Molecular genetics of the Rh blood group system: alleles and antibodies—a narrative review

Introduction

Nearly a century after the first publications which would lead to the recognition of the Rh blood group system (1,2), and 40 years after the molecular basis of the Rh antigens (Ag) were discovered (3,4), 55 Rh Ag, over 400 RHD and over 150 RHCE alleles are recognized by the International Society of Blood Transfusion (ISBT) (5). Many more alleles can be found in the Genbank database (6), published articles and conference abstracts. The Human RhesusBase inventories over 600 RHD alleles (7), and the recent RHeference database, over 700 (8). Which alleles to detect and how to manage allele carriers are recurring questions for immunohematologists.

There are 5 conventional alleles in the Rh system: RHD*01 (standard RHD) for the RHD gene, RHCE*01 (RHCE*ce), RHCE*02 (RHCE*Ce), RHCE*03 (RHCE*cE) and RHCE*04 (RHCE*CE) for the RHCE gene (9). RHD*01 and RHCE*01 are considered to be the reference sequences for the RHD and RHCE genes, respectively. The reference sequences have only recently been updated in RefSeq (10) to reflect this (NG_007494.1 for RHD and NG_009208.3 for RHCE). Formerly, RefSeq listed the RHD*10.00 (RHD*DAU0) and RHCE*01.01 (RHCE*ce48G) alleles. The broad term “Rh variants” (11,12) is commonly used to designate the products of alleles in the Rh blood group system differing from the conventional.

The allele repartition in different populations is far from homogeneous. Erythrogene database (13) presents an interesting overview through the analysis of blood group systems, including Rh, from the 1000 Genomes project. This approach has limitations, e.g., none of the RHCE*02 (RHCE*Ce) alleles were assigned a prevalence, probably because of the sequence identity between exon 2 of RHD*01 (conventional RHD) and RHCE*02. Some genetic variations are associated as if constituting an allele but could be explained by the association of two alleles, e.g., RHD c.186G>T, c.410C>T, c.455A>C, c.1048G>C and c.1136C>T are associated with a 0.91% prevalence in Africans, but do not constitute a known RHD allele, whereas the variations could be explained at the heterozygous state by the association of two alleles RHD*10.00 (RHD*DAU0, with the single substitution c.1136C>T) and RHD*04.01 (RHD*DIVa, associating c.186G>T, c.410C>T, c.455A>C and c.1048G>C), alleles common in Africans (37.75% and 1.06%, respectively, according to Erythrogene).

The clinical significance of blood group alleles and Rh variants is not easy to establish, for several reasons. Locating the reports in the vast literature is a tedious task. Individual variability to alloimmunization remains poorly understood (14,15), and most available evidence amount to case reports of antibody (Ab) formation, transfusion reactions, or hemolytic disease of the fetus and the newborn (HDFN). As the reports are real-life data, they are often incomplete, particularly regarding serology. Whether the Ab is an allo- or auto-Ab and the imputability of an Ab in a hemolytic reaction may be difficult to ascertain (16,17). The most robust way to demonstrate that an Ab is an allo-Ab is to show that it cannot be auto-adsorbed with the patient’s own red blood cells (RBCs) (18). However, auto-adsorptions cannot be performed in a recently transfused patient and may be inconclusive for very weakly expressed Ag.

Several definitions have been proposed for “partial” Rh Ag (12). In this work, we will use the term as a synonym for “at risk for Ab formation to the corresponding Rh Ag” (i.e., a partial D is at risk for allo-anti-D if exposed to the standard D Ag). Ab formation to the corresponding Ag is theoretically impossible in a heterozygous individual, because no epitopes of the Ag would be missing (i.e., a carrier of a conventional D Ag and a partial D variant has all D epitopes thanks to their conventional D; a carrier of a conventional C and a partial C variant has all C epitopes, etc.). Genotyping has become key to detect variants in the Rh system and resolve difficulties in laboratories, as serology cannot reliably distinguish all the subtleties of the Rh system (12,19,20).

