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Objective: To evaluate the incidence of variant hemoglobins of newborn samples from the Neonatal Screening Center in the state of Mato Grosso do Sul, Brazil, and to analyze the distribution and spatial autocorrelation of newborns with sickle cell trait., Methods: Samples from 35,858 newborns screened by the Neonatal Screening Center. The samples with inconclusive diagnosis were submitted to electrophoretic, chromatographic, cytological and molecular analyses. The spatial distribution analysis of newborns with sickle cell trait was performed by spatial autocorrelation., Results: A total of 919 newborns showed an abnormal hemoglobin profile; in that, ten genotypes had significant clinical impacts identified. Among the asymptomatic newborns, the sickle cell trait was the most frequent (incidence of 1.885 cases/100 newborns). The highest incidence rates were registered in the municipalities of Terenos, Figueirão, Corguinho and Selvíria. There was positive spatial autocorrelation between the proportion of declared individuals of black race/color and the incidence of newborns with sickle cell trait., Conclusion: The early diagnosis by neonatal screening and laboratory tests was very important to identify abnormal hemoglobin profiles and guide the spatial autocorrelation analysis of sickle cell trait newborns in Mato Grosso do Sul, serving as a support to anticipate health measures aimed to discuss efficient therapeutic behaviors and effective planning of municipalities with the greatest need for care, monitoring and orientations for affected families.

Objective: Plasma levels of the fibrinogen degradation product D-dimer are higher among African Americans (AAs) compared with those of European ancestry and higher among women compared with men. Among AAs, little is known of the genetic architecture of D-dimer or the relationship of D-dimer to incident cardiovascular disease., Approach and Results: We measured baseline D-dimer in 4163 AAs aged 21 to 93 years from the prospective JHS (Jackson Heart Study) cohort and assessed association with incident cardiovascular disease events. In participants with whole genome sequencing data (n=2980), we evaluated common and rare genetic variants for association with D-dimer. Each standard deviation higher baseline D-dimer was associated with a 20% to 30% increased hazard for incident coronary heart disease, stroke, and all-cause mortality. Genetic variation near F3 was associated with higher D-dimer (rs2022030, β=0.284, P =3.24×10 -11 ). The rs2022030 effect size was nearly 3× larger among women (β=0.373, P =9.06×10 -13 ) than among men (β=0.135, P =0.06; P interaction =0.009). The sex by rs2022030 interaction was replicated in an independent sample of 10 808 multiethnic men and women ( P interaction =0.001). Finally, the African ancestral sickle cell variant ( HBB rs334) was significantly associated with higher D-dimer in JHS (β=0.507, P =1.41×10 -14 ), and this association was successfully replicated in 1933 AAs ( P =2.3×10 -5 )., Conclusions: These results highlight D-dimer as an important predictor of cardiovascular disease risk in AAs and suggest that sex-specific and African ancestral genetic effects of the F3 and HBB loci contribute to the higher levels of D-dimer among women and AAs., (© 2017 American Heart Association, Inc.)

