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Molecular Genetics & Genomic Medicine Oct 2022Hemoglobinopathies, inherited disorders of hemoglobin (Hb), are the most common hereditary monogenic diseases of the red cell in the world. Few studies have been...
BACKGROUND
Hemoglobinopathies, inherited disorders of hemoglobin (Hb), are the most common hereditary monogenic diseases of the red cell in the world. Few studies have been conducted on hemoglobinopathies in Mauritania. Therefore, the aim of this work is to establish the molecular and epidemiological basis of hemoglobinopathies in a cohort of Mauritanian patients and to determine the haplotype of the β-globin gene cluster in sickle cell subjects.
METHODS
The molecular screening of Hb disorders in 40 Mauritanian patients was done by a polymerase-restriction fragment length polymorphism (RFLP) for the sickle cell disease (SCD) mutation, a PCR/sequencing method for β-thalassemia mutations, and by the multiplex polymerase chain reaction method for the α-thalassemia. The exploration of eight polymorphic sites (SNPs) within the β-globin gene cluster was conducted by PCR/RFLP method, to identify the HbS haplotypes from the sickle cell subjects.
RESULTS
The epidemiological study of our patients showed a high incidence in the Senegal River area (52.5%) and a high ethnic prevalence for the Heratin (47.5%) and the Pular (35%). Molecular study allowed us to identify eight different mutations in our sample analyzed. They are respectively: HbS (HBB:c.20A>T) (68.75%), Cd44 -C (HBB:c.135delC) (8.75%), -29A>G (HBB:c.-79A>G) (4.8%), -α-3.7 (g.34164_37967del3804) (3.75%), IVS-II-849A>G (HBB:c.316-2A>G) (2.25%) and Cd24T>A (HBB:c.75T>A), Hb Siirt (HBB:c.83C>G) and HbC (HBB:c.19G>A) each with (1.25%). Six different haplotypes are being explored among the SCD subjects with the Senegal haplotype as the most prevalent (66.7%), followed by Benin (10%), Arab-Indians (6.7%), Bantu (3.3%), and two atypical haplotypes.
CONCLUSION
Our findings enrich the epidemiological data in our population and could contribute to the establishment of a strategy of prevention and management through screening, genetic counseling, and prenatal diagnosis of Hemoglobinopathies in the Mauritanian population.
Topics: Anemia, Sickle Cell; Hemoglobinopathies; Humans; Mauritania; alpha-Thalassemia; beta-Globins
PubMed: 36106931
DOI: 10.1002/mgg3.2048 -
Frontiers in Oncology 2017Gliomas are the most common primary malignant brain tumor in humans. Lower grade gliomas are usually less aggressive but many cases eventually progress to a more... (Review)
Review
Gliomas are the most common primary malignant brain tumor in humans. Lower grade gliomas are usually less aggressive but many cases eventually progress to a more aggressive secondary glioblastoma (GBM, WHO Grade IV), which has a universally fatal prognosis despite maximal surgical resection and concurrent chemo-radiation. With the identification of molecular markers, however, there is promise for improving diagnostic and therapeutic strategies. One of the key molecular alterations in gliomas is the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, which is frequently mutated. One-third of pediatric GBM cases are also found to have the ATRX mutation and the genetic signatures are different from adult cases. The exact role of ATRX mutations in gliomagenesis, however, is unclear. In this review, we describe the normal cellular function of the ATRX gene product followed by consequences of its dysfunction. Furthermore, its possible association with the alternative lengthening of telomeres (ALT) phenotype is outlined. Lastly, therapeutic options potentiated through a better understanding of ATRX and the ALT phenotype are explored.
PubMed: 29359122
DOI: 10.3389/fonc.2017.00322 -
Hematology. American Society of... Dec 2021α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of... (Review)
Review
α-Thalassemia major (ATM) is a severe disease resulting from deletions in all 4 copies of the α-globin gene. Although it is usually fatal before birth, the advent of in utero transfusions has enabled survival of a growing number of children. Postnatal therapy consists of chronic transfusions or stem cell transplantation, similar to patients with β-thalassemia major. In this review, we discuss the experience with postnatal stem cell transplantation in patients with ATM, as well as the ongoing phase 1 clinical trial of in utero stem cell transplantation for this condition.
