Hybrids and microconversions in RH genes: investigation and implication in transfusion therapy

The discovery and characterization of the RH genes, i.e., RHD and RHCE, in the early 90s have been milestones in the field of blood group genetics. In addition to the single nucleotide variants (SNVs), which are commonly considered as the predominant molecular actors resulting in the variability of antigen expression, genetic exchange between both RH genes has been shown to be a frequent mutational mechanism. Indeed, dozens of hybrid alleles and microconversions associated with variant RH phenotype have been reported so far. Interestingly, these alleles display population-specific patterns of distribution. Also, they are directly involved in the qualitative and quantitative alteration of RH antigen expression, which has immediate consequences for diagnostics and transfusion management. Overall, hybrid alleles and microconversions contribute largely to the complexity of the RH blood group system. In the current state of knowledge, this narrative review: (I) defines and introduces the molecular determinants of the genetic exchange in the RH genes; (II) describes how these variant alleles may alter the expression of polymorphic and high-frequency antigens (HFAs) and/or result in the expression of low-frequency antigens (LFAs); (III) reports on their distribution at a low-resolution population scale; and (IV) discusses their relevance and identification in routine clinical practice for transfusion management at the laboratory level