Background: Red blood cell (RBC) polymorphisms are common in malaria endemic regions and are known to protect against severe forms of the disease. Therefore, it is important to screen for these polymorphisms in drugs or vaccines efficacy trials. This study was undertaken to evaluate associations between clinical malaria and RBC polymorphisms to assess biological interactions that may be necessary for consideration when designing clinical trials., Method: In a cross-sectional study of 341 febrile children less than five years of age, associations between clinical malaria and common RBC polymorphisms including the sickle cell gene and G6PD deficiency was evaluated between November 2008 and June 2009 in the middle belt of Ghana, Kintampo. G6PD deficiency was determined by quantitative methods whiles haemoglobin variants were determined by haemoglobin titan gel electrophoresis. Blood smears were stained with Giemsa and parasite densities were determined microscopically., Results: The prevalence of clinical malarial among the enrolled children was 31.9%. The frequency of G6PD deficiency was 19.0% and that for the haemoglobin variants were 74.7%, 14.7%, 9.1%, 0.9% respectively for HbAA, HbAC, HbAS and HbSS. In Multivariate regression analysis, children with the HbAS genotype had 79% lower risk of malaria infection compared to those with the HbAA genotypes (OR = 0.21, 95% CI: 0.06-0.73, p = 0.01). HbAC genotype was not significantly associated with malaria infection relative to the HbAA genotype (OR = 0.70, 95% CI: 0.35-1.42, p = 0.33). G6PD deficient subgroup had a marginally increased risk of malaria infection compared to the G6PD normal subgroup (OR = 1.76, 95% CI: 0.98-3.16, p = 0.06)., Conclusion: These results confirm previous findings showing a protective effect of sickle cell trait on clinical malaria infection. However, G6PD deficiency was associated with a marginal increase in susceptibility to clinical malaria compared to children without G6PD deficiency.

A 15 years old Muslim female presented with moderate anaemia, mild jaundice and hepatosplenomegaly with no history of blood transfusion in the past. Routine examination was suggestive of haemolytic jaundice. High pressure liquid chromatography (HPLC) electrophoresis of the patient's blood showed haemoglobin (Hb) SD disease. As it is a double heterozygous disease, family screening was done. It showed that the father was sickle cell trait. Mother was Hb D trait. Both the brothers were sickle cell trait and the only sister was normal. Hb SD disease is a very rare variety of haemoglobinopathy and the case is presented here due to its rarity.

Sickle hemoglobin (Hb S;betaGlu 6 Val) is due to an A>T transversion in codon 6 of the beta-globin gene. Other variant hemoglobins mimic Hb A, S, or C on newborn screening and clinical laboratory diagnostic tools, thus making their correct identification potentially difficult. Sickling disorders can result in individuals who are compound heterozygous for beta-globin mutations (e.g., Hb SC, HbSO(Arab)). The authors report a second case of HbS/Québec-CHORI, a severe compound heterozygous sickling disorder and their experience managing this patient with hydroxyurea.

There are approximately 1200 known natural mutations of the human globin genes. In most clinical laboratories, the diagnosis of hemoglobin disorders is based on blood counts, hemoglobin electrophoresis, or column chromatography, which can identify common variant hemoglobins such as Hb S, C, and E, but are unable to definitively diagnose most other hemoglobin variants and thalassemia mutations. We report two unrelated cases, both thought initially to have Hb S/beta-thalassemia. Subsequent mutational analyses revealed that one is Hb S/S with compound heterozygosity for nondeletional alpha-thalassemia mutations. The other is the first reported case of compound heterozygosity for Hb S and an unstable hemoglobin, Hb Volga. Correct diagnoses of these hereditary disorders are needed for prognosis and proper management and also for genetic counseling. These studies underscore the importance to correlate clinical course with laboratory diagnosis and to make DNA-based diagnostics more widely available for patients with unusual or complicated hemoglobin disorders., (2006 Wiley-Liss, Inc.)

A baby girl presented with symptomatic sickle cell disease exacerbated by mild hypoxemia, despite a newborn-screening diagnosis of sickle cell trait. DNA sequencing of the beta globin gene revealed that her maternal beta globin allele was normal. Her paternal allele had not only the expected sickle-trait mutation, betaGlu6Val, but also a second, charge-neutral mutation, betaLeu68Phe. Analysis of the patient's hemoglobin revealed that the double-mutant protein, which we called "hemoglobin Jamaica Plain," had severely reduced oxygen affinity. Structural modeling suggested destabilization of the oxy conformation as a molecular mechanism for sickling in a heterozygote at an ambient partial pressure of oxygen., (Copyright 2004 Massachusetts Medical Society.)

