Unusual Phenotypes and Rare Alleles

Cw
 originally considered an allele at the C/c locus.
 later studies showed that it can be expressed in combination with both C
and c and in the absence of either allele. It is now known that the
relationship between C/c and Cw is only phenotypic
 Cw is antithetical to the high-prevalence antigen MAR.Cw results in a single
amino acid change most often found on the RhCe protein.
 Cw is found in about 2% of whites and is very rare in blacks.
 Anti-Cw has been identified in individuals without known exposure to
foreign RBCs and after transfusion or pregnancy.
 Anti-Cw may show dosage (i.e., reacting more strongly with cells from
individuals who are homozygous for Cw).
 Because of the low prevalence of Cw, Cw antigen–negative blood is readily
available.

f (ce)
 expressed on the RBC when both c and e are present on the same
haplotype; it has been called a compound antigen
 a single entity resulting from conformational changes in the Rhce protein
The antigen f was included in a series of these compound antigens, which
were previously referred to as cis-products to indicate that the antigens
were on the same haplotype. It is now known they are expressed on the
Rhce protein.
 Phenotypically, the following samples appear the same when tested with
the five major Rh antisera: D+C+E+c+e+, resulting in the predicted
genotypes of DCE/dce or DcE/DCe. However, when tested with anti-f, only
the DCE/dce shows positive reactivity, confirming the former genotype.
 Anti-f is generally a weakly reactive antibody often found with other
antibodies. It has been reported to cause HDFN and transfusion reactions.
In case of transfusion, f-negative blood should be provided. Anti-f is not
available as a reagent; however c-negative or e-negative blood may be
provided since all c-negative or e-negative individuals are f-negative.
rhi (Ce)
 Similar to f, rhi was considered a compound antigen present when C and e
are on the RhCe protein. A sample with the phenotype D +C +E +c +e +
can be either DcE/DCe or DCE/dce. Anti-rhi shows positive reactivity only
with DCe/dce RBCs.
 Antigens cE and CE or Rh22 also exist, but antibodies produced to these
antigens are not commonly seen.

G
 G is an antigen present on most D-positive and all C-positive RBCs. The
antigen results from the amino acid serine at position 103 on the RhD,
RhCe, and RhCE protein.
 In antibody identification testing, anti-G reacts as though it were a
combination of anti-C plus anti-D because all C-positive and D-positive
cells are G+.
 G was originally described in an rr person who received D+C–E–c+e+
RBCs. Subsequently, the recipient produced an antibody that appeared to
be anti-D plus anti-C, which should be impossible because the C antigen
was not on the transfused RBCs. Further investigation showed the antibody
was directed toward D + G, not anti-C.
 This also explains situations in which an Rh-negative individual who has
received Rh-negative blood will look like they made anti-D. The Rh-
negative blood the patient received was C-positive, thus G-positive and the
antibody produced is actually anti-G, not anti-D and anti-C.
 Anti-G versus anti-D and anti-C is important when evaluating obstetric
patients. If the patient has produced anti-G and not anti-D, they are
considered a candidate for RhIg.
 Elaborate adsorption and elution studies, usually performed in an
immunohematology reference laboratory, are valuable in these situations to
discriminate anti-D from anti-C from anti-G.
 For transfusion purposes, it is not necessary to discriminate anti-D and anti-
C from anti-G, as the patient would receive D-C blood regardless if the
antibody is –D, –C or –G.

Rh13, Rh14, Rh15, and Rh16

 Rh13, Rh14, Rh15, and Rh16 define four different parts of the D mosaic, as
it was originally described. Although these parts are included in the partial-
D categories II to VII as defined by Tippett and Sanger, they are not
directly comparable. These antigens are now obsolete.
Rh17 (Hr0)
 Rh17, also known as Hr0
 an antigen present on all RBCs with the “common” Rh phenotypes (e.g.,
R1R1, R2R2, rr)
 In essence, this antibody is directed to the entire protein resulting from the
RHCE genes. When RBCs phenotype as D–, the most potent antibody they
make is often one directed against Rh17 (Hr0).

