Partial RHD genotypes in genome databases

Background Partial RHD genotypes permit anti‐D formation after D+ RBC exposure. Better understanding of partial RHD genotype frequencies (GF) could improve ancestry‐specific genotype testing and allele‐specific anti‐D risk estimation. Large genome databases are now easily accessible but quantification of multivariant RHD alleles in them has not been described. Study Design and Methods We obtained allele frequencies for single‐nucleotide‐variant (SNV) partial RHD alleles in the Genome Aggregation Database (gnomAD) and All of Us (AoU) databases and calculated hemizygous or homozygous GFs by Hardy–Weinberg formulas. For multivariant alleles, we obtained GFs from hemizygous or homozygous prevalences of informative variant pairs in gnomAD variant co‐occurrence (VCO) queries. We compared database GFs to those derived from USA RHD gene surveys primarily in Black individuals and sickle cell disease (SCD) patients. Results In African ancestry, DAU3, weak D type 4.0, DIIIa, DAU5 and DIVa (in descending order) each had gnomAD GFs of 0.45%–1.02%. African gnomAD GFs were statistically similar to Black/SCD gene survey GFs. Admixed American (formerly Hispanic/Latino) alleles were similar but at 10% of African frequencies. For others, the most common genotypes in gnomAD and AoU were: DVII in European (gnomAD 0.15%), Middle Eastern (0.17%) and South Asian (0.03%); type 15 in East Asian (0.002%); type 4.0 (0.13%) in Ashkenazi Jewish. Extended RHCE gene conversions such as DVI were undetected by VCO and likely were misaligned into RHCE . Discussion SNVs and VCO in large genome databases provided partial‐ RHD GFs in diverse populations. This information will be useful in estimating allele propensities for anti‐D formation.