A brief survey of abnormal hemoglobin variants among the major ethnic groups of Karachi was conducted; 202,600 subjects were studied. Patients with low hemoglobin (Hb), low mean cell volume (MCV) and mean cell hemoglobin (MCH) including anemia, microcytosis, hypochromic hemolysis and target cells, were refered for the identification of hemoglobinopathy by molecular methods. Population screening showed that 60% had iron-deficiency anemia and 40% had hemolytic anemia, of which 20.6% was due to beta-thalassemia major, 13% beta-thalassemia trait, 5.1% sickle cell disease, 0.76% hemoglobin D Punjab (HbD Punjab), 0.32% hemoglobin C (HbC), and 0.22% hereditary persistence of fetal hemoglobin (HPFH).

Hb O-Tibesti, carries in the same chain the substitution of Hb O-Arab [beta121(GH4)Glu-->Lys] and that of Hb Hamilton [beta11(A8)Val-->Ile]. Hb O-Tibesti may be distinguished from Hb O-Arab by polyacrylamide gel electrophoresis in the presence of urea and Triton-X100, and by reversed phase high performance liquid chromatography. It was found in a compound heterozygous condition with Hb S [beta6(A3)Glu-->Val] in a child of Chad-Sudanese descent, suffering from a sickle cell syndrome. Compared to the classical description of the Hb S/Hb O-Arab association, the additional Hb Hamilton mutation does not seem to modify the clinical presentation.

We have analysed, at the hematological and molecular level, 51 Hb lepore heterozygotes and three compound heterozygotes for Hb Lepore and HbS (HbLep/HbS) in 26 unselected Portuguese families. The Lepore Boston variant was present in one family, in association with classical haplotype V. All of the other Lepore alleles present haplotype III in association with XmnI (+)5' of (G)gamma gene, in tight linkage disequilibrium to the major mutation found in the Portuguese population, the Lepore Baltimore variant ( delta(68Leu)-beta(84Thr)). The three compound heterozygotes are the first HbLep/HbS individuals reported in the literature, with the Lepore Baltimore mutation linked to haplotype III. In agreement with other studies, these Lepore Baltimore heterozygotes have higher HbF (1.4-14.1% of total hemoglobin) than published cases of Lepore Boston (0.8-5.4%), which is associated with XmnI(-). Among the Lepore Baltimore heterozygotes, the (AT)xTy repeat region at -540 bp of the beta globin gene in trans to the Lepore chromosome, can account for much of the variability in HbF level. The allele (AT)7T7 is associated with lower HbF, and (AT)9T5 is associated with higher HbF. As we previously reported for beta thalassemic carriers, we observe in Lepore Baltimore carriers an effector in trans, linked to the (AT)xTy sequence, acting as an HPFH (Hereditary Persistence of Fetal Hemoglobin) determinant., (Copyright 2002 Wiley-Liss, Inc.)

When first tested for abnormal hemoglobins, a 2-year-old boy, appeared to have Hb F, Hb S and Hb A2. Confirmatory testing revealed a beta chain variant inherited from his father and beta S from his mother. Analysis of tryptic peptides in conjunction with automated DNA sequence analysis showed that the variant hemoglobin was Hb Shelby [beta 131(H9)Gln-->Lys (CAG-->AAG)]. Heat and mechanical stabilities of various liganded Hb Shelby tetramers were compared to those of Hb A and Hb S. Oxy-Hb Shelby precipitated more readily than oxy-Hb A, but was much more stable than oxy-Hb S during mechanical agitation. In contrast, oxy-Hb Shelby was much less stable than oxy-Hb A and oxy-Hb S following heat treatment. Met-Hb Shelby was most unstable compared to other liganded forms of Hb Shelby, while deoxy- and carbonmonoxy-forms of Hb Shelby showed similar heat-induced precipitation rates. These data indicate that heat instability of Hb Shelby is accompanied by heme oxidation, and that denaturation by mechanical agitation occurs in the absence of heme oxidation. Hb Shelby, like Hb A, can form hybrids with Hb S which participate in polymer formation in vitro. However, Hb S/Hb Shelby hybrids copolymerized with Hb S less than A/S hybrids. Since the patient's MCHC value is normal, this finding coupled with the elevated Hb A2 and Hb F levels, both of which are known to inhibit polymerization of Hb S, may contribute to the patient's mild clinical presentation.

