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Biomedical Reports Jun 2022The types of β-thalassemia mutations, α-thalassemia interactions, and Hb F-associated SNPs have been described in association with variable disease phenotypes. This...
The types of β-thalassemia mutations, α-thalassemia interactions, and Hb F-associated SNPs have been described in association with variable disease phenotypes. This study aimed to determine the updated spectrum of β-thalassemia mutations and evaluate the contribution of primary and secondary genetic modifiers and SNPs to disease severity, age at onset, and predicted life expectancy in southern Thai β-thalassemia patients. A total of 181 β-thalassemia patients were enrolled and 135 β-thalassemia/Hb E patients without α-thalassemia interactions were divided into three categories according to disease severity, age at onset, and predicted life expectancy. A total of 16 β-thalassemia mutations were identified in this study, and the three most common β-thalassemia mutations accounted for 61.4% of all mutations. It was also found that the I polymorphism and rs2071348 were associated with age at onset and the predicted life expectancy. More than 82% of β-thalassemia/Hb E patients with CC genotype (I) were 3 years old or younger at onset. Additionally, >90% of the higher predicted life expectancy in β-thalassemia/Hb E patients had the T allele of I. Therefore, genetic prediction for age at onset and life expectancy is beneficial and practical during prenatal diagnosis or newborn screening for better genetic counseling and optimal management.
PubMed: 35620315
DOI: 10.3892/br.2022.1535 -
Frontiers in Genetics 2022Thalassemia is a common inherited hematological disease with genetic disorders characterized by imbalanced synthesis of the globin chains. Due to the improvement of...
Thalassemia is a common inherited hematological disease with genetic disorders characterized by imbalanced synthesis of the globin chains. Due to the improvement of treatment methods, patients with thalassemia can survive for a long time. Therefore, it is not uncommon for patients with thalassemia suffering from malignant tumors. However, there are quite few reports on thalassemia patients complicated with breast cancer. Herein, we try to investigate the prevalence and genetic disorders spectrum of thalassemia in patients with breast cancer. Blood routing tests and serum ferritin analysis were conducted in 1887 breast cancer patients treated in the department of radiation oncology during 1 April 2020 and 30 March 2022. The suspected thalassemia carriers with small mean corpuscular volume (MCV), mean corpuscular hemoglobin content (MCH) or mean corpuscular hemoglobin concentration (MCHC) but the concentration of serum ferritin within normal limits were further investigated by polymerase chain reaction (PCR) and flow through hybridization gene chip to detect common mutations of α-globin and β-globin genes using Thalassemia Geno Array Diagnostic Kit. The prevalence and genetic mutation spectrum of thalassemia among breast cancer patients were analyzed. Four hundred and eighty-nine suspected thalassemia carriers were detected by complete blood cell counts and serum ferritin analysis among 1887 breast cancer patients. One hundred and seven cases (5.7%) were identified as carriers of thalassemia, of which 55 cases (51.4%) were α-thalassemia, 50 cases (46.7%) were β-thalassemia, and 2 cases (1.9%) were co-inheritance of α-thalassemia and β-thalassemia simultaneously. In α-thalassemia, the most prevalent genotype is -/αα; as for β-thalassemia, β/β is the most common genotype. The degree of anemia is more severe in β-thalassemia than in α-thalassemia. This is the first comprehensive molecular epidemiological investigation on thalassemia among breast cancer patients. Our data indicated that thalassemia was not uncommon in breast cancer patients. The physicians should have the knowledge to avoid misdiagnosis as iron deficiency anemia.
PubMed: 36330446
DOI: 10.3389/fgene.2022.1001369 -
Thrombosis Journal Nov 2023Alpha-thalassemia (α-thalassemia) is one of the most common monogenic diseases in Saudi Arabia and is associated with significant morbidity. Premarital testing programs...
BACKGROUND
Alpha-thalassemia (α-thalassemia) is one of the most common monogenic diseases in Saudi Arabia and is associated with significant morbidity. Premarital testing programs in Saudi Arabia reduce the burden of hemoglobinopathy disorders, and ongoing monitoring is required. We aimed to explore the molecular nature of α-globin genes and identify the most common genotypes and regions with a high risk of α-thalassemia in Saudi Arabia.
METHODS
This retrospective study was conducted between January 2021 and December 2022. Six hundred twenty-five samples from patients with microcytic hypochromic anemia in Saudi Arabia were analyzed using reverse dot blot hybridization (RDBH)-based multiplex-PCR, which screens for the known 21 mutations of α-globin genes.
