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Hemoglobin May 2020In this study, Hb A variants and their association with α- and β-thalassemia (α- and β-thal) were analyzed. We performed molecular analyses to identify α-thal...
In this study, Hb A variants and their association with α- and β-thalassemia (α- and β-thal) were analyzed. We performed molecular analyses to identify α-thal [- - (Southeast Asian), - - (Thai), -α (rightward) and -α (leftward)] deletions, and Hb Constant Spring (Hb CS; : c.427T>C), Hb A-Melbourne (: c.130G>A), Hb A' (: c.49G>C), Hb A-Lampang (: c.142G>A). β-Thalassemia mutations included codon 17 (A>T) (: c.52A>T), codons 41/42 (-TCTT) (: c.126_129delCTTT), codons 71/72 (+A) (: c.216_217insA) and IVS-I-1 (G>T) (: c.92+1G>T) in 23 samples which had a Hb A variant peak in zone 1 of the capillary electrophoresis (CE) electropherogram. Results showed that 20 patients (87.0%) carried Hb A-Melbourne with seven different genotypes for α- and β-thal, two (8.7%) carried Hb A' and one (4.3%) carried Hb A-Lampang. All three samples doubly heterozygous for Hb A-Melbourne/β-thal had Hb A levels lower than 4.0%, while summation of Hb A and Hb A-Melbourne ranged from 4.9-5.3%, reaching the accepted range (4.0-10.0%) for β-thal trait. Hb A-Melbourne is the most common δ-globin variant in the Thai population. Hb A variant and Hb A levels must be combined in order to diagnose carriers of β-thal. β-Globin haplotype analysis showed an association with a single β-globin haplotype [+ - - - - + +] of Hb A-Melbourne, Hb A' and Hb A-Lampang, indicating that they were of the same origin. We developed a multiplex allele-specific polymerase chain reaction (ASPCR) for simultaneous detection of these three Hb A variants.
Topics: Alleles; Capillary Electrochromatography; DNA Mutational Analysis; Erythrocyte Indices; Genetic Variation; Genotype; Hemoglobin A2; Hemoglobins, Abnormal; Humans; Mutation; Phenotype; Polymerase Chain Reaction; Population Surveillance; Thailand; alpha-Thalassemia; beta-Thalassemia
PubMed: 32482156
DOI: 10.1080/03630269.2020.1770099 -
Clinical Chemistry Mar 2023This is an editorial focusing on the clinical perspective of a long-read sequencing method in the prenatal diagnosis of alpha- and beta-thalassemia, including a...
This is an editorial focusing on the clinical perspective of a long-read sequencing method in the prenatal diagnosis of alpha- and beta-thalassemia, including a comparison between this method and standard PCR-based methods. Though incremental, the increased sensitivity and specificity using long-read sequencing is an important advantage of this methodology in the prenatal diagnostic arena due to false positive or false negative results having greater consequence when a family is making decisions about their pregnancy.
Topics: Pregnancy; Female; Humans; alpha-Thalassemia; Prenatal Diagnosis; beta-Thalassemia; Sequence Analysis, DNA; Sensitivity and Specificity
PubMed: 36648456
DOI: 10.1093/clinchem/hvac223 -
Clinica Chimica Acta; International... Jan 2022Since screening of α-thalassemia carriers by low HbA has a low positive predictive value (PPV), the PPV was as low as 40.97% in our laboratory, other more effective...
BACKGROUND
Since screening of α-thalassemia carriers by low HbA has a low positive predictive value (PPV), the PPV was as low as 40.97% in our laboratory, other more effective screening methods need to be devised. This study aimed at developing a machine learning model by using red blood cell parameters to identify α-thalassemia carriers from low HbA patients.
METHODS
Laboratory data of 1213 patients with low HbA used for modeling was randomly divided into the training set (849 of 1213, 70%) and the internal validation set (364 of 1213, 30%). In addition, an external data set (n = 399) was used for model validation. Fourteen machine learning methods were applied to construct a discriminant model. Performance was evaluated with accuracy, sensitivity, specificity, etc. and compared with 7 previously published discriminant function formulae.
