Unusual β-Globin Haplotype Distribution in Newborns from Bengo,Angola

Abstract

Mutations on the HBB gene are a common cause of hemoglobinopathies, including sickle cell anemia, a severe genetic condition that constitutes a major public health concern. The aim of this study was to determine the prevalence of sickle cell anemia and β-globin haplotype distribution in newborns from the Bengo region. The first two exons of β-globin gene were sequenced, and the variability at the single nucleotide polymorphism (SNP) defining the Hb S (HBB: c.20A>T) haplotypes, was analyzed by a SNaPshot^® Multiplex system. About 3.3% of the children were homozygous for Hb S, and 82.2% had as background the Bantu/Central African Republic (BAN/CAR) haplotype, 11.2% the Benin (BEN) and 6.6% the Senegal (SEN). The estimate of Hb S reached the very high value of 0.1476?±?0.0133, with the aggravating factor of 82.2% of the sickle alleles being anchored in the BAN/CAR haplotype, associated with the more severe sickle cell anemia phenotypes. Also, the high prevalence of the SEN haplotype was not expected, having therapeutic consequences since is associated with more severe outcomes. In addition, two β-thalassemia (β-thal) variants were also detected, IVS I-110 (G>A) (HBB: c.93-21G>A) and codon 39 (C>T) (HBB: c.118C>T), together totaling a frequency of 1.3%. Some of the newborns with these mutations were compound heterozygotes for Hb S, likely carrying genotypes consistent with sickle cell disease. As a whole, infants molecularly diagnosed with sickle cell disease accounted for 4.5% of newborns from Bengo, Angola, a figure that per se, highlights the urgent need of implementing policies warranting surveillance of these children, in parallel with community education in the region.     

Rare Association of Hb D-Los Angeles (HBB: c.364G>C) with Hb H Disease: Diagnosis and Clinical Implications

Abstract

Hb D-Los Angeles (or Hb D-Punjab) (HBB: c.364G?>?C) is found worldwide and is derived from a point mutation in the β-globin gene prevalent in the Punjab region of Northwestern India. Heterozygous or homozygous inheritance does not cause significant medical problems, whereas association with other hemoglobinopathies, especially β-thalassemia (β-thal) and sickle cell disease, changes the phenotype. Coinheritance of Hb D-Los Angeles with Hb H disease (α–/–?–) has never been reported before. The presence of this rare combination in a family of Greek origin is herein described, and the challenges involving clinical management are discussed.     

Molecular Variations Linked to the Grouping of β- and α-Globin Genes in Neonatal Patients with Sickle Cell Disease in the State of Pernambuco,Brazil

Various factors have been described as phenotypic modulators of sickle cell disease, such as levels of fetal hemoglobin (Hb F), presence of α-thalassemia (thal), and haplotypes of the β-globin genes. In order to characterize and determine the frequency of the β^S and β^C mutations and the prevalence of ?α^3.7-thal, 74 patients with sickle cell disease detected during neonatal screening in the State of Pernambuco, Brazil, were studied. The haplotypes of the β gene and ?α^3.7-thal were determined using polymerase chain reaction (PCR), and specific restriction endonucleases were used to establish the polymorphic sites of the haplotypes. The results showed the high frequency of the Central African Republic (CAR) or Bantu haplotype in the State of Pernambuco, Brazil. The low frequency of the Benin haplotype recorded in this study, in comparison with other states in northeast Brazil, suggests the diversity of origins of Afro-Brazilians in this region.     

