Frequency and characterization of known and novel RHD variant alleles in 37 782 Dutch D‐negative pregnant women

• Published in: British journal of haematology Vol. 173; no. 3; pp. 469 - 479
• Main Authors: Stegmann, Tamara C., Veldhuisen, Barbera, Bijman, Renate, Thurik, Florentine F., Bossers, Bernadette, Cheroutre, Goedele, Jonkers, Remco, Ligthart, Peter, Haas, Masja, Haer‐Wigman, Lonneke, Schoot, C. Ellen
• Format: Journal Article
• Language: English
• Published: England 01-05-2016
• Subjects: Alleles; blood group genotyping; D‐ phenotype; Female; Fetal Diseases - diagnosis; Fetal Diseases - genetics; Gene Frequency; Genetic Variation; Genotype; Humans; Mutation; Netherlands; Phenotype; Pregnancy; Rh blood group; Rh-Hr Blood-Group System - genetics; RHD variant alleles; Rho(D) Immune Globulin - genetics; D- phenotype; blood group genotyping; Rh blood group; RHD variant alleles
• ISSN: 0007-1048; 1365-2141
• DOI: 10.1111/bjh.13960

Summary
To guide anti‐D prophylaxis, Dutch D‐ pregnant women are offered a quantitative fetal‐RHD‐genotyping assay to determine the RHD status of their fetus. This allowed us to determine the frequency of different maternal RHD variants in 37 782 serologically D‐ pregnant women. A variant allele is present in at least 0·96% of Dutch D‐ pregnant women The D‐ serology could be confirmed after further serological testing in only 54% of these women, which emphasizes the potential relevance of genotyping of blood donors. 43 different RHD variant alleles were detected, including 15 novel alleles (11 null‐, 2 partial D‐ and 2 DEL‐alleles). Of those novel null alleles, one allele contained a single missense mutation (RHD*443C>G) and one allele had a single amino acid deletion (RHD*424_426del). The D‐ phenotype was confirmed by transduction of human D‐ erythroblasts, consolidating that, for the first time, a single amino acid change or deletion causes the D‐ phenotype. Transduction also confirmed the phenotypes for the two new variant DEL‐alleles (RHD*721A>C and RHD*884T>C) and the novel partial RHD*492C>A allele. Notably, in three additional cases the DEL phenotype was observed but sequencing of the coding sequence, flanking introns and promoter region revealed an apparently wild‐type RHD allele without mutations.