This review traces the evolution of RHD genotyping from the very early days of the discovery
of Rh polypeptides in 1982, and the pioneering work of the late 1980s and early 1990s that made the whole
approach of RH genotyping possible. This work is often overlooked in contemporary Rh literature with
citations of reviews being used which often do not give the complete background story. We have attempted
to rectify this here. This review focuses primarily on RHD genotyping, primarily because of space constraints
not to include RHCE but also because RHD is of greater clinical significance. In Europe many countries
offer routine non-invasive prenatal RHD screening to direct the use of prophylactic anti-D to mothers that
require it- namely are carrying D-positive fetuses. The genotyping approach is empirical (and wisely so) and
any potential variant identified in this process is treated as D-positive. In such cases although sometimes
unnecessary administration of prophylactic anti-D may be given, it only reflects the situation that predated
mass scale non-invasive testing, and many countries not offering RHD screening. The complexity of the
RHD gene and the known plethora of D variants (partial, weak D-elute and multiple genetic mechanisms
generating the D-negative phenotype) are explored but only inasmuch as the technology to detect them
is discussed. By far the most powerful means of accurate RHD genotyping, so called gold standard testing
is next-generation sequencing although our discussion is tempered by several caveats mainly involving the
rapid bioinformatic determination of a D variant from its resultant sequence. We stress however that next
generation sequencing (NGS) offers the substantial advantage over other conventional RHD genotyping
strategies in that novel variants can be identified whereas other methods require that the variant has been
previously described so as to direct sequence specific analysis