Multi Centric Origin of Hb D-Punjab [β121(GH4)Glu→Gln,GAA>CAA]

Hb D-Punjab [β121(GH4)Glu→Gln, GAA>CAA], common in the northern Indian province, is often unexpectedly found in other populations. To study the multi centric origin of this variant which is causing sickle cell disease in association with Hb S [β6(A3)Glu→Val, GAG>GTG], we have examined the haplotype of the Hb D allele in different populations. We studied 43 alleles from south Iran (Hormozgan and Fars provinces) and 14 from Holland and Belgium using high performance liquid chromatography (HPLC), capillary electrophoresis, direct sequencing and/or restriction enzyme analysis. In Iranians, four haplotypes were observed at different frequencies: haplotype I [+ ? ? – ?,+ +] at 67.5%, subhaplotype I' [+ – – – –,– +] at 17.5%, haplotype V [– + – – +,+ +] at 10.0% and haplotype III [– + – + +,+ +] at 5.0%. All European cases were on haplotype I. The occurrence of high Hb D frequencies on a single haplotype in specific regions can be expected if we consider founder effect and genetic drift mechanisms. However, considering that haplotype I is the most common haplotype worldwide, that Hb D-Punjab is reported in different populations on different haplotypes, and that codon β121 is a site on which six different mutations are reported, we may expect to observe Hb D-Punjab in different populations, possibly because of a relatively higher occurrence of de novo mutations, generating unexpected risk from mixtures of allochtonous Hb S and indigenous Hb D-Punjab or vice versa.     

High Frequency of Hb E-Saskatoon (HBB: c.67G > A) in Brazilians: A New Genetic Origin?

Hb E-Saskatoon [β22(B4)Glu→Lys, HBB: c.67G?>?A] is a rare, nonpathological β-globin variant that was first described in a Canadian woman of Scottish and Dutch ancestry and has since then been detected in several populations. The aim of the present study was to identify the origin of Hb E-Saskatoon in Brazil using β-globin haplotypes and genetic ancestry in carriers of this hemoglobin (Hb) variant. Blood samples were investigated by isoelectric focusing (IEF) and high performance liquid chromatography (HPLC) using commercial kits. Hb E-Saskatoon was confirmed by amplification of the HBB gene, followed by sequence analysis. Haplotypes of the β-globin gene were determined by polymerase chain reaction (PCR), followed by digestion with specific restriction enzymes. Individual ancestry was estimated with 48 biallelic insertion/deletions using three 16-plex PCR amplifications. The IEF pattern was similar to Hbs C (HBB: c.19G?>?A) and Hb E (HBB: c.79G?>?A) [isoelectric point (pI): 7.59-7.65], and HPLC results showed an elution in the Hb S (HBB: c.20A?>?T) window [retention time (RT): 4.26-4.38]. DNA sequencing of the amplified β-globin gene showed a mutation at codon 22 (GAA>AAA) corresponding to Hb E-Saskatoon. A total of 11 cases of this variant were identified. In nine unrelated individuals, Hb E-Saskatoon was in linkage disequilibrium with haplotype 2 [+ – – – –]. All subjects showed a high degree of European contribution (mean = 0.85). Hb E-Saskatoon occurred on the β-globin gene of haplotype 2 in all Brazilian carriers. These findings suggest a different genetic origin for this Hb variant from that previously described.     

Compound Heterozygote of Hb S (HBB: c.20A>T)/Hb Westdale (HBB: c.380_396delTGCAGGCTGCCTATCAG): Report of Four Cases from Odisha State,India

We report four cases of compound heterozygotes for Hb S (HBB: c.20A>T) and a rare β⁰-thalassemia (β⁰-thal) mutation, Hb Westdale (HBB: c.380_396delTGCAGGCTGCCTATCAG), characterized by a 17?bp deletion between codons 126 to 131 in exon 3 of the β-globin gene of human hemoglobin (Hb) confirmed by direct β-globin gene sequencing. All four cases were from four unrelated families belonging to the Agharia caste, an endogamous ethnic community of the Sundargarh and Jharsuguda districts of Odisha State, India. Detailed observations indicated that all four cases of Hb S/Hb Westdale were clinically severe. On family screening, six family members were found to be heterozygous for Hb Westdale and were asymptomatic. Deletional α-thalassemia (α-thal) and XmnI polymorphism were studied for all the Hb Westdale cases. The Hb S/Hb Westdale cases had an early median age at onset of symptoms and presentation, more requirement of blood transfusions, splenomegaly and hepatomegaly and were found to be clinically more severe when compared with the Hb S-β-thal with IVS-I-5 (G>C) (HBB: c.92?+?5G>C) cases. Overall, the findings indicate that this rare and hitherto unreported compound heterozygosity of Hb S/Hb Westdale is a clinically significant hemoglobinopathy and its finding in a large endogamous community of Odisha State, India will have important implication in the epidemiology and understanding of the clinical spectrum of sickle cell disease in Indian context and prenatal diagnosis.     