Hb Bab-Saadoun which has a Leu----Pro substitution at position 48 of the beta chain was detected in a young Arabian boy living in Tunisia. His parents did not have the variant which suggests that it occurred as a spontaneous mutation. The substitution is located in the interhelical CD segment; leucine at beta 48 is an invariable amino acid that may be important as part of a spacer sequence between the two helices and its replacement by proline may affect the stability of the hemoglobin molecule. Hb Bab-Saadoun is unstable in heat and isopropanol stability tests and its chain was best isolated by parachloromercuribenzoate precipitation. It appears unlikely that the presence of Hb Bab-Saadoun results in a hemolytic anemia.

The silent Hb Muscat with a Leu----Val replacement at position beta 32 was discovered by reversed phase high performance liquid chromatography in two members of an Arabian family from Oman; in one person Hb Muscat occurred with Hb S and in the other with Hb A. Hb Muscat is slightly unstable but its presence has no apparent adverse effect on the health of its carriers. Additional hemoglobin abnormalities observed in this family were a common alpha-thalassemia-2 (-3.7 kb) and Hb S. The beta S haplotypes in the heterozygous carriers and the two sickle cell anemia patients were #19 (Benin) and #20 (Bantu); the latter likely originated from an East African population.

Hb Iowa with a Gly----Ala mutation at position beta 119(GH2) was observed in a Black infant and her mother. The baby was also heterozygous for Hb S; Hb Iowa was confused with Hb F at birth because its electrophoretic mobility was similar to that of Hb F1. The beta chain of Hb Iowa could be readily separated from the beta A, alpha, and gamma chains by polyacrylamide gel electrophoresis and by reversed phase high performance liquid chromatography. Structural characterization was through amino acid analyses of peptides isolated from a tryptic digest of the aminoethylated beta-Iowa chain. The Gly----Ala replacement in Hb Iowa does not affect its stability and oxygen carrying properties; hematological data for mother and child were within normal ranges.

The gene frequencies of abnormal haemoglobins have been determined in a group of 100,000 Jamaican newborns screened over a period of 8 1/2 years. The population is predominantly of West African origin and the survey represents approximately one quarter of all island deliveries within the period of the study. The common beta globin chain abnormalities beta s and beta c occurred with gene frequencies of 0.055 and 0.019 respectively; beta thalassaemia was relatively rare. In contrast, alpha thalassaemia was quite common, occurring with a gene frequency of 0.183. In addition to these common abnormalities, the frequencies of 256 rare abnormal haemoglobins are described. This survey thus represents a complete and accurate documentation of the alpha and beta globin variants that occur in the Jamaican population.

In a survey of 601 pregnant women in Mozambique, 34 (5.6%) were sickle cell trait carriers. Beta thalassaemia trait did not appear to be common. There was a slight rise in Hb F values in 49 women of the type reported previously in early pregnancy.

The prevalence of different haemoglobins and their interaction with malaria have been studied in Garki, Kano State, Nigeria. Sickle cell trait was present in 24% of newborn and 29% of those aged over five years. Hb.AC was present in 0.7%. Frequency of both haemoglobin variants was greater in Hausa than Fulani. Sickle cell anaemia was almost invariably fatal in early childhood. The distribution curve of percentage of Hb.S in sickle cell trait subjects was normal, and did not demonstrate any high frequency of a gene for alpha-thalassaemia. The presence of beta-thalassaemia minor could not be tested, but Hb.S/beta-thalassaemia was not detected. Hb.S gene frequency appears to have been maintained by a fitness in heterozygotes of 21% over normal homozygotes; increased fertility and high mutation rate did not make any apparent contribution. Hb.AS subjects had on average lower frequency and considerably lower densities of Plasmodium falciparum trophozoites than Hb.AA from the age of 30 to 59 weeks; density was less in sickle cell trait up to age three years in the dry season only. It is suggested that the survival advantage and hence the prevalence of sickle cell trait may be greatest in some hyperendemic areas and less where malaria transmission is extremely high or when it is high and unvaried.