RESULTS
Seven mutations in the α-globin gene were identified in 88.96% (556) patients. The most frequent abnormality of a-globin genes was -α (62.3%), followed by α2 (20.7%) and α2 polyA-1 (α2) (14.1%). Interestingly, α2 polyA-2 (α2) was identified in Saudi and presented with -MED, causing Haemoglobin H disease. The incidence of α-thalassemia in Saudi Arabia's cities showed significant differences (P = 0.004). Jeddah City had the highest percentage of cases (25%), followed by Makkah (23%), Taif (13.3%), and Al-Ahassa (12.4%).
CONCLUSION
The study provides current knowledge about the molecular nature of α- thalassemia, highlights the common genotypes that could contribute to disease occurrence in the Saudi population, and sheds light on Saudi regions with a high incidence. It also recommends further studies in a larger population and with differently composed molecular assays to verify these findings.
PubMed: 37950286
DOI: 10.1186/s12959-023-00560-w -
Journal of Clinical Laboratory Analysis Mar 2024Thalassemia is an inherited hemolytic disease, the complications and sequelae of which have posed a huge impact on both patients and society. But limited studies have...
BACKGROUND
Thalassemia is an inherited hemolytic disease, the complications and sequelae of which have posed a huge impact on both patients and society. But limited studies have investigated the molecular characterization of α- and β-thalassemia in children from Guizhou, China.
METHODS
Between January 2019 and December 2022, a total of 3301 children, aged 6 months to 18 years, suspected of having thalassemia underwent molecular analysis.
RESULTS
Out of the total sample, 824 (25%) children were found to carry thalassemia mutations. The carrier rates of α-thalassemia, β-thalassemia, and α + β-thalassemia were determined as 8.1%, 15.6%, and 1.3%, respectively. Approximately 96.5% of the α-thalassemia gene mutations were --SEA (51%), αα (20.9%), -α (19.6%), and -α (5.0%). The most prevalent mutations of β-thalassemia were β (41.5%), β (37.7%), and β (11.3%). Additionally, we identified rare cases, including one case with αα/αα, two cases with triplicated α-thalassemia (one case with ααα/ααα and β/β and the other with ααα/αα and βE /β), and also one case with α α/-α and β/β.
CONCLUSIONS
Our study findings provide important insights into the heterogeneity of thalassemia carrier rates and molecular profiles among children in the Guizhou region. The findings support the development of prevention strategies to reduce the incidence of severe thalassemia in the future.
Topics: Child; Humans; Adolescent; beta-Thalassemia; alpha-Thalassemia; Genotype; China; Mutation
PubMed: 38506255
DOI: 10.1002/jcla.25022 -
Blood Mar 2017Hemoglobin (Hb) Bart's hydrops fetalis syndrome (BHFS) resulting from α-thalassemia is considered a universally fatal disorder. However, over the last 3 decades,... (Review)
Review
Hemoglobin (Hb) Bart's hydrops fetalis syndrome (BHFS) resulting from α-thalassemia is considered a universally fatal disorder. However, over the last 3 decades, improvements in intrauterine interventions and perinatal intensive care have resulted in increasing numbers of BHFS survivors. We have initiated an international registry containing information on 69 patients, of which 31 are previously unpublished. In this perspective, we analyze the available clinical information to document the natural history of BHFS. In the future, once we have accrued sufficient cases, we aim to build on this study and provide information to allow counseling of at-risk couples. To date, 39 patients have survived beyond the age of 5 years, 18 of whom are now older than 10 years. Based on the available cases, we find evidence to suggest that intrauterine therapy provides benefits during the perinatal and neonatal period; however, it may not provide additional benefits to long-term growth and neurodevelopmental outcomes. Growth retardation is a major adverse long-term outcome among BHFS patients with ∼40% being severely affected in terms of weight and ∼50% in terms of height. There is also an increased risk of neurodevelopmental delay as we find 20% (11/55) of BHFS survivors suffer from a serious delay of ≥6 months. Most patients in the registry require lifelong transfusion and often have associated congenital abnormalities and comorbidities. This perspective is a first step in gathering information to allow provision of informed counseling on the predicted outcomes of affected babies.
Topics: Adolescent; Adult; Child; Child, Preschool; Female; Hemoglobins, Abnormal; Humans; Hydrops Fetalis; Infant; Infant, Newborn; Male; Registries; Survivors; Young Adult; alpha-Thalassemia
PubMed: 28057638
DOI: 10.1182/blood-2016-08-697110 -
PloS One 2023Regions with a high prevalence of α-thalassemia (α-thal) require simple, rapid, and accurate tests for carrier screening and prenatal diagnosis. Diagnosis of multiple...