An Intriguing High Performance Liquid Chromatogram of a Double Heterozygosity for Hb Q-India/Hb D-Punjab

Cation exchange high performance liquid chromatography (HPLC) is commonly utilized as the first method of screening for thalassemias and hemoglobinopathies worldwide. This method of diagnosis requires knowledge of the clinical background and complete blood counts as well as skill and experience in interpreting the sometimes complex results produced. An asymptomatic 27-year-old pregnant North Indian woman was found to have a highly unusual chromatographic pattern with multiple unexpected peaks during routine antenatal screening. Most concerning was a C-window peak as Hb C (HBB: c.19G>A) is rare in ethnic Asian Indian populations. Cellulose acetate electrophoresis at alkaline pH (8.6) and parental screening were performed. These revealed the correct diagnosis to be a double heterozygosity for Hb Q-India (HBA1: c.193G>C) (an uncommon asymptomatic α-globin chain variant) plus Hb D-Punjab (HBB: c.364G>C) (a β-globin chain variant that is common in this region and is asymptomatic in the heterozygous state). The unexpected C-window peak was the hybrid of the abnormal α-Q-India and β-D-Punjab globin chains. Another small peak was explained as a variant Hb A₂ formed by the combination of α-Q-India and δ-globin chains. Hematopathologists should be cognizant of the complex pattern resulting from coinheritance of both α- and β-globin structural variants. Second-line testing and parental testing are invaluable in resolving unknown peaks, especially if rare or unexpected variants are being considered. Although both Hb Q-India and Hb D-Punjab are relatively common in northwestern India, to the best of our knowledge, only two recent reports describe a total of three cases of such diagnostically puzzling coinheritance.     

β-Globin Gene Haplotypes Linked with the Hb D-Punjab [β121(GH4)Glu→Gln,GAA>CAA] Mutation in Eastern India

Hb D-Punjab [β121(GH4)Glu→Gln] is prevalent in the northern states of the Indian subcontinent. Due to inadequate data from Asian countries, the origin and spread of the Hb D-Punjab mutation are uncertain. In a study of sickle cell hemoglobinopathies, we detected the Hb D-Punjab mutation in 25 subjects from 11 unrelated Agharia families. Twelve cases were Hb S [β6(A3)Glu→Val]/Hb D-Punjab compound heterozygotes and 13 were Hb D trait carriers. In 76.0% of the cases, the β^D gene was linked to haplotype I, whereas 24.0% had a novel haplotype. None of the haplotypes matched the β^A haplotype of the local population. In view of the ancestral origin of the subjects and the high prevalence of the β^D gene in the states of northern India, we suggest a North Indian origin for the β^D mutation in our population. The finding of a novel haplotype in eastern India supports the hypothesis of a multicentric origin of this mutation.     

