Genotype-phenotype correlation in NTD thalassemia patients with α-globin gene triplication and heterozygous β-globing gene mutation

Background β Thalassemia is one of the most common genetic disorders and is due to a β-globin deficiency. The intermediate form (thalassemia intermedia, TI) has an extremely variable phenotype ranging from completely asymptomatic pictures to severe anemia with various complications. A form of TI is due to the association of a heterozygous beta gene defect with α triplication genes. The correlation between genotype and phenotype in these forms is only partially understood, as well as the evolution of the disease and the correlated complications Materials and Methods A retrospective observational case-control study was performed on a cohort of patients with double heterozygosity β gene defect/triplication of the α gene (TI) and a group of carrier patients with β gene mutation alone, both referred to the Thalassemia and Hemoglobinopathies Reference Centre - San Luigi Gonzaga University Hospital between January 2000 and April 2024. All the information available about the anamnesis, clinical situation, hematological and laboratory tests, instrumental exams, and therapy performed were collected. Subsequently, the trends of the two groups in terms of anemization and transfusion rates were described. Finally, the variables that correlate with a higher risk of complications were evaluated. Results 133 patients with TI (mean age 28.0 years) were identified and 72 carriers (mean age 30.7 years) were selected over the analyzed time frame, for a total of 205 patients. The hemoglobin level at diagnosis was higher in men (11.9 g/dl) than in women (11.0 g/dl), and lower in patients with TI (10.1 g/dl) than in carriers (11.0 g/dl). Similarly, the minimum hemoglobin value was lower in TI (9.4 g/dl), compared to controls (10.8 g/dl). There was a cumulative risk of anemia with Hb < 8 g/dL of 50% by age 50 in TI women (compared to 25% at 70 years in carriers) and 25% by age 40 years in the male equivalent. The risk of receiving a transfusion in life is higher in women and especially in those affected, mainly in pregnancy-related circumstances. Patients with severe TI mutations are more at risk of complications such as splenomegaly, developed by 48% of patients, pulmonary hypertension (3%), cholecystitis (27%), and EMH (2%). In addition, these manifestations were more associated with a β0 defect. Conclusions TI due to the association of beta gene defect with α triplication genes is a heterogeneous disease in terms of severity. The usefulness of follow-up programs, based on criteria of greater risk of negative evolution, is suggested by the predisposition of women to develop more severe anemia, mainly during pregnancy, and of patients with severe β0 mutation to experience more complications such as splenomegaly. This underscores the critical need for targeted follow-up to prevent and properly manage the associated complications.