One of two main conducts are adopted by most transfusion specialists for the management of Rh variants in recipients. The first could be called a “preventive” attitude and consists in avoiding the exposure of carriers of partial Rh variants to the standard Ag, to prevent alloimmunization [in women of childbearing age and certain types of patients, e.g., with sickle cell disease (SCD)]. The second could be called a “palliative” attitude and consists in taking measures only when a patient has produced the Ab. Most countries recommend the preventive approach for variants at a high risk for Ab formation. Several countries recommend the preventive approach for Rh variants for which the risk for Ab formation is unknown. The choice between the preventive and palliative may be made on a case-by-case basis for each variant and this requires easily accessing the available evidence for Ab formation. The choice will also depend on the allele prevalence in the country or region, the alloimmunization risk that carriers face, the availability of anti-D immunoglobulins and of RBC units of different phenotypes, e.g., in a country where partial D variants and D negative RBC units are rare, the attitude will probably be different than in a country where partial D variants are common and D negative units are more readily available.

The present review gathers the current published evidence regarding allo-Ab formation associated with RHD and RHCE alleles. Null alleles are not discussed, as, by definition, they do not express the Ag and carriers are consequently able to form Ab when exposed to the Ag, e.g., individuals with RHD null alleles are at risk for anti-D as much as homozygous RHD*01N.01 (RHD deletion) individuals are.

We present the following article in accordance with the Narrative Review reporting checklist (available at http://dx.doi.org/10.21037/aob-20-84).

RHD alleles

The earliest reports of anti-D in D positive patients have been associated with variant D phenotypes. The DVI phenotype and RHD*06 (RHD*DVI) alleles have been responsible for many anti-D alloimmunizations with severe consequences (7,21-23). This has given rise to recommendations for reagent selection, adopted by many countries, so that RHD*06 carriers are typed as D negative and are managed as such (24,25). Patients with the DFR phenotype, attributed to RHD*17 (RHD*DFR) alleles, have also made allo-anti-D (26-28). Many RHD alleles, listed in Table 1, have since been associated with anti-D formation in carriers of these alleles, in the absence of conventional RHD*01.

A few common RHD alleles have a somewhat controversial status regarding anti-D formation risk, such as RHD*10.01 (RHD*DAU0) (29,37,41,58,63,76,79,104,105), RHD*09.03 (RHD*weak D type 4.0) and RHD*09.04 (RHD*weak D type 4.1) (76,79,106-108). Both auto- and allo-anti-D have been reported in carriers. Several studies in populations with a high prevalence for these alleles have reported no anti-D in carriers, with the inherent limits of retrospective studies (50,109,110). None of the allo-anti-D descriptions were able to demonstrate that the anti-D could not be auto-absorbed on the carrier’s own RBCs (104,111). Nevertheless, the incidence of presumed allo-anti-D is very low compared to the alleles’ prevalence. Erythrogene (13) reports RHD*09.03 as being present in 1.21% in Africa, and reports a very high prevalence for RHD*10.01 in all populations assessed (Africa: 37.75%; America: 12.54%; East Asia: 8.83%; Europe: 4.47%; South Asia: 12.68%).

Many rare RHD alleles, not listed in Table 1, have been associated with anti-D formation at least once in published articles, including RHD*02 (RHD*DII) (112,113), RHD*19 (RHD*DHMi) (7,21,114), RHD*27 (RHD*DDE) (7,21), RHD*33 (RHD*DWI) (115), RHD*38 (RHD*DNT) (7,21), RHD*39 (RHD*307C) (80), RHD*47 (RHD*DMI) (7,21,54), RHD*50 (RHD*1060A) (116), RHD*weak D type 57 (RHD*01W.57) (73), RHD*710T {provisional name: [7] RHD*01W.155} (55). Some have been associated with anti-D formation in abstract form, including: RHD*03.02 (RHD*DIIIb Caucasian) (117), RHD*03.08 (RHD*DIII type 8) (118), RHD*24 (RHD*DNAK) (119), RHD*48 (RHD*DNS) (120), RHD*01W.33 (RHD*weak D type 33) (121,122), as well as several alleles not yet listed by ISBT: RHD*95A (123), RHD*325G (124), RHD*470G (125), RHD*455C,968A (118), RHD*1048C (65).

A few cases of allo-anti-D have been reported in abstract form for RHD*01W.1 (RHD*weak D type 1) (126), RHD*01W.2 (RHD*weak D type 2) (127) and RHD*01W.3 (RHD*weak D type 3) (128,129), but these reports are extremely rare compared to the number of carriers and the consensus is that these alleles should be considered to produce normal D antigen (104).

