Dominantly Inherited beta-Thalassemia

Area of Science:

• Hematology
• Molecular Genetics
• Biochemistry

Background:

• Dominantly inherited beta-thalassemia (thal) is molecularly diverse, often caused by mutations in or near the beta-globin gene locus.
• Many cases involve exon 3 mutations, leading to unstable, truncated, or elongated beta-globin products.
• A phenotypic overlap exists between dominant beta-thalassemia and certain highly unstable hemoglobin (Hb) variants.

Purpose of the Study:

• To review dominantly inherited beta-thalassemia.
• To present two new cases of hyperunstable hemoglobin (Hb) variants, Hb Stara Zagora and Hb Jambol, associated with severe hemolytic anemia.

Main Methods:

• Genetic sequencing of the beta-globin gene.
• RNA/DNA analysis for complex genomic rearrangements.
• DNA analysis for paternity confirmation.
• Hematological and clinical observations.

Main Results:

• Hb Stara Zagora: A 6 bp deletion in the beta-globin gene resulted in the loss of three amino acids and the introduction of one, causing hyper instability and severe hemolytic anemia in a 2-year-old boy.
• Hb Jambol: A complex genomic rearrangement, including insertions and deletions in the beta-globin gene, led to an elongated beta chain (151 residues) and severe hemolytic anemia in a 2-year-old girl.
• Both cases presented with inclusion bodies and severe anemia requiring transfusions, despite normal hemoglobin analysis.

Conclusions:

• Dominantly inherited beta-thalassemia can result from novel hyperunstable Hb variants.
• These variants, like Hb Stara Zagora and Hb Jambol, cause severe hemolytic anemia due to extreme instability of the beta-globin chain.
• Molecular characterization is crucial for understanding the pathogenesis of these rare genetic disorders.