Double heterozygous RhAG mutations causing regulator-type Rhnull phenotype

Rhnull is the rarest blood type worldwide; its scarcity makes compatible blood almost unobtainable once alloantibodies arise.

To define the genetic basis of regulator-type Rhnull in a healthy blood donor and translate the findings into transfusion guidance.

Serology, Sanger and long-read sequencing of RhD, RhCE and RhAG were performed in the donor and his family.

The donor displayed Rhnull with normal RhD/CE genes but compound-heterozygous RhAG mutations: c.419 A > C (p.Gln140Arg, novel) and c.1108G > A (p.Gly370Arg). Father and son carry only c.419 A > C and have standard DCCee phenotypes, confirming recessive null inheritance. In-silico and structural modeling predict both substitutions disrupt RhAG-RhCE assembly.

We identify a new RhAG allele that abolishes Rh expression and is readily transmitted. Early autologous blood storage and extended RhAG genotyping are recommended for these ultra-rare individuals to avert future transfusion crises.