As underlined recently (130), the alleles RHD*01W.33 and RHD*01W.45 have quite a high prevalence: in America (0.14%) for the former, and in America and Europe (0.29% and 0.20%, respectively) for the latter (13). Very rare anti-D have been reported in carriers of these alleles (69,121,122), which may reveal a very low anti-D formation risk, perhaps comparable to that of RHD*01W.1, RHD*01W.2 and RHD*01W.3. The paucity of anti-D reports may also be biased by the genotyping strategies in place and by the difficulty to present or publish case reports for such data.

Next to RHD*01W.1, RHD*01W.2, and RHD*01W.3, the most important RHD allele for which no allo-anti-D has ever been reported despite a large number of carriers is RHD*01EL.01 (RHD*1227A). Erythrogene reports RHD*01EL.01 with: America 0.29%, East Asia 0.69% and Europe 0.10%. Erythrogene also reports RHD*01EL.36, which differs from the first by c.1073+152C>A only (a genetic variation reported in all populations and also found with other genetic variants) (13) with: Africa 1.13%, America 0.14%, East Asia 0.20%, Europe 0.60%, South Asia 1.94%. Several studies support the absence of anti-D formation risk in carriers of this allele (131-133), but others urge caution and recommend waiting for the results of an ongoing prospective study on the matter (134).

Table 2 lists other RHD alleles frequently reported in immunohematology studies, reported in a large number of carriers, or associated with a prevalence in Erythrogene (13), and for which no anti-D has been reported. In the absence of prospective studies following Ab formation in a large number of carriers, it may be premature to definitely rule out any anti-D formation risk in these alleles. This is particularly true for alleles which tend to type as D negative, as carriers are less likely to be exposed to D positive RBC units (see Table 2), and molecular analysis is less likely to be performed in an apparently D negative patient with anti-D.

Some RHD alleles produce low prevalence Ag which may be responsible for Ab formation in an individual exposed to the Ag. Table 3 lists reports of such alloimmunization, including many with severe hemolytic consequences in pregnancy.

RBCs carrying variants in the Rh system can also induce Ab formation in recipients negative for the corresponding Ag. There are comparatively few reports, mainly of D variants with a DEL (226) or very weak D phenotype (any variant with a stronger reactivity is of course capable of inducing Ab formation in carriers). Cases of primary alloimmunization, including RHD*01EL.01 (227,228), RHD*01W.1 (229), RHD*01W.67 (230) and cases of anti-D reactivation, including RHD*01EL.01 (231), RHD*01W.26 (81) have been reported.

RHCE alleles

Most RHCE alleles are responsible for the expression of a pair of RhCE Ag: C (RH2), E (RH3), c (RH4), e (RH5). The RHCE alleles associated with Ab formation to the corresponding Ag are listed in Table 4.

A few RHCE alleles, for which no RH10 or RH20 phenotype, no prevalence in Erythrogene and, more importantly, no Ab report could be found, but are worth mentioning are: RHCE*02.02 (RHCE*CeFV) (232), RHCE*02.03 (RHCE*CeJAHK) (233), RHCE*02.11 (RHCE*Ce286A) (234).

As for RHD, a few RHCE alleles have a controversial status. Both allo- and auto-anti-e Ab have been reported for RHCE*01.01 (RHCE*ce48C) and RHCE*01.20 alleles (comprising c.733C>G) (32,60,187). Erythrogene reports RHCE*01.20.01 in Africa (15.28%), America (2.31%), and Europe (0.30%). The prevalence of RHCE*01.01 reported by Erythrogene is overestimated, probably because RHCE*02 alleles could not be recognized. Nevertheless, other sources list the allele as common, particularly in Africans (161).

Some studies with immunization data and the clinical consequences of Ab were performed before molecular typing became standard (235). Unfortunately, molecular typing has not since been published for these samples.

Similarly to what is observed for RHD alleles, some RHCE alleles produce low prevalence Ag, which may be responsible for Ab formation in an exposed individual (Table 3).

Discussion

For only a fraction of RHD and RHCE reported to-date, Ab to the expressed Ag have been reported. The list presented here may not be comprehensive. Some Ab may have been reported in other languages, or not reported at all. It should be underlined that the data presented in abstract form only have not undergone peer-review. It may be that doubts arose later as to the specificity of the Ab.