RESULTS
The optimal model was based on random forest with 5 clinical features. The PPV of the model was more than twice the PPV of HbA, and the model had a high negative predictive value (NPV) at the same time. Compared with seven formulae in screening of α-thalassemia carriers, the model had a better accuracy (0.915), specificity (0.967), NPV (0.901), PPV (0.942) and area under the receiver operating characteristic curve (AUC, 0.948) in the independent test set.
CONCLUSION
Use of a random forest-based model enables rapid discrimination of α-thalassemia carriers from low HbA cases.
Topics: Erythrocytes; Hemoglobin A2; Humans; Mass Screening; alpha-Thalassemia; beta-Thalassemia
PubMed: 34883090
DOI: 10.1016/j.cca.2021.12.003 -
Pediatric Hematology and Oncology Sep 2022Hemoglobin H (Hb H) disease is a subtype of α-thalassemia caused by deletional and/or non-deletional mutations in three alpha-globin genes in which the various...
Hemoglobin H (Hb H) disease is a subtype of α-thalassemia caused by deletional and/or non-deletional mutations in three alpha-globin genes in which the various genotypes determine the disease severity. This study was aimed to investigate the frequency of alpha gene mutations and genotypes and their correlation with hematological and clinical characteristics in Iran. Among 202 patients diagnosed with Hb H disease through a national study in Iran according to standard methods, we had access to the hematologic and clinical findings and genetic data of 101 patients in whom genetic study was performed. Genomic DNA from peripheral blood was extracted and analyzed for identification of α-globin gene mutations using Multiplex Gap Polymerase Chain Reaction, Reverse Hybridization Assay, and finally Direct DNA Sequencing method. Twenty-one different mutations and thirty genotypes were detected in 101 patients with Hb H disease. In total, 39 patients (38.6%) were deletional and 62 patients (61.4%) were non-deletional type of the disease. The mutation was highly prevalent in almost half of the patients (56.4%). Among various genotypes, -/-a (29.7%) and -α/-α (6.9%) were the most prevalent genotypes found in the studied group. Patients with non-deletional type presented with more severe hematological and clinical findings. Hb H percentage and serum ferritin levels were significantly higher in non-deletional patients in comparison to the deletional group ( < 0.05). 12 (11.9%) and 40 (39.6%) out of 101 patients were on regular and occasional transfusions, respectively. 83% of those with regular transfusion belonged to the non-deletional group. Among transfusion-dependent patients, -/αα and α/-α were the most common genotypes. In this study, two patients with -α/αα and -/α genotypes experienced thrombotic events. This study indicated that although non-deletional genotypes of Hb H disease were responsible for more clinical severity of the disease, due to the presence of severe phenotypes even in deletional types, no definite correlation was found between genotype and phenotype.
Topics: Genotype; Humans; Iran; Mutation; Phenotype; alpha-Globins; alpha-Thalassemia
PubMed: 34951342
DOI: 10.1080/08880018.2021.2017529 -
Hemoglobin May 2020Hb Westmead (α122(H5)His>Gln) (: c.369C>G) is a common α-globin variant causing α-thalassemia (α-thal) in Mainland China. In this study, we report the hematological...
Hb Westmead (α122(H5)His>Gln) (: c.369C>G) is a common α-globin variant causing α-thalassemia (α-thal) in Mainland China. In this study, we report the hematological characteristics in Hb Westmead carriers in a Chinese population. There were 546 individuals carrying Hb Westmead based on their molecular diagnosis: 514 Hb Westmead heterozygotes and 32 compound heterozygotes for Hb Westmead and α-thal. Compared to common deletional α-thal, Hb Westmead was associated with higher mean corpuscular hemoglobin (Hb) (MCH) values. Compound heterozygotes for Hb Westmead and α-thal showed significantly higher Hb, mean corpuscular volume (MCV) and MCH values than subjects with deletional Hb H disease. When compared to α-thal carriers, compound heterozygotes for Hb Westmead and α-thal showed similar Hb values, but significantly lower MCV and MCH values. Our results indicate that Hb Westmead is a silent nondeletional α-thal, with a deficiency of α-globin chain milder than deletional α-thal, and compound heterozygotes for Hb Westmead/α-thal have a phenotype similar to simple α-thal.
