Compound Heterozygosity for Hb Adana (HBA2: c.179G>A) and the –α3.7/αα Thalassemia Deletion in Greece: Clinical Phenotype and Genetic Counseling

Hb Adana (HBA2: c.179G>A) is found worldwide but is extremely rare and carriers are asymptomatic, with red cell indices similar to α⁺-thalassemia (α⁺-thal) carriers. First line screening tests are unable to detect the unstable hemoglobin (Hb). Coinheritance with the α-thal (–α^3.7) deletion is herein presented and the challenges involving genetic counseling of couples carrying the mutations are discussed.     

Coinheritance of Hb Bristol-Alesha [β67(E11)Val→Met; HBB: c.202G>A] and the α212 Patchwork Allele in a Brazilian Child with Severe Congenital Hemolytic Anemia

Hb Bristol-Alesha [HBB: c.202G>A; β 67 Val>Met] is a rare structural variant of hemoglobin (Hb) resulting from a GTG>ATG substitution at codon 67 of the β-globin gene that leads to the replacement of valine by methionine in the corresponding position of the β-globin chain. The methionine residue is subsequently modified to aspartic acid [β67(E11)Val-Met→Asp], possibly by autoxidation mechanisms. This substitution prevents normal non-polar binding of Val67 to the heme group, resulting in molecular instability and severe hemolysis. We identified Hb Bristol-Alesha (in the heterozygous state), as the cause of severe congenital hemolytic anemia in an 11-month-old girl of mixed (native Indian and European) ethnic origin from the Midwestern region of Brazil, whose parents were clinically and hematologically normal. The mutation on the β-globin gene was found to have been coinherited with the α212 patchwork allele.     

Hb Kalavasos [HBA2: c.275T > A; p.Leu92His]: a Novel α Chain Hemoglobin Variant

We present a case of a novel pathogenic variant, Hb Kalavasos [α91(FG3)Leu→His (α2); HBA2: c.275T?>?A; p.Leu92His (NM_000517.4)]; this codon was previously numbered 91 on the α2-globin gene that was discovered following routine Hb A_1c testing on a 65-year-old female of Cypriot origin. The band, seen by high performance liquid chromatography (HPLC) but not capillary zone electrophoresis (CZE), was confirmed as a hitherto undescribed a chain variant, that we have named Hb Kalavasos for the Cypriot village of family origin of the proband.     

Role of polymorphic sequences 5′ to the Gγ gene and 5′ to the β gene on the homozygous β thalassemic phenotype

Sixty‐seven homozygous male and female thalassemic patients with different phenotypes, aged between 8 and 33 years, were divided into three groups, according to the severity of their β‐thalassemia (thal) mutations. We investigated whether some co‐inherited genetic factors could influence the phenotype. Patients with milder β‐thal defects, homozygotes or compound heterozygotes for the IVS‐I‐6 (T→C) or ?87 (C→G) mutations had a milder disease. In addition, determination of the co‐inheritance of the ?158 (C→T) ^Gγ polymorphism and the (AT)₉T₅ repeat motif in the region ?540 to ?525, 5′ to the β‐globin gene, showed that in some patients with severe or mild/severe β‐thal mutations, linked to haplotype III, there was higher Hb F expression. We conclude that in homozygous β‐thal patients, the severity of the mutations is the most important factor influencing the phenotype, but some polymorphisms such as the ?158 (C→T) ^Gγ and (AT)₉T₅ repeat motif, increasing the Hb F expression and ameliorate the clinical course of the disease.     

Mutation Spectrum of β-Thalassemia and Other Hemoglobinopathies in Chittagong,Southeast Bangladesh

Abstract

Thalassemia is one of the most common autosomal recessive blood disorders in the world. It shows a variety of clinical expression, starting from asymptomatic to severe blood transfusion dependence. More than 500 alleles have been characterized in or around the β-globin region. Moreover, most geographical regions have their own characteristics, frequency and availability of these alleles, predominantly circulating within the communities present in that particular region. In this study, we explored the spectrum of β-thalassemia (β-thal) alleles present in Chittagong, Southeast Bangladesh. This study comprises β-thal and Hb E (HBB: c.79?G?>?A) patients from in and around the area of Chittagong. Not only exploring the complete β-globin mutation spectrum of the area, but we also tried to look at the origin of the mutated alleles. The β-thal mutations of Bangladesh show a relatively wide spectrum of alleles, which further demonstrates the heterogeneity of the disease in this country. Although our study showed that the majority of the mutations have their origin in neighboring countries such as India, countries of Southeast Asia, Pakistan, etc., some unusual alleles do not originate in neighboring countries and put a little more diversity in the overall spectrum of β-thal-specific alleles. Overall, this study demonstrates the mutation spectrum related to β-thal in Chittagong, Southeast Bangladesh.     