In many of the studies referenced in this review, the serology of the Ab is not detailed. Ab to Rh antigens may combine allo- and auto-Ab components and be difficult to interpret. In many cases, it does not serve any practical purpose to perform extensive serology testing once a variant has been identified, except for research purposes, as the findings would have no effect on patient management (e.g., if a patient has anti-D and a D variant, they will receive D negative RBC units regardless). This is particularly true for the more common alleles and for those previously associated with allo-Ab formation. Some studies seem to have found allo-Ab in individuals with apparently normal RH alleles (e.g., anti-e in an individual with RHCE*01), which interrogates the allo-Ab listed in the same study with Rh variants (could auto-Ab explain some of the findings?). More serology data would often be valuable. It would be valuable to the community if, whenever possible, allo- and auto-Ab were identified and studies could report the analyses performed for this purpose, even when incomplete testing was performed.

The common practice of using the term “partial” Ag as a synonym with “at risk for Ab formation to the corresponding Ag” should continue to be questioned. This leads to considering Ab formation risk as a binary, putting all Rh variants on the same level and limits our ability to adjust policies depending on the variants. The variants discussed here are not all equivalent in terms of Ab formation risk, as mentioned above for several RHD alleles. From our experience, RHD*03.01 (RHD*DIIIa), RHD*10.05 (RHD*DAU5), RHD*04.01 (RHD*DIVa) and RHD*49 (RHD*DWN) are among the alleles particularly prone to anti-D formation. This is observed in our setting where carriers are relatively common thanks to the African and Afro-Caribbean heritage of many French people, even if we cannot estimate the prevalence precisely. These variants are not screened by our routine phenotyping methods and carriers are unlikely to receive D negative RBC units or anti-D immunoglobulins to prevent anti-D alloimmunization (which would be the standard patient management when D variants at risk for anti-D are detected in our country because of weakened Ag expression). These variants are regularly detected in D positive individuals after forming anti-D. This observation in our setting may not be as relevant in populations with a different genetic makeup, or with different policies for patient management.

The prevalence listed here is only indicative, as the quality of the 1000 Genomes project data is imperfect (236). Many alleles have no prevalence associated: either the genetic variation(s) are too rare, or the variations could not be phased, especially for hybrid alleles or equivalent (none of the RHCE*02 alleles has a prevalence, as mentioned in the introduction).

With the expansion of genotyping, an increasing number of genotyping studies revealing the Rh genetic makeup of different populations is being published. When possible, the Ab found in the same population would be worth presenting together with the genotyping data. Authors should make sure to provide serological data, even when incomplete, and present the clinical consequences of the alloimmunization, if any.

Antibodies can cause HDFN or hemolytic transfusion reactions (HTR). The risk is considered to be possible for any Rh allo-antibody, and patients with Ab are usually not re-exposed to the offending Ag to avoid such complications. Therefore, hemolytic consequences of alloimmunization have been reported in only a subset of the alleles discussed here and the available data must be interpreted with caution. The most severe HTR, with hyperhemolysis, occur in SCD patients (237). In these patients, the causality of a specific Ab is particularly hard to establish (16,17). HTR with hyperhemolysis can occur in patients with multiple Ab, can be caused by auto-Ab or Ab not usually considered clinically significant, or even occur in the absence of Ab, making the interpretation for a single Ab difficult (32,237-239).

HTR or decreased survival of RBCs have been reported for anti-D associated with partial D, including RHD*04.01 (RHD*DIVa) (32), RHD*10.04 (RHD*DAU4) (29,32,61), RHD*03.01 (RHD*DIIIa) and RHD*weak partial D 4.2 (RHD*DAR) (29), anti-C associated with partial C of RHD*03N.01 [RHD*DIIIa-CE(4-7)-D] (32,188), and anti-c associated with partial c of RHCE*01.20.07 (RHCE*ceJAL) (174), among others (29,32,239,240). Decreased survival of transfused RBC has been reported for anti-e associated with several alleles predicted to be RH:–19 and/or RH:–31 in SCD patients (29,32). Many RHCE alleles have been reported as RH:–19 and/or RH:–31 but anti-RH19 and anti-RH31 may sometimes be reported as anti-e or anti-e-like (161). The clinical consequences of anti-RH19 and anti-RH31 may depend on the underlying alleles but it is difficult from the available data to compare them. Further monitoring of anti-RH19 and anti-RH31 Ab formation and potential hemolytic consequences, with molecular data and robust serological workups could shed light on the heterogeneity of these cases to better inform transfusion decisions.