Regions with a high prevalence of α-thalassemia (α-thal) require simple, rapid, and accurate tests for carrier screening and prenatal diagnosis. Diagnosis of multiple deletions in a single tube is necessary to clearly identify individuals with α0-thalassemia in the routine setting, especially in at-risk couples. Therefore, we aimed to develop a single-tube multiplex real-time PCR with EvaGreen and high-resolution melting (HRM) analysis for the identification of α0-thalassemia Southeast Asian (SEA), Thai and Chiang Rai (CR) type deletions. The results of the HRM analysis indicated that the amplified fragments from α0-thal--CR,--THAI,--SEA, and the wild-type α-globin gene had specific peak heights at mean melting temperature (Tm) values of 85.40°C, 86.50°C, 87.65°C, and 91.04°C, respectively. The frequencies of α0-thal--SEA,--THAI,--CR obtained from routine testing in 2,135 samples were 17.89%, 0.19% and 0.19%, respectively. This method would be useful for preventing Hb Bart's hydrops fetalis. Detection of multiple deletions in a single run is cost-effective, highly accurate and timesaving. This technique could enable wider α-thalassemia diagnosis in high prevalence areas and served as an example for thalassemia routine setting.
Topics: Pregnancy; Female; Humans; alpha-Thalassemia; Thailand; Real-Time Polymerase Chain Reaction; Southeast Asian People; Hydrops Fetalis; Prenatal Diagnosis; Hemoglobins, Abnormal
PubMed: 37930985
DOI: 10.1371/journal.pone.0293838 -
Mediterranean Journal of Hematology and... 2019The finding of many Thai Hb E-β-thalassemia patients with non-transfusion dependent thalassemia (NTDT) phenotype without co-inheritance of α-thalassemia has prompted...
BACKGROUND
The finding of many Thai Hb E-β-thalassemia patients with non-transfusion dependent thalassemia (NTDT) phenotype without co-inheritance of α-thalassemia has prompted us to investigate the existence of other genetic modifying factors.
METHODS
Study was done on 122 adult Thai patients with NTDT Hb E-β-thalassemia patients without co-inheritance of α-thalassemia. Multiple single-nucleotide polymorphisms (SNPs) associated with γ-globin gene expression including the γ-I of HBG2 gene, rs2297339, rs4895441, and rs9399137 of the HBS1L-MYB gene, rs4671393 in the BCL11A gene, and G176AfsX179, T334R, R238H and -154 (C-T) in the KLF1 gene were investigated using PCR and related techniques.
RESULTS
Heterozygous and homozygous for γ-I of HBG2 gene were detected at 70.5% and 7.4%, respectively. Further DNA analysis identified the rs2297339 (C-T), rs4895441 (A-G), and rs9399137 (T-C) of HBS1L-MYB gene in 86.9%, 25.4%, and 23.0%, respectively. The rs4671393 (G-A) of the BCL11A gene was found at 31.2%. For the KLF1 gene, only T334R was detected at 9.0%.
CONCLUSIONS
It was found that these SNPs, when analyzed in combination, could explain the mild phenotypic expression of all cases. These results underline the importance of these informative SNPs on phenotypic expression of Hb E-β-thalassemia patients.
PubMed: 31308914
DOI: 10.4084/MJHID.2019.038 -
PLoS Genetics Nov 2022Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as...
Telomerase activity is the principal telomere maintenance mechanism in human cancers, however 15% of cancers utilise a recombination-based mechanism referred to as alternative lengthening of telomeres (ALT) that leads to long and heterogenous telomere length distributions. Loss-of-function mutations in the Alpha Thalassemia/Mental Retardation Syndrome X-Linked (ATRX) gene are frequently found in ALT cancers. Here, we demonstrate that the loss of ATRX, coupled with telomere dysfunction during crisis, is sufficient to initiate activation of the ALT pathway and that it confers replicative immortality in human fibroblasts. Additionally, loss of ATRX combined with a telomere-driven crisis in HCT116 epithelial cancer cells led to the initiation of an ALT-like pathway. In these cells, a rapid and precise telomeric elongation and the induction of C-circles was observed; however, this process was transient and the telomeres ultimately continued to erode such that the cells either died or the escape from crisis was associated with telomerase activation. In both of these instances, telomere sequencing revealed that all alleles, irrespective of whether they were elongated, were enriched in variant repeat types, that appeared to be cell-line specific. Thus, our data show that the loss of ATRX combined with telomere dysfunction during crisis induces the ALT pathway in fibroblasts and enables a transient activation of ALT in epithelial cells.
