Genotypic and Phenotypic Spectrum of Pediatric β-Thalassaemia: Insights from a 30-Year Single-Center Experience

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Abstract
Thalassaemia was the first human disease for which a genetic basis was elucidated. The marked clinical heterogeneity of this monogenic disorder has attracted research interest, particularly towards the identification of genetic and other modifiers of disease phenotype. The aim of the present study was to investigate genotype–phenotype correlations in pediatric patients with thalassaemia followed at a Pediatric Thalassaemia Unit. Medical records of patients with thalassaemia followed at the Pediatric Thalassaemia Unit of Northern Greece over a 30-year period were retrospectively reviewed for demographic characteristics, genetic findings, transfusion dependency, and disease-related complications. Among 82 pediatric patients with β-thalassaemia, 54 were transfusion-dependent. Thirty different β-globin variants were identified, with HBB:c.93-21G>A (IVSI-110 G>A) being the most frequent and associated with a significantly younger age of transfusion initiation. Among the small number of patients carrying the HBB:c.-151C>T (−101 C>T) promoter variant in combination with either a β0 or β+ variant, an association with an NTDT phenotype was observed. All 36 patients carrying homozygous β0/β0 or β+/β+ variants, or compound heterozygous β0/β+ mutations were transfusion-dependent, whereas the remaining TDT patients carried β0 or β+ and silent β-globin variants or α-globin gene triplication. Four genotypes found in 16 patients were associated with both transfusion-dependent and non-transfusion-dependent phenotypes. Notably, two pairs of related patients carrying the same genotype exhibited discordant clinical phenotypes. The clinical heterogeneity of β-thalassaemia is further highlighted by the discordant phenotypes observed among patients carrying the same genotype, underscoring the need to identify additional factors that influence clinical expression. Characterization of these factors is important, not only for more accurate genetic counseling and prognostic assessment, but also for individualization of treatment strategies and appropriate selection of candidates for emerging therapeutic approaches.

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