Impact of RHCE variability and complexity in transfusion medicine: a narrative review

Background and Objective: Rh is one of the most clinically important blood group systems. It comprises five major antigens (D, C, c, E, and e) in addition to several low and high prevalence antigens. RhD and RhCE proteins are encoded by two adjacent genes namely RHD and RHCE. These genes are highly homologous and polymorphic resulting in numerous variant alleles that encode variant antigens. In this review, we will discuss RHCE genetic diversity, frequency of RHCE variant alleles and their clinical aspects, complexities, and the importance of RH genotyping to prevent alloimmunization. Methods: A search restricted to English language was performed using the PubMed electronic database to retrieve publications until June 2021, on RHCE variability and complexity. The Medical Subject Headings and free terms used were Rh-Hr Blood-Group System/genetics, sickle cell disease (SCD), RHCE, RHCE variants, and Rh antibodies. Other relevant articles were found by checking the reference list of the articles collected in the initial search. Key Content and Findings: Common RhCE antigens are highly immunogenic, and their alloantibodies have been involved in delayed hemolytic transfusion reactions (DHTRs) and hemolytic disease of the fetus and newborn (HDFN). Because the distribution of C/c and E/e is different among ethnic groups, several treatment centers adopt prophylactic CE matching protocols to prevent alloimmunization in chronically transfused patients. Despite measures, alloantibody formation against RhCE antigens is still a problem due to numerous variant phenotypes, mainly in individuals of African origin. Elucidation of molecular basis for RHCE variants has allowed to determine the frequency of these alleles in patients and donors of African descent, however, the clinical significance of the Rh alloantibodies elicited by most RHCE variants is still unclear. Conclusions: Molecular assays allowed considerable progress in the identification of genetic basis and characterization of RHCE variant alleles in patients with SCD and blood donors. Advances in molecular techniques may enable the screening of rare RhCE donors and improve the support for patients carrying variant RhCE phenotype. However, some questions remain to be answered, mainly regarding the clinical significance of the RHCE variants.