Topics: Alleles; China; DNA Mutational Analysis; Erythrocyte Indices; Genetic Association Studies; Genetic Predisposition to Disease; Hemoglobins, Abnormal; Heterozygote; Homozygote; Humans; Mutation; Phenotype; Polymerase Chain Reaction; Sequence Deletion; alpha-Globins; alpha-Thalassemia
PubMed: 32436451
DOI: 10.1080/03630269.2020.1768109 -
The Journal of Obstetrics and... May 2022To explore the effect of thalassemia on pregnancy outcomes of women with gestational diabetes mellitus (GDM).
AIM
To explore the effect of thalassemia on pregnancy outcomes of women with gestational diabetes mellitus (GDM).
METHODS
This retrospective study reviewed the medical records of women with GDM delivered at the Chongqing Maternal and Child Health Hospital in China between July 2017 and December 2020. The live singleton pregnancies with α or β-thalassemia were identified as the thalassemia group, included α-thalassemia subgroup and β-thalassemia subgroup, whereas pregnant women without thalassemia were randomly selected as the non-thalassemia group according to a control-to-case ratio of 10:1 by computerized randomization. Logistic regression analyses were used to explore the potential association between thalassemia and pregnancy outcomes.
RESULTS
A total of 223 pregnant women with GDM and thalassemia were analyzed, including women with α-thalassemia (n = 143) and β-thalassemia (n = 80). There were no significant differences in the incidence of adverse neonatal outcomes such as preterm birth and low-birth weight among groups. However, among pregnancy complications, significant differences were detected in the incidence of placenta increta, polyhydramnios, and postpartum anemia between the thalassemia group and the non-thalassemia group. Logistic regression results indicated that β-thalassemia increased the risk of polyhydramnios (odds ratio [OR] = 3.95, 95% confidence interval [CI]: 1.14-13.65, p = 0.030) and chorioamnionitis (OR = 3.61, 95%CI: 1.04-12.49, p = 0.043) compared with the non-thalassemia group.
CONCLUSION
In our study, thalassemia did not increase adverse neonatal outcomes, but β-thalassemia increased the risk of pregnancy complications, including polyhydramnios and chorioamnionitis.
Topics: Chorioamnionitis; Diabetes, Gestational; Female; Humans; Infant, Newborn; Polyhydramnios; Pregnancy; Pregnancy Complications; Pregnancy Outcome; Premature Birth; Retrospective Studies; alpha-Thalassemia; beta-Thalassemia
PubMed: 35212088
DOI: 10.1111/jog.15206 -
Human Genetics Jul 2022Epigenetic diseases can be produced by a stable alteration, called an epimutation, in DNA methylation, in which epigenome alterations are directly involved in the... (Review)
Review
Epigenetic diseases can be produced by a stable alteration, called an epimutation, in DNA methylation, in which epigenome alterations are directly involved in the underlying molecular mechanisms of the disease. This review focuses on the epigenetics of two inherited metabolic diseases, epi-cblC, an inherited metabolic disorder of cobalamin (vitamin B) metabolism, and alpha-thalassemia type α-ZF, an inherited disorder of α2-globin synthesis, with a particular interest in the role of aberrant antisense transcription of flanking genes in the generation of epimutations in CpG islands of gene promoters. In both disorders, the epimutation is triggered by an aberrant antisense transcription through the promoter, which produces an H3K36me3 histone mark involved in the recruitment of DNA methyltransferases. It results from diverse genetic alterations. In alpha-thalassemia type α-ZF, a deletion removes HBA1 and HBQ1 genes and juxtaposes the antisense LUC7L gene to the HBA2 gene. In epi-cblC, the epimutation in the MMACHC promoter is produced by mutations in the antisense flanking gene PRDX1, which induces a prolonged antisense transcription through the MMACHC promoter. The presence of the epimutation in sperm, its transgenerational inheritance via the mutated PRDX1, and the high expression of PRDX1 in spermatogonia but its nearly undetectable transcription in spermatids and spermatocytes, suggest that the epimutation could be maintained during germline reprogramming and despite removal of aberrant transcription. The epivariation seen in the MMACHC promoter (0.95 × 10) is highly frequent compared to epivariations affecting other genes of the Online Catalog of Human Genes and Genetic Disorders in an epigenome-wide dataset of 23,116 individuals. This and the comparison of epigrams of two monozygotic twins suggest that the aberrant transcription could also be influenced by post-zygotic environmental exposures.