βS-Globin Gene Cluster Haplotypes in the West Bank of Palestine

Sickle cell disease is an inherited autosomal recessive disorder of the β-globin chain. In Palestine it is accompanied by a low level of Hb F (mean 5.14%) and a severe clinical presentation. In this study, 59 Palestinian patients, homozygotes for Hb S were studied for their haplotype background. Eight polymorphic sites in the β-globin gene cluster were examined. The Benin haplotype was predominant with a frequency of 88.1%, followed by a frequency of 5.1%?for the Bantu haplotype. One chromosome was found to carry the Cameroon haplotype (0.85%). Three atypical haplotypes were also found (5.95%). Heterogeneity was observed in Hb F production, ranging between 1.5 and 17.0%, whereas the ^Gγ ratio was homogeneous among all haplotypes with a normal amount of about 41%. Our results are in agreement with previous reports of the Benin haplotype origin in the Mediterranean.     

MOLECULAR CHARACTERIZATION OF Hb D-PUNJAB [β121(GH4)Glu→Gln] IN THAILAND

We describe the hematological and DNA characterization of Hb D-Punjab [β121(GH4)Glu→Gln] in Thailand. Nine patients from five unrelated families were studied; four patients were simple carriers of Hb D-Punjab, two were compound heterozygotes for Hb D-Punjab/β⁺-thalassemia;another two patients were double heterozygotes for Hb D-Punjab and α-thalassemia-2, and one patient was a compound heterozygote for Hb D-Punjab and Hb E [β26(B8)Glu→Lys]. Typical thalassemic indices with hypochromic microcytosis were observed in compound Hb D-Punjab/β⁺-thalassemia and Hb D-Punjab/Hb E but normal hematological profiles were observed in the remaining cases. DNA sequencing of the β-globin gene identified the G AA→C AA substitution at codon 121 causing Hb D-Punjab in all cases, and the ?28 (A→G) mutation for the β⁺-thalassemia alleles. β-Globin gene haplotype analysis demonstrated, for the first time, that all these Asian β^D-Punjab globin genes were associated with haplotype [?++?+++], previously undescribed in other populations. The finding of Hb D-Punjab in Thailand is compatible either with an independent origin of this abnormal hemoglobin or a spread of the Hb D-Punjab gene with a single origin among Asians.     

Effect of Assorted Globin Haplotypes and α-Thalassemia on the Clinical Heterogeneity of Hb S-β-Thalassemia

Abstract

Hemoglobinopathies and thalassemias are the most commonly encountered monogenic disorders of blood in humans, posing a major genetic and public health problem round the globe. Hb S (HBB: c.20A>T)-β-thalassemia (β-thal) is a compound aberrant heterozygosity with inconsistent phenotypic expression, which are poorly described and clinically mapped. Comprehensive genetic characterization of such a population is highly warranted for complete understanding of the clinical heterogeneity, disease prognosis and therapeutic management. In this study, Hb S-β-thal (n?=?60) patients, strictly defined by varying degrees of clinical presentations, were selected to evaluate their genotype-phenotype agreement. Furthermore, β-globin (n?=?120) and α-globin gene clusters (n?=?60) were genetically characterized and statistically correlated with clinical terminologies to explain the clinical heterogeneity. Our results revealed the association of the Arab-Indian haplotypes with nine different frameworks of β-thal together with the modulating role of α-thalassemia (α-thal). The study subjects, including carriers of β-thal haplotype III [– – – – – – –] (8.0%), presented with varying severe patterns of clinical symptoms such as painful crisis, multiple infections and splenomegaly, as an outcome of significantly less Hb F and higher Hb S levels (p?<?0.5). The study findings indicated that together with α-thal, β-thal haplotypes and Hb F levels, may possibly provide a close justification to support the clinical heterogeneity in the study population.     

