Calling for Diversity: Improving Transfusion Safety Through High-Throughput Blood Group Microarray Genotyping

: Blood transfusions, conducted between donors compatible in their red blood cell (RBC) antigens, play a life-saving role in transfusion medicine. Genetic differences at blood group loci between ethnicities result in diversity and altered frequency of RBC antigens that need to be considered in blood transfusions. Consequently, comprehensive and accurate blood group antigen typing is especially relevant for interethnic blood transfusions and for minorities underrepresented in the donor population. Blood group microarray genotyping is a cost-efficient and scalable method for comprehensive blood group typing. Previously, however, microarray typing was challenging for the clinically important blood group systems Rh and MNS, as these feature highly paralogous genomic loci, which lead to mixed signals. Here, we present an approach for accurately typing blood group systems, including Rh and MNS variations. We benchmarked this approach in an ethnically diverse cohort. We tested its performance using gold-standard, diagnostic-grade matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) data from 1052 samples, including 334 Centre d'Etude du Polymorphisme Humain (CEPH)-diversity samples. Overall, we obtained a 99.95% benchmarking concordance and a 99.65% call rate. In summary, we provide a highly accurate and cost-efficient high-throughput genotyping method for comprehensive blood group analysis that is also suitable for ethnically diverse sample sets (https://github.com/ikmb/BloodTypingArray).