## 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 severely reduced β-globin chain production. ### Molecular Defects The mutations in β-thalassemia major include: - **Point mutations** in the coding sequence (missense, nonsense) - **Splice site mutations** affecting mRNA processing - **Deletions** of the β-globin gene or regulatory regions - **Insertions** causing frameshift mutations These defects result in: 1. No functional β-globin mRNA (β⁰-thalassemia) 2. Severely reduced β-globin mRNA (β⁺-thalassemia) ### Pathophysiology The absence or severe reduction of β-globin chains leads to: - Excess α-globin chains that precipitate and damage RBCs - Severe hemolytic anemia - Ineffective erythropoiesis - Transfusion dependence **High-Yield:** β-Thalassemia major is autosomal recessive; both alleles must be affected for the severe phenotype. The severity depends on the degree of β-globin synthesis reduction. **Clinical Pearl:** Patients with β-thalassemia major typically present in infancy (6–12 months) with severe anemia, hepatosplenomegaly, and growth retardation if untreated.
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