Hb Tianshui (HBB: C.119A > G) in Compound Heterozygosity with Hb S (HBB: C.20A > T) from Odisha,India

We describe here a rare β-globin gene variant, Hb Tianshui [β39(C5)Glu→Arg; HBB: c.119A?>?G], detected during routine screening in Odisha, India. This is the second report of Hb Tianshui and the first to describe the cation exchange high performance liquid chromatography (HPLC) and DNA studies of two cases of this variant. Both cases had coinherited Hb S (HBB: c.20A?>?T) but none presented with typical symptoms of sickle cell disease. One of the cases was heterozygous for a common α-thalassemia (α-thal) allele (?α^3.7) (rightward) (NG_000006.1: g.34164_37967del3804) and marginally raised Hb F percentage, while the other Hb S/Hb Tianshui case was completely benign and healthy. An atypical Asian Indian haplotype [+???+???+] could be assigned to the Hb Tianshui variant. Hb Tianshui seems to mimic a few other Hb variants in cation exchange HPLC. However, we report two specific patterns in the chromatograms that are characteristic to Hb Tianshui. Combining an alkaline electrophoresis result with cation exchange HPLC at screening would be preferred to detect this rare variant, especially in regions with considerable frequency of Hb E [β26(B8)Glu→Lys; HBB: c.79G?>?A] or Hb S.     

β-Globin gene haplotype in Hb SC disease

We asked the question, is the haplotype found with the sickle hemoglobin gene associated with different hematological characteristics in patients who were combined heterozygotes for sickle hemoglobin and hemoglobin C (Hb SC disease)? In 73 adults with Hb SC disease, a Benin haplotype chromosome was present in 56%, and Bantu (or Central African Republic; CAR), Senegal, and atypical haplotype chromosomes were found in 25%, 6%, and 12%, respectively. No significant differences were found in hematological characteristics or fetal hemoglobin levels of patients with Benin/C, CAR/C, Senegal/C, and atypical/C haplotypes. There were 71%C I, 18% C II, and 11% other β^c haplotypes. Fetal hemoglobin levels are lower in Hb SC disease than in sickle-cell anemia. Perhaps because haplotype has no discernible effect on fetal hemoglobin level in Hb SC disease, it does not modulate its hematological features. © 1996 Wiley-Liss, Inc.     

β-globin gene haplotypes linked with the Hb D-Punjab [β121(GH4)Glu→Gln, GAA>CAA] mutation in eastern India

Hb D-Punjab [β121(GH4)Glu→Gln] is prevalent in the northern states of the Indian subcontinent. Due to inadequate data from Asian countries, the origin and spread of the Hb D-Punjab mutation are uncertain. In a study of sickle cell hemoglobinopathies, we detected the Hb D-Punjab mutation in 25 subjects from 11 unrelated Agharia families. Twelve cases were Hb S [β6(A3)Glu→Val]/Hb D-Punjab compound heterozygotes and 13 were Hb D trait carriers. In 76.0% of the cases, the β(D) gene was linked to haplotype I, whereas 24.0% had a novel haplotype. None of the haplotypes matched the β(A) haplotype of the local population. In view of the ancestral origin of the subjects and the high prevalence of the β(D) gene in the states of northern India, we suggest a North Indian origin for the β(D) mutation in our population. The finding of a novel haplotype in eastern India supports the hypothesis of a multicentric origin of this mutation.     

Genetic Modifiers of Sickle Cell Disease: A Genotype-Phenotype Relationship Study in a Cohort of 82 Children on Mayotte Island

