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Carrier Screening For Inherited Genetic Conditions
Published in Vincenzo Berghella, Obstetric Evidence Based Guidelines, 2022
Whitney Bender, Lorraine Dugoff
Alpha-thalassemia results from a gene deletion of two or more copies of the four alpha-globin genes on chromosome 16. It is common among individuals of Southeast Asian, African, West Indian, and Mediterranean ancestry. Deletion of two genes, alpha-thalassemia trait, causes a mild hemolytic anemia. The deletions may occur on the same chromosome (cis aa/-) or on two different chromosomes (trans a-/a-). Individuals of Southeast Asian descent are more likely to carry the cis configuration compared to their African counterparts. Individuals with alpha-thalassemia trait are at increased risk for having a child with a more severe form of alpha-thalassemia. Hemoglobin H disease is caused by the deletion of three alpha-globin genes. Affected individuals have mild to moderate hemolytic anemia. Alpha-thalassemia major (Hb Bart disease) results from the absence of functional alpha-globin genes. Fetal hydrops and intrauterine fetal demise is the expected outcome in these cases due to the inability to produce functional HbF. Hemoglobin Bart disease does not usually occur in fetuses of alpha-thalassemia carriers of African origin, since individuals of African descent usually have the trans-configuration genotype. See Chap. 14 in Maternal-Fetal Medicine Evidence Based Guidelines.
The Red Blood Cell In Thalassemia *
Published in Ronald L. Nagel, Genetically Abnormal Red Cells, 2019
Eliezer Rachmilewitz, Ariella Oppenheim, Oded Shalev
The α-thalassemias are usually characterized by partial or complete deficiency or a-globin chains. Normally there are four a-globin genes per diploid genome, located on the short arm of chromosome 16. The two α genes on each chromosome are arranged in tandem, adjacent to each other. In a nonthalassemic individual the four genes are expressed at an approximately equal rate. α-Thalassemia may result from a deletion or malfunction of one, two, three, or all four genes. Deletion or dysfunction of a single gene is essentially asymptomatic. In the absence of two genes the condition is known as α-thalassemia trait. Patients with hemoglobin H disease have only one functioning α gene, and produce about 25% of the α chains. Deletion or mutations in all four genes is lethal and results in a condition known as hydrops fetalis. Molecular analysis revealed that in most cases α-thalassemia results from deletion of either one or both tandemly located α genes.16,18 The extent of the deletions and their end points vary, and they may encompass the entire α gene cluster, including the two embryonic ζ genes. There are also nondeletion α-thalassemias, caused by point mutations, usually in one of the two neighboring α genes. A case with identical point mutations on the two adjacent genes (situated in cis on the same chromosome) has been recently described.19 As suggested by the authors, this finding may reflect a recent gene conversion event within the human α-globin locus.
Clinical and genetic characteristics of hemoglobin H disease in Iran
Published in Pediatric Hematology and Oncology, 2022
Hassan Abolghasemi, Sharareh Kamfar, Azita Azarkeivan, Mehran Karimi, Bijan Keikhaei, Fahimeh Abolghasemi, Mohammad H. Radfar, Peyman Eshghi, Samin Alavi
The hemoglobin (Hb) molecule is a tetrameric protein including two alpha and two beta subunits that are synthesized independently by 2 multigene clusters located on chromosome 16 and 11 respectively.1 Thalassemic mutations in globin genes lead to the reduced or absent synthesis of hemoglobin chains.2 Alpha-thalassemia (α) as one of the most prevalent monogenic diseases in the world especially in Southeast Asia and the Middle East,3,4 is characterized by changes in the level of α-globin gene expression due to deletions or point mutations in one or more alpha globin genes.5–7 On the other hand, according to the frequency of missed or nonfunctional α-globin genes, α thalassemia can be classified to silent alpha thalassemia (single α-gene deletion (-α/αα)), alpha thalassemia trait (two alpha gene deletions in cis (–/αα) or in trans (- α/- α)), hemoglobin H disease (Hb H) (mutations in three α-globin genes (–/-α or –/αTα) and Hb Bart’s hydrops fetalis (deletion of four α-genes (- -/- -)).8,9
Detecting rare thalassemia in children with anemia using third-generation sequencing
Published in Hematology, 2023
Zhen-min Ren, Wu-jiao Li, Zhi-hao Xing, Xiao-ying Fu, Ju-yan Zhang, Yun-sheng Chen, De-fa Li
In addition to the TDT case, TGS confirmed one case of severe non-deletional HbH disease (–SEA/α−91α). HbH disease is divided into deletional and non-deletional types, with the non-deletional type being more severe [13,14]. In this study, –SEA/α−91α corresponded to the non-deletional type of HbH disease, characterized by splenomegaly and blood transfusion dependence since infancy. However, the –SEA/αCD30α in this study only presented mild anemia, consistent with a report by Chen et al. [15], but not with another report by Ma et al. [16]. The heterogeneity of hemoglobin H disease may be related to race or modified genes, requiring further research.
Analysis of Hb levels and degree of anemia in relation to genotype in 615 patients with hemoglobin H disease
Published in Expert Review of Hematology, 2020
Shiqiang Luo, Xingyuan Chen, Lizhu Chen, Qingyan Zhong, Qiuhua Wang, Zehui Xu, Jun Huang, Tizhen Yan, Ning Tang
The high prevalence of thalassemia makes it one of the major health problems in Southern China. Confirming previous data, our results demonstrate that thalassemia and hemoglobinopathies are highly prevalent and heterogeneous in Guangxi, with over 20 different genotypes being identified [7]. Alpha thalassemia most frequently results from deletion of one or both alpha genes from the chromosome and can be classified according to its genotype/phenotype correlation. The normal complement of four functional alpha-globin genes may be decreased by 1, 2, 3 or all 4 copies of the genes, explaining the clinical variation and increasing severity of the disease. Thalassemia can be divided into mild, moderate, and severe types according to the degree of anemia. Moderate thalassemia includes Hb H disease and β-thalassemia intermedia. The occurrence of three α-gene defects causes serious insufficiency in the synthesis of α-globin chain; the ratio of α/β-globin is severely imbalanced, and the β-globin chain is overexpressed, thereby forming Hb H, which causes a series of pathophysiological changes, resulting in Hb H disease (Hb H). Compound heterozygotes and some homozygotes have a moderate to severe form of alpha thalassemia called HbH disease. Hb H disease is a double heterozygote of α0 thalassemia and α+ thalassemia, that is, there are 3 α gene deletions or defects, and the genotypes are -α/ – or α-/–, or ααT/–(αT represents a mutation, such as Hb ConstantSpring). Hemoglobin H disease is the severest form of α-thalassemia compatible with postnatal life and occurs when α-thalassemia mutations interact to reduce α-globin synthesis to levels approximately equivalent to the output of a single α-globin gene [8]. The Hb H levels of patients with non-deletional Hb H such as – SEA/αCSα and – SEA/αQSα were generally higher than those with deletional Hb H. It is the levels of Hb H in the circulation have a major influence on the clinical severeity of Hb H disease because Hb H does not release oxygen to the tissues. In addition, Hb H is an unstable hemoglobin molecule and tends to precipitate in the red blood cells, especially if the patient is febrile, leading to an increased degree of hemolysis. The more Hb H in the red blood cells the higher the tendency of the patient to present with hemolysis [9,10]. Hb H disease can be classified into two major groups based on genotype: deletional and non-deletional. This study showed that among 615 patients with Hb H disease, the genotype was mainly deletional, accounting for 65.18% of cases, which is consistent with related reports [11].