Topics: DNA Methylation; Epigenesis, Genetic; Humans; Male; Metabolic Diseases; Oxidoreductases; Semen; alpha-Thalassemia
PubMed: 35190856
DOI: 10.1007/s00439-021-02414-9 -
BMC Medicine Oct 2023Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Single low-dose primaquine (SLDPQ) effectively blocks the transmission of Plasmodium falciparum malaria, but anxiety remains regarding its haemolytic potential in patients with glucose-6-phopshate dehydrogenase (G6PD) deficiency. We, therefore, examined the independent effects of several factors on haemoglobin (Hb) dynamics in falciparum-infected children with a particular interest in SLDPQ and G6PD status.
METHODS
This randomised, double-blind, placebo-controlled, safety trial was conducted in Congolese and Ugandan children aged 6 months-11 years with acute uncomplicated P. falciparum and day (D) 0 Hbs ≥ 6 g/dL who were treated with age-dosed SLDPQ/placebo and weight-dosed artemether lumefantrine (AL) or dihydroartemisinin piperaquine (DHAPP). Genotyping defined G6PD (G6PD c.202T allele), haemoglobin S (HbS), and α-thalassaemia status. Multivariable linear and logistic regression assessed factor independence for continuous Hb parameters and Hb recovery (D42 Hb > D0 Hb), respectively.
RESULTS
One thousand one hundred thirty-seven children, whose median age was 5 years, were randomised to receive: AL + SLDPQ (n = 286), AL + placebo (286), DHAPP + SLDPQ (283), and DHAPP + placebo (282). By G6PD status, 284 were G6PD deficient (239 hemizygous males, 45 homozygous females), 119 were heterozygous females, 418 and 299 were normal males and females, respectively, and 17 were of unknown status. The mean D0 Hb was 10.6 (SD 1.6) g/dL and was lower in younger children with longer illnesses, lower mid-upper arm circumferences, splenomegaly, and α-thalassaemia trait, who were either G6PDd or heterozygous females. The initial fractional fall in Hb was greater in younger children with higher D0 Hbs and D0 parasitaemias and longer illnesses but less in sickle cell trait. Older G6PDd children with lower starting Hbs and greater factional falls were more likely to achieve Hb recovery, whilst lower D42 Hb concentrations were associated with younger G6PD normal children with lower fractional falls, sickle cell disease, α-thalassaemia silent carrier and trait, and late treatment failures. Ten blood transfusions were given in the first week (5 SLDPQ, 5 placebo).
CONCLUSIONS
In these falciparum-infected African children, posttreatment Hb changes were unaffected by SLDPQ, and G6PDd patients had favourable posttreatment Hb changes and a higher probability of Hb recovery. These reassuring findings support SLDPQ deployment without G6PD screening in Africa.
TRIAL REGISTRATION
The trial is registered at ISRCTN 11594437.
Topics: Male; Female; Humans; Child; Child, Preschool; Primaquine; Antimalarials; alpha-Thalassemia; Artemether, Lumefantrine Drug Combination; Artemether; Malaria, Falciparum; Hemoglobins; Glucosephosphate Dehydrogenase Deficiency; Plasmodium falciparum
PubMed: 37858129
DOI: 10.1186/s12916-023-03105-0 -
Pediatric Blood & Cancer Oct 2019Our objective was to investigate the combined and differential effects of alpha-thalassemia -3.7 kb deletion and HbF-promoting quantitative trait loci (HbF-QTL) in...