Topics: Humans; Telomerase; Telomere Homeostasis; X-linked Nuclear Protein; alpha-Thalassemia; Telomere; Neoplasms
PubMed: 36350851
DOI: 10.1371/journal.pgen.1010485 -
PLoS Genetics Mar 2018Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little...
Co-inheritance of α-thalassemia has a significant protective effect on the severity of complications of sickle cell disease (SCD), including stroke. However, little information exists on the association and interactions for the common African ancestral α-thalassemia mutation (-α3.7 deletion) and β-globin traits (HbS trait [SCT] and HbC trait) on important clinical phenotypes such as red blood cell parameters, anemia, and chronic kidney disease (CKD). In a community-based cohort of 2,916 African Americans from the Jackson Heart Study, we confirmed the expected associations between SCT, HbC trait, and the -α3.7 deletion with lower mean corpuscular volume/mean corpuscular hemoglobin and higher red blood cell count and red cell distribution width. In addition to the recently recognized association of SCT with lower estimated glomerular filtration rate and glycated hemoglobin (HbA1c), we observed a novel association of the -α3.7 deletion with higher HbA1c levels. Co-inheritance of each additional copy of the -α3.7 deletion significantly lowered the risk of anemia and chronic kidney disease among individuals with SCT (P-interaction = 0.031 and 0.019, respectively). Furthermore, co-inheritance of a novel α-globin regulatory variant was associated with normalization of red cell parameters in individuals with the -α3.7 deletion and significantly negated the protective effect of α-thalassemia on stroke in 1,139 patients with sickle cell anemia from the Cooperative Study of Sickle Cell Disease (CSSCD) (P-interaction = 0.0049). Functional assays determined that rs11865131, located in the major alpha-globin enhancer MCS-R2, was the most likely causal variant. These findings suggest that common α- and β-globin variants interact to influence hematologic and clinical phenotypes in African Americans, with potential implications for risk-stratification and counseling of individuals with SCD and SCT.
Topics: Adult; Black or African American; Anemia, Sickle Cell; Cohort Studies; DNA Copy Number Variations; Erythrocytes, Abnormal; Glomerular Filtration Rate; Glycated Hemoglobin; Hemoglobin, Sickle; Humans; Phenotype; Sickle Cell Trait; Young Adult; alpha-Globins; alpha-Thalassemia
PubMed: 29590102
DOI: 10.1371/journal.pgen.1007293 -
Taiwanese Journal of Obstetrics &... Sep 2023Hemoglobin Quong Sze (Hb QS) is one of the most common non-deletional α-thalassemia (α-thal), which is prevalent in the Southern Chinese population. However, there are...
OBJECTIVE
Hemoglobin Quong Sze (Hb QS) is one of the most common non-deletional α-thalassemia (α-thal), which is prevalent in the Southern Chinese population. However, there are still few comprehensive researches on the molecular characterization of Hb QS. So it is important to find out appropriate diagnosis and characterization of Hb QS carrier for genetic counseling.
MATERIALS AND METHODS
A hematological screening including hematological indices and hemoglobin analysis was performed in 113,400 individuals from Huizhou city, Southern China. Then, suspected thalassemia carriers were detected by a suspension-array system and DNA sequencing for α- and β-thal.
RESULTS
In our study, we identified 521 subjects who were Hb QS carriers, including fourteen different genotypes. Among them, 445 Hb QS heterozygotes showed a decrease in the mean corpuscular hemoglobin (MCH), 16 compound heterozygotes for Hb QS/α-thal presented mild thalassemia, 28 Hb QS in combination with --/αα manifested as Hb H disease, varying clinical symptoms from only moderate anemia to severe anemia and requiring blood transfusion, and 29 double heterozygotes for Hb QS and β-thal behaved as β-thal trait. The mean corpuscular volume (MCV) and MCH were significantly reduced and no Hb H peak could be detected in one patient with Hb H-Hb QS and β-thal. Meanwhile, we identified two homozygous Hb QS carriers, who showed mild to moderate anemia and increased Hb A level but negative results from a sequencing analysis for the first time. Additionally, Comparison of hematological parameters among the major four genotype groups showed significant differences in most box-whisker plots.
CONCLUSION
People who originated from Huizhou city showed many genotypes and diversity in the clinical manifestations of Hb QS carriers. This study enlarges the mutation spectrum of α-thal and emphasizes that reliable detection of the gene mutations is important for genetic counseling. It also strengthens the prevention and control of thalassemia.
Topics: Humans; Clinical Relevance; Hemoglobins, Abnormal; alpha-Thalassemia; China
PubMed: 37678999
DOI: 10.1016/j.tjog.2023.07.012