Some RHCE alleles can probably be considered at a low risk for Ab formation or severe hemolytic complications: RHCE*01.01 (RHCE*ce48C), RHCE*01.20.01 (RHCE*ce733G) and RHCE*01.20.02 (RHCE*ce48C,733G). Severe hemolytic consequences attributable to these alleles have not been reported in the literature, and many countries do not take prophylactic measures for alloimmunization when transfusing carriers. If the c (RH4) and e (RH5) Ag produced by these alleles were at a risk for severe hemolytic complications, the incidence would remain very low compared to the alleles’ prevalence in some populations (29,32).

It is hard to say if the literature over- or under-estimates the clinical consequences of Ab to low prevalence Ag. On the one hand, these Ab may be difficult to detect and characterize. On the other hand, case reports with these Ab may be more likely to be published. A more systematic approach to study these Ab could be helpful (241,242).

A better understanding of which Ab are at the highest risk for hemolytic complications could be a key to improving our inventory management while guaranteeing patient safety. Next-generation sequencing is also expanding the possibilities and revealing unexpected complexity (243,244). Hopefully, data will continue to be reported to guide us. Moving forward, it may become possible to classify the alloimmunization and hemolytic risks associated with more Rh variants and adapt the recommendations for each variant. Such recommendations would take into account the alloimmunization risk associated with a variant, the risk of hemolytic complications, the prevalence of the variant in the population, and the availability of Ag negative RBC units in the population.

Web resources

ISBT RHD allele tables (last update Feb 2018, accessed: Nov 2020)

• http://www.isbtweb.org/fileadmin/user_upload/Working_parties/WP_on_Red_Cell_Immunogenetics_and/RHD_Partial_D_blood_group_alleles_v5.0_180207.pdf
• http://www.isbtweb.org/fileadmin/user_upload/Working_parties/WP_on_Red_Cell_Immunogenetics_and/004_RHD_weak_D_and_Del_alleles_v5.0_180207.pdf
• http://www.isbtweb.org/fileadmin/user_upload/Working_parties/WP_on_Red_Cell_Immunogenetics_and/004_RHD_negative_null_blood_group_alleles_v4.0_180208.pdf

ISBT RHCE allele table (last update July 2019, accessed: Nov 2020)

• http://www.isbtweb.org/fileadmin/user_upload/ISBT004-RHCE-15th_July_2019.pdf

The Human RhesusBase (last update March 2020, accessed: Nov 2020)

• http://www.rhesusbase.info/

Erythrogene (last update Nov 2017, accessed: Nov 2020)

• http://www.erythrogene.com/

Reference Sequence database (RefSeq)

• RHD: https://www.ncbi.nlm.nih.gov/nuccore/171184448 (last update Oct 2020, accessed: Nov 2020);
• RHCE: https://www.ncbi.nlm.nih.gov/nuccore/588480537 (last update Oct 2020, accessed: Nov 2020).

RHeference database (last update April 2021, accessed: April 2021)

• https://www.rheference.org/

Acknowledgments

The author would like to thank Pr. France Pirenne, Dr. Christophe Tournamille, Dr. Btissam Chami, Dr. Isabelle Vinatier, Etablissement français du sang Ile-de-France and Dr. Connie M. Westhoff, Christine Lomas-Francis and Sunitha Vege, New York Blood Center, for fruitful discussions.

Funding: This study was supported by the French National Research Agency, Laboratory of Excellence GR-Ex (funded by the “Investissements d’avenir” program), reference (ANR-11-LABX-0051) and (ANR-11-IDEX-0005-02); Genci grand équipement national de calcul intensif - Centre Informatique National de l’Enseignement Supérieur GENCI–CINES, grants (2018-A0040710370, 2020-A0070710961 and 2020-A0080711465).

Footnote

Provenance and Peer Review: This article was commissioned by the Guest Editor (Yann Fichou) for the series “Molecular Genetics and Genomics of Blood Group Systems” published in Annals of Blood. The article has undergone external peer review.

Reporting Checklist: The author has completed the Narrative Review reporting checklist. Available at http://dx.doi.org/10.21037/aob-20-84.

Conflicts of Interest: The author has completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/aob-20-84). The series “Molecular Genetics and Genomics of Blood Group Systems” was commissioned by the editorial office without any funding or sponsorship. The author has no other conflicts of interest to declare.

Ethical Statement: The author is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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