Pitfalls in the genetic diagnosis of Hb S

Patients homozygous for Hb S need to be properly identified to start as early as possible a treatment that should avoid complications. For prevention and genetic counseling, carriers of Hb S have to be screened. Hb S is easily detected by several analytical systems, but other variants, usually harmless, may behave as Hb S, leading to false positive diagnosis. Some interactions may also cause difficulties in the qualitative or quantitative interpretation of a chromatography or electrophoresis profile. These problems may result from several causes among which the simultaneous presence of an α chain variant leading to the formation of tetramers having both an α and a β chain modified, the presence of a second mutation within the Hb S allele, the existence of a compound heterozygous state leading to some “Hb S trait with dominantly transmitted sickle cell disease (SCD)”, and the presence of thalassemic allele affecting the intracellular proportion of Hb S. In case of any “dominant Hb S trait” a thorough Hb study is always required. This work reports some of the difficulties observed by us, or reported in the literature, and propose how to avoid them and reach a correct diagnosis.

► In the various analytical systems several variants may behave as Hb S. ► The Hb S mutation needs to be properly identified. ► A single test is insufficient to recognize Hb S with 100% certainty. ► Presence of other mutations could modify the presentation of Hb S.