Unusual causes of β thalassemia trait: discovery of another three novel SUPT5H variants

Abstract

Beta (beta) thalassemia is an inherited disorder that occurs following mutations or deletions in the beta 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 SUPT5H revealed by next generation sequencing. This, gene has been progressively acknowledged as a mimicker of beta thalassemia trait in two independent individuals and one family. These individuals have the same features, including hypochromic microcytic indices, increased Hb A(2) levels, without mutations in the beta globin gene. The three novel SUPT5H 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 in silico 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 SUPT5H associated with a beta 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 HbA(2) and unexplained inconsistency of phenotype and genotype of beta thalassemia intermedia.