Rh23, Rh30, and Rh40

 Rh23, Rh30, and Rh40 are all low-prevalence antigens associated with a
specific category of partial-D.
 These low-prevalence antigens result from the formation of the hybrid
proteins seen in individuals with partial-D phenotypes.
 Rh23 (also known as Wiel and Dw) is an antigenic marker for category Va
partial-D.
 Rh30 (also known as Goa or Dcor) is a marker for partial DIVa.
 Rh40 (also known as Tar or Targett) is a marker for partial DVII.
 Rh52 or BARC is associated with some partial-DVI types.

Rh33 (Har)
 The low-prevalence antigen Rh33 is most often found in whites and is
associated with the rare variant haplotype called R0Har.60 R0Har gene codes
for normal amounts of c, reduced amounts of e, reduced f, reduced Hr0, and
reduced amounts of D antigen written as (D)c(e).
 The D reactions are frequently so weak that the cells are often typed as Rh-
negative.
 R0Har or DHAR results from a hybrid gene RHCE-RHD-RHCE in which only
a small portion of RHD is inserted into the RHCE gene.

Rh32
 Rh:32 is a low-prevalence antigen associated with a variant of the

R1[D(C)(e)] haplotype called RN.
 The C antigen and e antigen are expressed weakly. The D antigen
expression is exaggerated or exalted. This gene has been found primarily in
blacks.
Rh43 (Crawford)
 Rh43, also known as the Crawford antigen, is a low-prevalence antigen on
a variant Rhce protein.
 The Crawford (ceCF) antigen is of very low prevalence found in
individuals of African descent.

e Variants
 some individuals of African or mixed ethnic backgrounds possess e antigen
that exhibits similar qualities as those described for partial-D phenotypes—
that is, an individual may phenotype e-positive but produce antibodies
behaving as anti-e.
 These variant types result from multiple mutations in the RHCE gene.
Individuals who possess two altered RHCE genes may phenotype e-positive
but produce antibodies behaving as anti-e.
 The Rh antigens hrB and hrS are rarely considered in routine blood banking.
They are normally present in individuals who possess normal RhCe or
Rhce protein but are lacking in individuals with normal RhcE or RhCE pro-
teins (i.e., e-negative).
 Several antigens, most notably hrB and hrS, are lacking on the resulting
Rhce proteins encoded by some variant RHCE genes. If individuals with
these variant genes who are hrB-negative or hrS-negative are immunized,
they may produce anti-hrB or anti-hrS.
 In routine antibody identification, these antibodies are generally
nonreactive with e-negative red cells (and therefore are also hrB-negative
and hrS-negative), appearing to have anti-e-like specificity.
 To further complicate this, the variant RHCE gene associated with the hrB-
negative phenotype is usually found with a variant RHD-CE-D hybrid gene.
 The RHCE is inserted in the middle of the RHDIIIa gene. The resulting
protein lacks D antigen but possesses an unusual form of the C antigen. The
hybrid gene occurs in 22% of individuals of African decent.
 This haplotype that includes the RHDIIIa-RHCE- DIIIa hybrid gene and
variant RHCE genes is referred to as r’s[(C)ces].
V and VS
 V and VS are antigens of low prevalence in the Caucasian population but
are more prevalent among African Americans. These antigens can be used
as predictors of an individual’s ethnic background because of this
difference in prevalence.
 The V antigen, also historically referred to as ceS, is found in about 30% of
randomly selected African Americans.
 It is most often found in individuals with Gly263 amino acid change in
Rhce; several other mutations also occur in this gene.
 The VS antigen, also known as eS, occurs in 32% in blacks.
 It results from a single amino acid change that occurs at position Val245 in
the Rhce protein. Most hrB- individuals with r’s genotype are VS+. The
 Val245 mutation in this haplotype is found in the hybrid RHDI- IIa-RHCE-
RHDIIIa gene .
 Most V+ individuals are also VS+.