Abstract

Sickle cell disease presents a great clinical variability that remains largely misunderstood. New disease protective genetic modifiers acting mainly through an increased Hb F level have recently been described. We studied relations between clinical and hematological phenotypes and known sickle cell disease genetic modifiers in patients from Mayotte Island, a remote French territory located in the Indian Ocean. Eighty-two children with sickle cell disease were enrolled; their median age was 5.9 years (range 1-18). Clinical and hematological features of sickle cell disease were retrospectively collected. Genetic studies included determination of β-globin genotypes [Hb SS, Hb S-β⁰-thalassemia (Hb S-β⁰-thal), Hb S-β⁺-thal], β^S-globin locus haplotype, α-thalassemia (α-thal), and single nucleotide polymorphisms (SNPs) located in quantitative trait loci for Hb F expression (XmnI polymorphism, BCL11A rs4671393 and rs11886868, intergenic region of HBS1L-MYB rs28384513, rs4895441 and rs9399137). Univariate and multivariate analyses were conducted. Twenty-eight percent of the patients had Hb S-β-thal (eight different mutations in 21 patients), 55.0% had the ?α^3.7 (rightward) deletion and 88.0% of the homozygous Hb SS patients were carrying a homozygous Bantu haplotype. In the multivariate model, the prognosis role of the SNP BCL11A rs4671393 was confirmed in the studied population showing a significant association with an elevated Hb F level and with a low hospitalization rate. The ?α^3.7 deletion, XmnI polymorphism and intergenic region HBS1L-MYB SNPs were not significantly linked to any clinical criteria of severity. This report, the first to describe the main features of children with sickle cell disease on Mayotte Island, highlights the protective effect of the BCL11A polymorphism in this population.     

Two New Hemoglobin Variants: Hb Tallahassee [α3(A1)Ser→Tyr; HBA2: c.11C>A] and Hb Madison-NC [β119(GH2)Gly→Ser; HBB: c.358G>A]

Of the 1570 reported hemoglobin (Hb) variants detected to date, 390 are α2-globin chain (some variants have yet to be identified by DNA analyses and are therefore presumed) and 827 are the result of mutations of the β-globin chain. Due to their location on the Hb structure, only a minority of these variants result in a clinical phenotype; most are silent and are detected during routine surveillance, are found incidentally during other disease-related investigations or following newborn screening programs. In this report we discuss phenotype/genotype and molecular characteristics of two new Hb variants, both of which were clinically silent. One is an α2-globin chain variant located at codon 3 [α3(A1)Ser→Tyr; HBA2: c.11C?>?A] named Hb Tallahassee and the other is a β-globin chain variant located at codon 119 [β119(GH2)Gly→Ser; HBB: c.358G?>?A] called Hb Madison-NC.     

Sickle cell disease in the Kurdish population of northern Iraq

Epidemiological studies have revealed that sickle cell disease patients are clustered in two geographical areas in Iraq, one among the Arabs in the extreme south, another among the Kurdish population in the extreme north, where they constitute major health problems. However, no studies have focused on the genotypes responsible for sickle cell disease or the β-globin gene haplotypes associated with it. For the latter purpose, a total of 103 unrelated Kurdish sickle cell disease patients were evaluated by restriction fragment length polymorphism (RFLP) for the sickle cell mutation, followed by multiplex polymerase chain reaction (PCR) and reverse hybridization for β- and α-thalassemia (β- and α-thal) mutations, whenever indicated. Results showed that the most common genotype was sickle cell anemia (68.0%) followed by Hb S/β(0)-thal and Hb S/β(+)-thal at frequencies of 24.2 and 7.8%, respectively. Eight β-thal mutations were associated with the latter two genotypes including: IVS-II-1 (G>A), IVS-I-110 (G>A), codon 8 (-AA), codon 44 (-C), codon 22 (-7 bp), IVS-I-1 (G>A), codon 30 (G>C) and IVS-I-6 (T>C). In Hb SS patients, the -α(3.7) deletion was documented in 10.0% and was the only α-thal mutation detected. Furthermore, 5' β-globin gene cluster haplotyping of 128 β(S) chromosomes revealed that the most common haplotype seen in 69.5% was the Benin haplotype, followed by the Arab-Indian haplotype in 12.5%. These latter findings closely resemble reports from neighboring Turkey, Syria, Jordan, Lebanon and Mediterranean countries, suggesting a possible common origin, but are in contrast to findings from the Eastern Arabian Peninsula and Iran.     