Hb Calais [β76(E20)Ala→Pro]: A Family Study of a Variant With Decreased Oxygen Affinity

Secondary to the detection of a chronic anemia with a slightly increased Hb F level in a 7‐year-old boy carrying a hemoglobin (Hb) variant, we investigated the members of his family and found that they were related to the original case of Hb Calais. In the present study, we report the clinical and biological impacts of this Hb variant in various members of three generations of this family.     

Hb F-Columbus-Ga or a2 Gγ2 94(FGJ)Asp→Asn

A new γ chain variant with an electrophoretic mobility at pH 8.1 between those of Hb S and Hb C was isolated and quantitated by DEAE-cellulose chromatography. It was readily identified with the use of various micro-chromatographic and sequencing procedures as α²Gγ² 94(FGl)Asp→Asn. The hemoglobin was named Hb F-Columbus-Ga. The quantity of this GY chain variant (as % total γ chain) was about 39% and the percentages of the normal Gγ and AγI chains were 37% and 24%, respectively.     

Genetics of Hb F/F Cell Variance in Adults and Heterocellular Hereditary Persistence of Fetal Hemoglobin

Hb F and F cell values in normal adults vary considerably with a continuous distribution that is substantially skewed to the right implicating a polygenic influence. The high values of Hb F and F cells are transmitted in the condition referred to as heterocellular hereditary persistence fetal hemoglobin which should be regarded as a multifactorial quantitative trait, quite distinct from the classical pancellular hereditary persistence of fetal hemoglobins. Several factors have been shown to influence F cell/Hb F levels in normal adults including age, gender, genetic determinants linked and unlinked to the β-globin locus on chromosome 11p. Two trans-acting quantitative trait loci for F cell variance have been mapped, one on 6q and the other on Xp, with at least one other implicated. As an initial step towards hunting for the other quantitative trait loci we have carried out a preliminary analysis of F cell variance in 182 pairs of monozygotic and 373 pairs of dizygotic twins. The correlation coefficient of F cell variance in monozygotic twins was 0.89, while that in the dizygotic twins was 0.51. Overwhelming evidence for a strong genetic component in the control of Hb F/F cell levels is provided by a heritability of 0.87. However, the role and extent of contribution from the quantitative trait loci on 6q and Xp are still not known.     

Hb Grand Junction (HBB: c.348_349delinsG; p.His117IlefsX42): A New Hyperunstable Hemoglobin Variant

Hyperunstable hemoglobinopathy (HUH) [dominantly inherited β-thalassemia (β-thal)] is a relatively rare form of congenital hemolytic anemia in which mutations occur in the genes encoding for α and β chains, or both chains of the hemoglobin (Hb) molecule. We describe two Hispanic adolescents with a new unstable Hb variant (HBB: c.348_349delinsG; p.His117IlefsX42), resulting from a frameshift mutation at codons 115/116 of the β-globin gene. Both patients also have a 3.7?kb deletion on one α gene, leading to a decreased imbalance between α and β chain formation, and subsequently a milder phenotype than that seen in other hyperunstable Hb variants.     

Hemoglobins With High Oxygen Affinity Leading to Erythrocytosis. New Variants and New Concepts

This review brings some new insights on erythrocytosis of genetic origin related to problems of oxygen delivery by hemoglobin (Hb). A few molecular mechanisms are individualized among the about 100 Hb variants that cause compensatory erythrocytosis. The most frequently observed structural modifications are localized in the α1β2 interface, or at the C-terminal. They impair formation of a stable T state. Others mutations modify directly or indirectly the surrounding of the heme and the site where oxygen binds. A special interest is brought to the dose effect considering the possibility for formation of hybrid tetramers with altered oxygen binding properties. Homozygous cases, and patients who are compound heterozygotes for a high oxygen affinity Hb and a thalassemia (thal), are discussed. Several examples are provided, specially documented for Hb Olympia [β20(B2)Val→Met] and Hb Saint Nazaire [β103(G5)Phe→Ile]. Other mechanisms leading to erythrocytosis are discussed, and finally, an algorithm is proposed for etiological diagnosis.