Topics: Blood Transfusion; Blood Transfusion, Intrauterine; Disease Management; Hematopoietic Stem Cell Transplantation; Humans; Prenatal Diagnosis; alpha-Thalassemia
PubMed: 34889445
DOI: 10.1182/hematology.2021000295 -
Genes Aug 2022Congenital malformations diagnosed by ultrasound screening complicate 3-5% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of... (Review)
Review
Congenital malformations diagnosed by ultrasound screening complicate 3-5% of pregnancies and many of these have an underlying genetic cause. Approximately 40% of prenatally diagnosed fetal malformations are associated with aneuploidy or copy number variants, detected by conventional karyotyping, QF-PCR and microarray techniques, however monogenic disorders are not diagnosed by these tests. Next generation sequencing as a secondary prenatal genetic test offers additional diagnostic yield for congenital abnormalities deemed to be potentially associated with an underlying genetic aetiology, as demonstrated by two large cohorts: the 'Prenatal assessment of genomes and exomes' (PAGE) study and 'Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study' performed at Columbia University in the US. These were large and prospective studies but relatively 'unselected' congenital malformations, with little Clinical Genetics input to the pre-test selection process. This review focuses on the incremental yield of next generation sequencing in single system congenital malformations, using evidence from the PAGE, Columbia and subsequent cohorts, with particularly high yields in those fetuses with cardiac and neurological anomalies, large nuchal translucency and non-immune fetal hydrops (of unknown aetiology). The total additional yield gained by exome sequencing in congenital heart disease was 12.7%, for neurological malformations 13.8%, 13.1% in increased nuchal translucency and 29% in non-immune fetal hydrops. This demonstrates significant incremental yield with exome sequencing in single-system anomalies and supports next generation sequencing as a secondary genetic test in routine clinical care of fetuses with congenital abnormalities.
Topics: Female; Fetus; High-Throughput Nucleotide Sequencing; Humans; Hydrops Fetalis; Infant, Newborn; Pregnancy; Pregnancy Trimester, First; Prospective Studies; Ultrasonography, Prenatal
PubMed: 36140685
DOI: 10.3390/genes13091517 -
Pakistan Journal of Medical Sciences 2017Alpha (α) thalassemia is a hereditary disorder and is caused by deletions or mutations in globin genes. It is present in two clinically significant forms: hemoglobin...
BACKGROUND & OBJECTIVE
Alpha (α) thalassemia is a hereditary disorder and is caused by deletions or mutations in globin genes. It is present in two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease. It is highly prevalent in South-East Asia or Mediterranean countries. The most common deletion reported in alpha thalassemia in Pakistani population was -α with a frequency of 8.3%, and the rare forms were -α (0.2%) and ααα (0.9%). In our study, diagnosis of severe anemia cases without any α and β mutations or deletions were made by using extended alpha thalassemia deletions panel. The main objective of this study was to determine the prevalence and to study the spectra of alpha thalassemia gene deletions in beta thalassemia patients with the use of an extended panel including --, --, --, --, -- in addition to -α, -α & -ααα.
METHODS
The samples were collected in ethylenediaminetetraacetic acid (EDTA) vacutainers. A total of 156 samples were analyzed for alpha thalassemia mutations. This cohort included 121 samples of beta thalassemia major, nine samples of beta thalassemia minor and 26 without any evidence of beta thalassemia mutations. DNA was extracted with Qiagen extraction kit. The primers for determination of different subsets of alpha thalassemia deletions were included. PCR amplification was performed and result interpreted on agarose gel.
RESULTS
Co-inheritance of alpha thalassemia (-α -α) with homozygous beta thalassemia was detected in 30% cases of studied cohort (37 out of 121). The most common found was -α deletion (35/37) as single/double deletions or in combination with -ααα. In undiagnosed cases screened for beta thalassemia major, we found Mediterranean (-α) deletion at specifically 875 bp on agarose gel. This is distinctive finding in case of detecting -α instead of any other deletion from Pakistan.
CONCLUSION
Alpha thalassemia deletions (-α -α) are the common co-inherited deletions found in beta thalassemia major patients. On the basis of results, we propose an extended alpha thalassemia genetic mutation panel should be used for screening of children presenting with anemia with suspicion of haemoglobinopathy.
PubMed: 28523047
DOI: 10.12669/pjms.332.11834 -
BMC Medical Genetics Oct 2020HbH disease results from dysfunction of three, less commonly two, α-globin genes through various combinations of deletion and non-deletion mutations. Characterization...