Hb Presbyterian (HBB: c.327C>G) in a Nicaraguan Family

Hemoglobin (Hb) is the protein responsible for oxygen transportation. It is a tetrameric protein comprising two α- and two β-globin subunits. In the literature, a large number of mutations in the α- and β-globin genes have been documented. Among these mutations, Hb Presbyterian (HBB: c.327?C>G), is a naturally occurring mutant exerting low oxygen affinity. The C to G exchange (AAC>AAG) at codon 108 of the β-globin gene results in the substitution of asparagine by lysine. Here, we document the identification of HBB: c.327?C>G in a 6-year-old female patient and her father from Nicaragua and Cuba, respectively. The presence of the abnormal Hb was confirmed by cellulose acetate electrophoresis, high performance liquid chromatography (HPLC) and genomic DNA sequencing. The β-globin gene sequences for both, father and daughter, disclosed the heterozygous mutation at codon 108 to be Hb Presbyterian or HBB: c.327?C>G. The mutant Hb was previously reported in four families from North America, Germany, Japan and Spain, respectively. This is the fifth family carrying HBB: c.327?C>G described to date and the first report from Latin America.     

Gender and haplotype effects upon hematological manifestations of adult sickle cell anemia

In Africa, the β-globin gene cluster haplotype may be associated with variation of Hb F levels in subjects with sickle cell anemia (SS). These observations have not yet been conclusively confirmed in SS out of Africa, perhaps because of small sample sizes, the predominance of haplotype heterozygotes, and diverse influences, including gender, upon Hb F levels. We studied 384 adult African-American SS patients (mean age, 31 years) and explored the relationship of gender, β-globin gene cluster haplotype, and α thalassemia to hematological values and Hb F levels. Both haplotype and gender influenced Hb F concentration. In the total sample, Hb F was higher in females than in males (8.2 vs. 6.5%). In 35 males who were either homozygous for the Senegal chromosome or had the Senegal/Benin haplotype, the mean percent Hb F (8.0%) was equivalent to the Hb F level in females with Benin and Bantu haplotypes (-7.5%). Both females and males homozygous for the Senegal haplotype chromosome or with the Senegal/Benin combination had a significant increase in Hb F compared to other groups. In 44 Senegal/Senegal or Senegal/Benin females the Hb F was 10.9%, or 1.0 g/dl, the highest value observed in all primary analysis groups. Preliminary analyses suggested that the presence of a Bantu chromosome blunted the gender-associated difference in Hb F, but Hb F differences between females with the Senegal/Benin haplotype (11.2%) and the Senegal/Bantu haplotype (8.8%) were not statistically significant. Hemoglobin concentrations were higher in males than in females except in subjects with at least one Senegal haplotype chromosome, where hemoglobin levels were equal. As expected, α thalassemia reduced the MCV, increased hemoglobin concentration, and lowered reticulocyte counts, regardless of haplotype. Hb F levels were not affected by the presence of α thalassemia in any group. We conclude that gender and β-globin gene cluster haplotype interact significantly in the modulation of Hb F and anemia in adults with SS. ©1995 Wiley-Liss, Inc.     

Hereditary Persistence of Fetal Hemoglobin Caused by Single Nucleotide Promoter Mutations in Sickle Cell Trait and Hb SC Disease

Hereditary persistence of fetal hemoglobin (HPFH) can be caused by point mutations in the γ-globin gene promoters. We report three rare cases: a child compound heterozygous for Hb S (HBB: c.20A?>?T) and HPFH with a novel point mutation in the ^Aγ-globin gene promoter who had 42.0% Hb S, 17.0% Hb A and 38.0% Hb F; a man with Hb SC (HBB: c.19G?>?A) disease and a point mutation in the ^Gγ-globin gene promoter who had 54.0% Hb S, 18.0% Hb C and 25.0% Hb F; a child heterozygous for Hb S and HPFH due to mutations in both the ^Aγ- and ^Gγ-globin gene promoters in cis [^Gγ^Aγ(β⁺) HPFH], with 67.0% Hb A, 6.5% Hb S and 25.0% Hb F.