A novel deletion of at least 26 kilobase of DNA, including both alpha-globin genes, the psi alpha- and psi zeta-globin genes, but sparing the functional zeta-gene was found in a 10-year-old black boy with HbH disease and sickle cell trait. This particular deletion has not previously been described in blacks. Its existence makes it likely that the absence of Hb Barts hydrops fetalis in blacks is due to the rarity of the chromosome lacking two alpha-globin genes rather than a result of early embryonic death due to the failure to synthesize embryonic hemoglobins because of deletion of functional zeta-globin genes.

In a family of Low-Zaïre, a child with sickle cell beta+-thalassaemia disease, aged 7, presented 33.6% haemoglobin A. The clinical evolution was benign, except for the occurrence of an extensive bilateral ischemic necrosis of the ribs. This is the third case of sickle cell thalassaemia with the haemoglobin phenotype SFA reported in Zaïrians, whereas the SF phenotype has repeatedly been found: beta+-thalassaemia seems therefore much rarer in Zaïrians than betadegrees-thalassaemia. Besides the thalassaemia trait and the sickle cell trait, hereditary elliptocytosis was also segregating in this family; double heterozygotes for Hb S and elliptocytosis or for beta-thalassaemia and elliptocytosis did not show any definite sign of genetic or clinical interaction between both traits.

The rarity of hemoglobin (Hb) H disease in combination with sickle trait may be due in part to the absence of actual Hb H in individuals who, nonetheless, have inherited the deletion of three alpha-globin genes. We describe here a boy with persistent microcytic, hypochromic anemia despite adequate iron stores, who exhibited splenomegaly with a normal reticulocyte count and only rare inclusions in circulating erythrocytes. Starch gel electrophoresis and isoelectric focusing at age 5 yr showed 21% Hb S, persistent Hb Bart's, but no Hb H. Recticulocyte alpha/non-alpha globin chain synthesis ratio was 0.58 at age 5. The mother (Asian) had laboratory evidence of alpha-thalassemia trait and the father (Black) had sickle trait. The nature of alpha-thalassemia in this patient was investigated both by liquid hybridization and by the Southern method of gene mapping, in which DNA is digested with restriction endonucleases and the DNA fragments that contained the alpha-globin structural gene identified by hybridization with complementary DNA. The patient had only one alpha-globin structural gene, located in a DNA fragment shorter than that found in normal or alpha-thalassemia trait individuals, but similar to that present in other patients with Hb H disease. Morphologic studies of bone marrow by light and electron microscopy revealed erythroid hyperplasia with inclusions in polychromatic and orthochromatic erythroblasts, suggesting early precipitation of an unstable hemoglobin. The lack of demonstrable Hb H may be the result of both diminished amounts of beta(A) available for Hb H formation (since one beta-globin gene is beta(S)) and the greater affinity of alpha-chains for beta(A) than beta(S)-globin chains leading to the formation of relatively more Hb A than Hb S. The presence of a beta(S) gene may thus modify the usual clinical expression of Hb H disease.

A total of 102 apparently healthy and randomly selected Turks who either immigrated from Western Thrace or were still living there were studied for haemoglobin variants, high Hb A2 beta thalassaemia, G6PD deficiency, and haptoglobin types. The incidence of haemoglobins S and O Arab were 2.9 and 3.9% respectively. The incidence of high A2 beta thalassaemia was 10.8% and that of G6PD deficiency 5%. The gene frequencies of Hp1 and Hp2 were 0.326 and 0.674, respectively.