BACKGROUND
Our objective was to investigate the combined and differential effects of alpha-thalassemia -3.7 kb deletion and HbF-promoting quantitative trait loci (HbF-QTL) in Senegalese hydroxyurea (HU)-free children and young adults with sickle cell anemia (SCA).
PROCEDURE
Steady-state biological parameters and vaso-occlusive crises (VOC) requiring emergency admission were recorded over a 2-year period in 301 children with SCA. The age of the first hospitalized VOC was also recorded. These data were correlated with the alpha-globin and HbF-QTL genotypes. For the latter, three different genetic loci were studied (XmnI, rs7482144; BCL11A, rs1427407; and the HBS1L-MYB region, rs28384513) and a composite score was calculated, ranging from zero (none of these three polymorphisms) to six (all three polymorphisms at the homozygous state).
RESULTS
A positive clinical impact of the HbF-QTL score on VOC rate, HbF, leucocytes, and C-reactive protein levels was observed only for patients without alpha-thalassemia deletion. Conversely, combination of homozygous -3.7 kb deletion with three to six HbF-QTL was associated with a higher VOC rate. The age of the first hospitalized VOC was delayed for patients with one or two alpha-thalassemia deletions and at least two HbF-QTL.
CONCLUSION
Alpha-thalassemia -3.7 kb deletion and HbF-QTL are modulating factors of SCA clinical severity that interact with each other. They should be studied and interpreted together and not separately, at least in HU-free children.
Topics: Anemia, Sickle Cell; Child; Female; Fetal Hemoglobin; Genotype; Hemoglobin H; Humans; Male; Quantitative Trait Loci; Senegal; alpha-Thalassemia
PubMed: 31322815
DOI: 10.1002/pbc.27934 -
Human Genomics Aug 2023Thalassemia is an extremely prevalent monogenic inherited blood disorder in southern China. It is important to comprehensively understand the molecular spectrum of...
BACKGROUND
Thalassemia is an extremely prevalent monogenic inherited blood disorder in southern China. It is important to comprehensively understand the molecular spectrum of thalassemia in an area with such a high prevalence of thalassemia before taking appropriate actions for the prevention and treatment of this disorder. Herein, we explored the clinical feasibility of using next-generation sequencing (NGS) for large-scale population screening to illustrate the prevalence and spectrum of thalassemia in Southern Jiangxi.
METHODS
Blood samples collected from 136,312 residents of reproductive age in Southern Jiangxi were characterized for thalassemia by NGS. A retrospective analysis was then conducted on blood samples determined to be positive for thalassemia.
RESULTS
In total, 19,827 (14.545%) subjects were diagnosed as thalassemia carriers, and the thalassemia prevalence rate significantly varied by geographical region (p < 0.001). A total of 40 α-thalassemia genotypes including 21 rare genotypes were identified, with -@-/αα being the most prevalent genotype. 42 β-thalassemia genotypes including 27 rare genotypes were identified, with the most common mutation IVS II-654 C > T accounting for 35.257% of these β-thalassemia genotypes. Furthermore, 74 genotypes were identified among 608 individuals with combined α- and β-thalassemia. Notably, most individuals with rare thalassemia mutations had mildly abnormal hematologic parameters including microcytic hypochromia.
CONCLUSIONS
Our findings demonstrate the great heterogeneity and diverse spectrum of thalassemia in Southern Jiangxi, emphasizing the importance and necessity of persistent prevention and control of thalassemia in this region. Additionally, our findings further suggest that NGS can effectively identify rare mutations and reduce the misdiagnosis rate of thalassemia.
Topics: Humans; beta-Thalassemia; Retrospective Studies; alpha-Thalassemia; High-Throughput Nucleotide Sequencing; China
PubMed: 37592328
DOI: 10.1186/s40246-023-00520-5