IVS-II-16 (G>C) (HBB: c.315+16G>C) or IVS-II-666 (C>T) (HBB: c.316-185C>T) Mutations Trigger an Hb S (HBB: c.20A>T)/β+-Thalassemia Phenotype in an Hb S Trait Patient

Abstract

Sickle cell trait is a medical condition caused by the presence of both mutant Hb S (HBB: c.20A>T) and normal Hb A alleles. Although sickle cell trait is typically considered to be asymptomatic and benign, genetic modifiers and mutations can lead to severe clinical complications. In this study, the possible pathogenicity of the IVS-II-16 (G>C) (HBB: c.315+16G>C) and IVS-II-666 (C>T) (HBB: c.316-185C>T) mutations, which are considered to be neutral polymorphisms, and the association between the Hb S mutation are presented. To the best of our knowledge, these polymorphisms have not been previously reported in any sickle cell trait patient, and no relevant studies have been conducted. We recently studied a 40-year-old woman (proband), diagnosed to be an Hb S/β-thalassemia (β-thal) carrier. β-Globin mutations were analyzed using a DNA sequencer based on the Sanger method. The HbVar and ClinVar databases show IVS-II-16 and IVS-II-666 to be intronic mutations. However, statements in these data banks contradict our findings. In the present study, a transfusion-dependent Hb S patient, behaving as an Hb S/β-thal case due to these mutations, was reported. These mutations have not been previously reported in an Hb S patient. Although the IVS-II-16 and IVS-II-666 mutations were previously reported as benign, they converted the Hb S phenotype to transfusion-dependent Hb S/β-thal when combined with Hb S. In this regard, IVS-II-16 and IVS-II-666 mutations may not be innocent, as previously thought.