Unusual Causes of β Thalassemia Trait: Discovery of another Three Novel <i>SUPT5H</i> Variants

Beta (β) thalassemia is an inherited disorder that occurs following mutations or deletions in the β globin gene. Rarely, it is caused by variants in genes coding for erythroid transcriptional factors or trans-acting factors. Here, we report three novel variants of <i>SUPT5H</i> revealed by next generation sequencing. This, gene has been progressively acknowledged as a mimicker of β thalassemia trait in two independent individuals and one family. These individuals have the same features, including hypochromic microcytic indices, increased Hb A₂ levels, without mutations in the β globin gene. The three novel <i>SUPT5H</i> variants identified in this study (c.1168_1169del, c.2688del and c.307+1G>A) are frameshift variants leading to a premature stop codon or an intronic variant predicted to alter the splice site consensus sequence by <i>in silico</i> software. All three variants are characterized as Loss-of-Function variants either by generating a truncated protein or haplo-insufficiency due to nonsense-mediated decay. These findings confirm the general observation that most variants in <i>SUPT5H</i> associated with a β thalassemia trait phenotype are Loss-of-Function variants. This gene should be considered as a potential target gene in the genetic diagnosis of any unsolved cases of increased HbA₂ and unexplained inconsistency of phenotype and genotype of β thalassemia intermedia.