BACKGROUND
HbH disease results from dysfunction of three, less commonly two, α-globin genes through various combinations of deletion and non-deletion mutations. Characterization of the mutations and the underlying genotypes is fundamental for proper screening and prevention of thalassaemia in any region. The aim of this study was to explore the genetic arrangements of HbH disease and to correlate the genotypes with the clinical phenotypes.
METHODS
A total of 44 HbH disease patients were enrolled in this study. They were clinically and haematologically assessed. The patients were tested for 21 common α-globin gene mutations using multiplex PCR and reverse hybridization. According to the genotype, the patients were categorized into two separate sub-groups, deletion and non-deletion types HbH disease.
RESULTS
Within the studied HbH disease patients, eight different α-globin gene mutations were detected in nine different genetic arrangements. The -- and -α deletions were the two most frequently encountered mutations (37.5 and 35.2% respectively). Patients with deletion genotypes constituted 70.4%. The most common detected genotype was --/-α (59.1%), followed by αα/αα (13.6%). For the first time, coinheritance of two relatively mild mutations (-α/αα) was unpredictably detected in a 1.5 year-old child with Hb of 7.1 g/dL.
CONCLUSION
The HbH disease patients' clinical characteristics were variable with no ample difference between the deletion and non-deletion types. These results can be of benefit for the screening and management of thalassaemia in this region.
Topics: Adolescent; Adult; Aged; Child; Child, Preschool; Female; Genetic Association Studies; Genotype; Hemoglobin H; Humans; Infant; Iraq; Male; Middle Aged; Mutation; Phenotype; Young Adult; alpha-Globins; alpha-Thalassemia
PubMed: 33059634
DOI: 10.1186/s12881-020-01141-8 -
Frontiers in Pediatrics 2023Alpha thalassemia is one of the most common hereditary hemoglobin disorders worldwide, particularly in the Middle East, including Iran. Therefore, determining the...
BACKGROUND
Alpha thalassemia is one of the most common hereditary hemoglobin disorders worldwide, particularly in the Middle East, including Iran. Therefore, determining the spectrum and distribution of alpha thalassemia mutation is a fundamental component of preventive approaches and management strategies.
METHODS
The present study reviews the genetic testing and blood laboratory results of 455 candidates eligible for marriage who were suspected of being thalassemia carriers and on whom genetic testing was performed from 21 March 2013 to 31 December 2020 in Rasht City.
RESULTS
A total of 114 (25.05%) alpha thalassemia cases were identified. Fifteen different alpha mutations were found. The most common mutation among the study population was -α deletion in 55 patients (48.24%), followed by Hb Constant Spring (C.S) in 21 patients (18.42%) and poly A2 in 16 (14.03%). Also, most of the patients were silent carriers. The deletion type of mutation was much more common than non-deletion mutations.
CONCLUSION
Our study reveals genetic heterogeneity and alpha thalassemia diversity among the Rasht City population. We expect that these findings will help guide premarital screening and genetic counseling, prenatal diagnosis of thalassemia, preventive strategy development, as well as a compilation of the alpha thalassemia catalog in Guilan province.
PubMed: 37033172
DOI: 10.3389/fped.2023.1039148 -
Acta Medica Portuguesa Jul 2023Microcytosis and hypochromia result from deficient hemoglobin synthesis in red blood cells and are easily detected in a complete blood count test. These conditions are...
INTRODUCTION
Microcytosis and hypochromia result from deficient hemoglobin synthesis in red blood cells and are easily detected in a complete blood count test. These conditions are mainly due to iron nutritional deficiency, but may also result from some genetic diseases, such as thalassemia. The aim of this study was to determine the contribution of β- and α-thalassemia to these abnormal hematological phenotypes in a representative sample of adult individuals living in Portugal who participated in the first Portuguese National Health Examination Survey (INSEF).
MATERIAL AND METHODS
Among the 4808 INSEF participants, 204 had microcytosis, hypochromia or both. The corresponding 204 DNAs were screened for changes in the β-globin gene by next-generation sequencing and Sanger sequencing. In addition, α-thalassemia deletions within the α-globin cluster were investigated by Gap-PCR and multiplex ligation-dependent probe amplification.
RESULTS
In this selected subgroup of INSEF participants, 54 had α-thalassemia (26%), predominantly caused by the -α3.7kb deletion, and 22 were β-thalassemia carriers (11%) mainly due to point mutations in the β-globin gene previously known in Portugal.
CONCLUSION
Thalassemia trait is a frequent cause of microcytosis or hypochromia in Portugal since this genetic condition was found in 37% of the investigated cases.
