Molecular genetics of β-thalassemia

Abstract

β-thalassemia is a hereditary hematological disease caused by over 350 mutations in the β-globin gene (HBB). Identifying the genetic variants affecting fetal hemoglobin (HbF) production combined with the α-globin genotype provides some prediction of disease severity for β-thalassemia. However, the generation of an additive composite genetic risk score predicts prognosis, and guide management requires a larger panel of genetic modifiers yet to be discovered.Presently, using data from prior clinical trials guides the design of further research and academic studies based on gene augmentation, while fundamental insights into globin switching and new technology developments have inspired the investigation of novel gene therapy approaches.Genetic studies have successfully characterized the causal variants and pathways involved in HbF regulation, providing novel therapeutic targets for HbF reactivation. In addition to these HBB mutation-independent strategies involving HbF synthesis de-repression, the expanding genome editing toolkit provides increased accuracy to HBB mutation-specific strategies encompassing adult hemoglobin restoration for personalized treatment of hemoglobinopathies. Allogeneic hematopoietic stem cell transplantation was, until very recently, the curative option available for patients with transfusion-dependent β-thalassemia. Gene therapy currently represents a novel therapeutic promise after many years of extensive preclinical research to optimize gene transfer protocols.We summarize the current state of developments in the molecular genetics of β-thalassemia over the last decade, including the mechanisms associated with ineffective erythropoiesis, which have also provided valid therapeutic targets, some of which have been shown as a proof-of-concept.

Dutch-beta thalassemia: A rare mutation from India

“…Beta Thalassemia is an inherited blood disorder caused by over 350 mutations in the HBB gene which is responsible for the synthesis of a protein called beta-globin, a subunit of haemoglobin [ 1 ]. Mutations in this gene can result in decreased (β + ) or no (β 0 ) β-globin production leading to autosomal recessive disorders like β-Thalassemia and sickle cell anemia.…”

“…Beta Thalassemia is a hereditary blood disease caused by numerous mutations in the HBB gene [ 1 ]. Mutations in this gene can result in variable β-globin production leading to autosomal recessive disorders like β-Thalassemia (quantitative β-chain defect) and sickle cell anemia (qualitative β-chain defect).…”

Non-Transfusion-Dependent Thalassemia: A Panoramic Review

“…Primary modifiers are the vast diversity of mutations that affect the β-globin gene in the homozygous or compound heterozygous state [ 6 ]. There are currently more than 350 β-thalassemia alleles identified [ 7 ]. These range from mutations resulting in a variable reduction in β-globin chain synthesis (β + ) to the complete absence of β-globin (β 0 ) [ 7 ].…”

“…There are currently more than 350 β-thalassemia alleles identified [ 7 ]. These range from mutations resulting in a variable reduction in β-globin chain synthesis (β + ) to the complete absence of β-globin (β 0 ) [ 7 ].…”

“…Secondary modifiers are the genetic abnormalities that modify the degree of α-/β-globin chain imbalance. These include the coinheritance of different mutations in the α- and γ-chains and genes involved in the γ-chain expression [ 6 , 7 ]. The presence of α-thalassemia may ameliorate the symptoms, whereas the presence of a triplicated or quadruplicated α-genotype can lead to an increased production of α-globin chains that may aggravate the clinical presentations [ 7 ].…”