Primary HBB gene mutation severity and long-term outcomes in a global cohort of β-thalassaemia

In β-thalassaemia, the severity of inherited β-globin gene mutations determines the severity of the clinical phenotype at presentation and subsequent transfusion requirements. However, data on associated long-term outcomes remain limited. We analysed data from 2109 β-thalassaemia patients with available genotypes in a global database. Genotype severity was grouped as β⁰ /β⁰ , β⁰ /β⁺ , β⁺ /β⁺ , β⁰ /β⁺⁺ , β⁺ /β⁺⁺ , and β⁺⁺ /β⁺⁺ . Patients were followed from birth until death or loss to follow-up. The median follow-up time was 34·1 years. Mortality and multiple morbidity outcomes were analyzed through five different stratification models of genotype severity groups. Interestingly, β⁰ and β⁺ mutations showed similar risk profiles. Upon adjustment for demographics and receipt of conventional therapy, patients with β⁰ /β⁰ , β⁰ /β⁺ , or β⁺ /β⁺ had a 2·104-increased risk of death [95% confidence interval (CI): 1·176-3·763, P = 0·011] and 2·956-increased odds of multiple morbidity (95% CI: 2·310-3·784, P < 0·001) compared to patients in lower genotype severity groups. Cumulative survival estimates by age 65 years were 36·8% for this subgroup compared with 90·2% for patients in lower genotype severity groups (P < 0·001). Our study identified mortality and morbidity risk estimates across various genotype severity groups in patients with β-thalassaemia and suggests inclusion of both β⁺ and β⁰ mutations in strata of greatest severity.