In order to evaluate the polymorphism of hemoglobin in a population of Equatorial Africa, we undertook a prospective study of 146 births at a rural maternity hospital close to Brazzaville (P.R. Congo). This showed among the mothers 31 (22%) carriers of the sickle cell trait (AS), six with delta mutation, and two with beta-thalassemia trait. Among the children, 27 (18.5%) had sickle cell trait and one had sickle cell homozygosity. The frequency of the HbF Sardinia trait was 7.5%. This and other studies suggested a dilution gradient from Europe to Africa. Hemoglobin Bart's could be visually detected in 23.3% of the new-born babies. We attempted to distinguish between those infants with a high level of Hb Bart's (Bart's ++ group: 13.7%) and a group with a detectable Hb Bart's level that in our experimental conditions is between 1 and 2% (Bart's + group: 9.6%). Mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) were 88.6 +/- 5.7 fl and 29.0 +/- 2.1 pg in the Bart's ++ group; 94.5 +/- 10.9 fl and 30.6 +/- 4.1 pg in the Bart's + group; whereas they were 101.0 +/- 8.7 fl and 33.9 +/- 2.5 pg in the control group. Since iron deficiencies are very rare in new-borns and selecting according to published data on black people as homozygous alpha-thalassemia of the type I (-alpha/-alpha), individuals of the Bart's ++ group whose MCV was below 95 fl and MCV below 30 pg, the gene frequency is estimated to be 34% and that of heterozygotes (-alpha/alpha alpha) 45%. These high frequencies were confirmed in AS mothers: 45% showed a significant decrease of the S fraction.

A Turkish Cypriot family was investigated for suspected heterozygous sickle cell disease, which had been reported in a maternal branch of the family resident in England. Two maternal grandparents were of African Negro origin. Pseudosickling was noted in members of the family who were found to have an abnormal hemoglobin fraction. This abnormal fraction proved to be Hemoglobin Setif (alpha 94 Asp leads to Tyr). Family studies demonstrated the presence of this hemoglobin in varying proportions in the mother and 2 of the 4 children. alpha and beta thalassemia traits are also present in several family members.

Two siblings assumed on the basis of clinical and hematological evidence to have homozygous sickle cell (SS) disease were found to have a mother without sickle hemoglobin. Subsequent investigation and hemoglobin structural studies indicated the diagnosis to be sickle cell-Hb Lepore Boston syndrome. This syndrome generally manifests clinically significant sickle cell disease, and this genotype should be borne in mind in apparent SS disease where a parent without sickle hemoglobin in discovered.

The present paper describes a homozygote patient for the gene of hemoglobin S. The patient is the first child of non-consanguineous parents. The family study revealed 11 heterozygote subjects for the sickle cell disease.

We report the results of a systematic survey carried on 8.961 healthy Guadeloupean blood donors, where we looked for hemoglobinopathies. The results are expressed in regard of the race and site of living (urban or rural) of the subjects. Of these 8.961 subjects, aged 18 to 60, 7.75% were sickle cell trait carriers, 2.36% were heterozygous for Hb C and 0,2% had a significant elevation of Hb F. Were also report some less frequent phenotypes : three Hb AD, five Hb SC, one Hb CC, two Hb SF, one Hb CF and one case of isolated Hb, A2 elevation. Two rare hemoglobinopathies are reported: a case of Hb Korle Bu associated with Hb S an a case of Hb N-Baltimore. Our datas regarding race and sex of Hb S and Hb C carriers are evaluated. These results are compared to previous studies carried on healthy blood donors in Guadeloups. Problems related to the detection of hemoglobin abnormalities in a blood transfusion center are reviewed.

The ratio of total globin alpha to beta chain synthesis was determined in reticulocytes isolated from the blood of the members of a black family, some of whom had sickle cell trait with low blood HbS concentrations (25-30%). The results support the hypothesis that sickle cell trait individuals with low HbS concentrations also carry a gene for alpha-thalassemia.