Identification of a novel high‐prevalence red blood cell antigen on junctional adhesion molecule‐ A defines a new blood group system

Background and Objectives Availability of new technologies has accelerated the pace of blood group discovery, with nine of 48 known systems being discovered in the past 5 years alone, and yet uncharacterized antigens remain. This study involved investigations of samples from a female patient presenting with a moderate strength pan‐reactive antibody to a high‐prevalence antigen present on all red blood cells (RBCs) tested other than her own and her brother's. Materials and Methods Samples underwent extensive serological testing; however, the antibody specificity could not be assigned to any known blood group antigens. Therefore, whole exome sequencing was performed alongside antigen expression studies to identify the gene variant responsible for this rare phenotype. Results Both individuals were found to carry a homozygous variant c.644G>A (rs755819660; gnomAD allele frequency 0.0000044) in exon 6 of the F11R gene, encoding junctional adhesion molecule‐A (JAM‐A). This variant encodes p.Arg215Gln located on the second extracellular immunoglobulin domain of JAM‐A. Expression of JAM‐A was demonstrated on all RBCs tested by flow cytometry, with cells of both the patient and her brother showing lower expression than control cells. Control (Arg215) and variant (Gln215) forms of JAM‐A were expressed as both soluble Fc fusion proteins and on Chinese hamster ovary cells. In both cases, mouse monoclonal anti‐JAM‐A recognized both forms, whilst the patient antibody only reacted with the Arg‐215‐JAM‐A control. Conclusion These data demonstrate that JAM‐A carries a new high‐prevalence RBC antigen, lacking in the patient and her brother, thereby defining a novel blood group system encoded by F11R .