Topics: Humans; alpha-Thalassemia; Portugal; Prevalence; beta-Thalassemia; beta-Globins
PubMed: 36898140
DOI: 10.20344/amp.19162 -
Scientific Reports Nov 2022Anemia is a major public health problem in many areas of Southeast Asia. Ascertaining anemia and defining its underlying causes is essential for providing appropriate...
Anemia is a major public health problem in many areas of Southeast Asia. Ascertaining anemia and defining its underlying causes is essential for providing appropriate care, management, and establishment of a control program. Limited studies on these have been carried out on people living at the borders of Thailand, Lao PDR, and Cambodia. This cross-sectional study was done in four areas along the borders of Thailand, Lao PDR, and Cambodia. Blood specimens were collected from subjects aged 15-18 years in four districts including Kantharalak, Si Sa Ket province (n = 36), Nam Khun (n = 109), Nam Yuen (n = 98), and Na Chaluai (n = 128), Ubon Ratchathani province, Thailand. RBC parameters were recorded, and serum ferritin (SF) level was measured. Diagnosis of thalassemia and hemoglobinopathies was based on hemoglobin (Hb) and DNA analyses. Measurement of C-reactive protein was performed to exclude false-negative result of iron deficiency. The prevalence of anemia was found to be 25.1%. ID accounted for only 10.5%. Various types of thalassemia were identified in 67.7% of the subjects. The overall prevalence of thalassemia included 3.5% α-thalassemia, 0.8% β-thalassemia, 47.7% Hb E, and 53.6% α-thalassemia. The proportions of ID, thalassemia and combined ID and thalassemia among anemic subjects were 6.5%, 66.6%, and 20.4%, respectively. The results indicate that thalassemia and hemoglobinopathies rather than ID are major causes of anemia in Thailand-Lao PDR-Cambodia triangle. This information should prove useful for implementing an anemia control program in the regions.
Topics: Humans; Iron Deficiencies; Thailand; Cross-Sectional Studies; Cambodia; Laos; Hemoglobinopathies; alpha-Thalassemia; beta-Thalassemia; Anemia, Iron-Deficiency
PubMed: 36333424
DOI: 10.1038/s41598-022-22016-3 -
Journal of Clinical Laboratory Analysis Feb 2019There is paucity of data on the influence of alpha thalassemia on the clinical and laboratory parameters among Nigerian sickle cell anemia (SCA) patients. This study...
BACKGROUND
There is paucity of data on the influence of alpha thalassemia on the clinical and laboratory parameters among Nigerian sickle cell anemia (SCA) patients. This study aimed to determine the prevalence of alpha thalassemia and the influence of alpha thalassemia on laboratory parameters and clinical manifestations in a group of young Nigerian SCA patients.
METHODS
This was a cross-sectional retrospective study conducted on 100 patients with SCA and 63 controls. The diagnosis of SCA was confirmed by DNA studies. Alpha thalassemia genotyping was performed by multiplex gap-PCR method. Laboratory parameters including complete blood count, hemoglobin quantitation, serum lactate dehydrogenase (LDH), and bilirubin were determined with standard techniques.
RESULTS
Alpha thalassemia was found in 41 (41.0%) patients compared to 24 (38.1%) controls (P = 0.744), and all were due to the 3.7 κb α-globin gene deletions. Alpha thalassemia was associated with more frequent bone pain crisis, higher hemoglobin concentration, red blood cell count, and HbA level among the patients. On the contrary, patients with alpha thalassemia had lower mean corpuscular volume, mean corpuscular hemoglobin, and white blood cell count (WBC) (P ˂ 0.05). There were 6 (6.0%) patients with leg ulcers, and none of them had alpha thalassemia, P = 0.04.
CONCLUSION
This study confirms that coexistence of alpha thalassemia with SCA significantly influences both the clinical and laboratory manifestations of young Nigerian SCA patients. The coexistence of this genetic modifier is associated with increased bone pain crisis and protects against sickle leg ulcers among the patients.
Topics: Adolescent; Adult; Anemia, Sickle Cell; Blood Cell Count; Child; Child, Preschool; Cross-Sectional Studies; Female; Gene Frequency; Hemoglobins; Humans; Male; Nigeria; Polymerase Chain Reaction; Retrospective Studies; Young Adult; alpha-Thalassemia
PubMed: 30129219
DOI: 10.1002/jcla.22656