, from typical transfusion-dependent thalassemia major to non-transfusion-dependent thalassemia intermedia phenotype. Since it is so widespread in these West Bank populations, the IVS-I-6 mutation may date back to ancient times. The nonsense mutation at codon 37 (G → A) was found at a relatively high frequency of 11.3%, supporting the hypothesis that it originated in this region. The other mutations, at decreasing frequencies ranging from 9.5–1.5%, were: IVS-I-110 (G → A), frameshift codon 5 (?CT), IVS-I-1 (G → A), IVS-II-1 (G → A), Hb S [β6(A3)Glu → Val], frameshift codons 8/9 (+G), codon 39 (C → T), and ?30 (T → A). Our findings will improve health care for the Palestinian population, and also has implications for the study of the origin and spread of thalassemia in the Middle East.     

IDENTIFICATION OF Hb VILLEJUIF [β123(H1)Thr→Ile] IN SOUTHERN ITALY

Hb Villejuif [β123(H1)Thr→Ile] is a silent and asymptomatic variant described in 1989 in an 87-year-old woman of French origin suffering from coincidental polycythemia vera. This paper reports the second observation of Hb Villejuif in three related subjects from Montesarchio, Southern Italy. All routine techniques for hemoglobin analysis yielded normal results with the exception of a slight increase in the Hb A₂ value. The occurrence of a variant β-globin was rapidly assessed by liquid chromatography mass spectrometric analysis and the abnormal chain purified by high performance liquid chromatography. The amino acid replacement Thr→Ile at β123 was determined by tandem electrospray mass spectrometric analysis of the tryptic digest of the variant β chain. The corresponding DNA mutation was established as C→T at the second position of codon 123 (ACC → ATC) by polymerase chain reaction amplification techniques.     

A KOREAN FAMILY WITH A DOMINANTLY INHERITED β-THALASSEMIA DUE TO Hb DURHAM-N.C./BRESCIA [β114(G16)Leu→Pro]

We describe the molecular and the hematological characteristics of a Korean family with a dominantly inherited β-thalassemia. Carriers were characterized by moderate anemia, hypochromia, microcytosis, elevated Hb A₂ and Hb F levels, and splenomegaly. DNA analysis revealed a CTG (Leu) to CCG (Pro) substitution at codon 114 of the β-globin gene, that leads to a highly unstable hemoglobin variant, Hb Durham-N.C./Brescia, and this was linked to the β haplotype V, [+????+?], and framework 2. RNA analysis showed that the proband had comparable levels of mutant and normal β-mRNA. Translation of the mutant mRNA would give rise to non-functional hyperunstable β-globin chains, and their degradation would, by placing an additional burden on the proteolytic process of the red blood cell precursors, result in a more severe phenotype.     

COMPOUND HETEROZYGOSITY FOR Hb SPANISH TOWN [α27(B8)Glu→Val], Hb S [β6(A3)Glu→Val] AND THE −α(3.7 kb) THALASSEMIA DELETION

Hemoglobin Summer Hill was found in a Lebanese woman living in Sydney, New South Wales, Australia. Its structure was shown to be β52(D3) Asp→His. It is a stable hemoglobin which has no significant change in oxygen affinity or heme-cooperativity.     

Hb L'Aquila [β106(G8)Leu→Val,CTG→GTG]: A Novel Thalassemic Hemoglobin Variant

A new β-globin variant at codon 106 (CTG→GTG), and which we named Hb L'Aquila [β106(G8)Leu→Val], was detected by DNA analysis. The proband and her father presented with the features of a mild β⁺-thalassemia (thal), confirmed by their α/β-globin chain biosynthesis ratios.     

Hemoglobin Sunshine Seth - α2(94 (G1) Asp→His)β2

Hemoglobin Sunshine Seth in which a histidyl is substituted for an aspartyl residue at position 94 of the α chain was detected at birth in a Caucasian male infant during cord blood screening and is present also in the mother and a male sibling. Although the substitution is in the α₁β₂ contact, it is without obvious deleterious effect on the hematological parameters or the health of the affected individuals.     

β-THALASSEMIA IN TURKEY: A REVIEW OF THE CLINICAL,EPIDEMIOLOGICAL, MOLECULAR,AND EVOLUTIONARY ASPECTS

Hb Andrew-Minneapolis is a comparatively rarely encountered abnormal hemoglobin (Hb). It was first discovered by Zak et al (1). In this report, we present a case of the same abnormal Hb in a Bulgarian family from the Shumen district. This is the first observation of this variant in Bulgaria.     

Hb SIAM [α15(A13)Gly → Arg (α1) (GGT → CGT)] IS A TYPICAL α CHAIN HEMOGLOBINOPATHY WITHOUT AN α-THALASSEMIC EFFECT

A Thai family with a complex thalassemia syndrome caused by α- and β-globin defects is described. The proband was a 14-year-old boy who had chronic hypochromic microcytic anemia. Hemoglobin (Hb) and DNA analyses demonstrated that he carried Hb Beijing [α16(A14)Lys→Asn], Hb E [β26(B8)Glu→Lys] and α-thalassemia-1 (α-thal-1). Interaction of the α^Beijing with the β^E globin chains in the proband leads to a new Hb variant, namely Hb EBeijing with different characteristics to both Hb E and Hb Beijing. Family studies showed that his father carried Hb Beijing and Hb E, whereas his mother was a simple α-thal-1 carrier. The genotype-phenotype relationship observed in this Thai family with complex hemoglobinopathies is presented and a simple DNA assay based on allele specific polymerase chain reaction (ASPCR) for detection of Hb Beijing is described.     

Mild β+-Thalassemia Associated With Two Linked Sequence Variants: IVS-II-839 (T>C) and IVS-II-844 (C>A)

We report four unrelated families with a mild β⁺-thalassemia (β⁺-thal) allele consisting of two sequence variants at the 3' end of IVS-II: IVS-II-839 (T>C) (HBB: c.316-12T>C) and IVS-II-844 (C>A) (HBB: c.316-7C>A). These sequence variants alter the conserved polypyrimidine tract of the consensus splice acceptor sequence (Y₁₁NYAG/G), which could reduce splicing efficiency. This may represent a common, yet under-diagnosed β⁺-thal allele in African populations.     

Hb S-San Martin: A New Sickling Hemoglobin With Two Amino Acid Substitutions [β6(A3)Glu→Val;β105(G7)Leu→Pro] In An Argentinean Family

A new sickling hemoglobin (Hb) detected in an Argentinean family from San Martín, Buenos Aires, Argentina, is hereby described. Two mutations were identified on the same β-globin gene resulting in a new variant named Hb San Martin. One mutation was found on exon 1, corresponding to Hb S [β6Glu→Val, GAG>GTG] and the second one on exon 3 at β105(G7)Leu→Pro, CTC>CCC. The replacement of leucine by proline will likely impair the structure breaking helix G and causing instability of the molecule and the clinical manifestations typical of unstable Hbs. The mutation at β105 seemed to be a de novo one in our patients, arising on a previously mutated gene, due to the fact that Hb S is the most frequent structural variant.