The role of Next Generation Sequencing in the identification and characterization of beta thalassemia genetic modifiers

Abstract

During this work, we identified and described several genetic modifiers influencing β-thalassemia phenotypes. We reported the first case of a double heterozygote for HbE and Hb Adana—a rare and highly unstable α-globin variant, which compensates the imbalance between α- and β-globin chains and underscores the importance of integrating biochemical and hematological analysis with molecular sequencing in the appropriate diagnosis of thalassemia.

In addition, we demonstrated how next-generation sequencing technologies enabled the discovery of new genetic modifiers of β-thalassemia, further emphasizing the growing impact of advanced sequencing methods in understanding disease complexity. The SUPT5H gene was the first modifier identified in our study detected using whole exome sequencing analysis of several members of two independent Dutch families exhibiting a typical beta thalassemia minor phenotype without any other causative variant in the HBB gene.

Another beta-thalassemia modifier we identified was the first segmental triplication of the entire alpha-globin gene cluster including the MCS1-4 consistent with the presence of eight copies of the alpha globin gene in two beta-thalassemia carriers. In combination with a beta++-thalassemia variant (NM_000518.5(HBB):c.*113A>G), this resulted in a moderately severe phenotype of beta-thalassemia intermedia. Whole Genome Sequencing played a crucial role in understanding and characterizing this complex rearrangement.