Which of the following genetic defects characterizes β-thalassemia major?

Explanation

## Genetic Basis of β-Thalassemia Major **Key Point:** β-thalassemia major results from homozygous or compound heterozygous mutations in the β-globin gene on chromosome 11, leading to absent or severe reduction in β-globin chain production. ### Molecular Defects The mutations in β-thalassemia major include: - **Point mutations** — most common; affect transcription, translation, or splicing - **Deletions** — variable size; remove part or all of the β-globin gene - **Insertions** — less common; disrupt the reading frame **High-Yield:** In β-thalassemia major, **both alleles** are mutated (homozygous or compound heterozygous), resulting in **absent or <10% normal β-globin production**. ### Pathophysiology 1. Severe reduction in β-globin chains 2. Excess α-globin chains precipitate → hemolysis 3. Ineffective erythropoiesis and hemolytic anemia 4. Extramedullary hematopoiesis and iron overload **Clinical Pearl:** β-thalassemia trait (heterozygous) shows mild anemia with target cells and normal or elevated RBC count; β-thalassemia major presents in infancy with severe hemolytic anemia requiring transfusion. ### Differential Genetic Defects | Feature | β-Thalassemia Major | α-Thalassemia | Hereditary Persistence of HbF | | --- | --- | --- | --- | | Gene affected | β-globin (Chr 11) | α-globin (Chr 16) | γ-globin regulation | | Inheritance | Autosomal recessive | Autosomal recessive | Autosomal dominant | | Severity | Severe (homozygous) | Varies with # deletions | Benign | [cite:Robbins 10e Ch 12]