RHD*03N.01 - RHD*DIIIa-CEVS(4- 7)-D
(ISBT table: RHD negative v4.0)
This entry is an hybrid RHD allele.
Molecular data
Nucleotides:
186G>T; 410C>T; 455A>C; 505A>C; 509T>G; 514A>T; 544T>A; 577G>A; 594A>T; 602C>G; 667T>G; 697G>C; 712G>A; 744C>T; 787G>A; 800A>T; 916G>A; 932A>G; 941G>T; 968C>A; 974G>T; 979A>G; 985GG>CA deletion-insertion; 989A>C; 992A>T; 1006G>T; 1025T>C; 1048G>C; 1053C>T; 1057GGA>TGG deletion-insertion; 1060GC>AA deletion-insertion;
Amino acids: L62F; A137V; N152T; M169L; M170R; I172F; S182T; E193K; K198N; T201R; F223V; E233Q; V238M; S248S; G263R; K267M; V306I; Y311C; G314V; P323H; S325I; I327V; G329H; Y330S; N331I; G336C; I342T; D350H; T351T; G353W; A354N;
Hybrid allele encompassing at least one RHCE exon:
RHD(DIIIa)-RHCE(ceS(4-7))-RHD
Comments on the molecular basis:
- Part of r’S haplotype, type 1 hybrid
- additional intronic mutations in all samples: IVS2+51C>T, IVS2+135A>G, IVS2-26G>A
- Exon 8 is of RHD origin
- hybrid structure was deduced from the PCR pattern
- PCR pattern, exons 3, 4, 5, 6, 7 and 9
Extracellular position of one or more amino acid substitutions:
Splicing:
Unconventional prediction methods:
Phenotype
Main D phenotype: D negative (DEL excluded) (last update: Aug. 7, 2020)Reports by D phenotype
Other RH phenotypes: RH:2, -3, -10, -19, 20, -31, -34, 42, -54, 2,
Serology with monoclonal anti-D
Antigen Density (Ag/RBC)
More phenotype data
Rhesus Similarity Index
Haplotype
Main CcEe phenotype association: Often Ccee phenotype because this allele is responsible for a C positive (or weak) phenotype (last update: June 21, 2020)ce | Ce | cE | CE | |
---|---|---|---|---|
ce | 16 | 68 | 0 | 0 |
Ce | 0 | 0 | 0 | |
cE | 0 | 0 | ||
CE | 0 |
Reports by CcEe phenotype
Reports by allele association
- RHCE*ce(48C,733G,1006T) (RHCE*ce.20.03)
- RHCE*01 or RHCE*ce48,733,1006
- RHCE*ce733 or RHCE*ce48,733,1006
- RHCE*02 or RHCE*ce48,733,1006
- RHCE*cE(361T) or RHCE*ceVS.03
- RHCE*ceVS.01 or RHCE*ceVS.03
- RHCE*ce.01 or RHCE*ceVS.03
- RHCE*Ce or RHCE*ceVS.03
- RHCE*ceVS.03
- RHCE*ceVS.03 or RHCE*ce.01
- RHCE*ceVS.03 or RHCE*ceBI
- RHCE*ceCF or RHCE*ce
- RHCE*ceVS.02 or RHCE*ceVS.03
Alloimmunization
Antibodies in carriers
Antibody specificity: C (RH2)
Summary: allo-anti-C (last update: March 31, 2020)Detailed information
-
Sippert E et al. Blood Transfus (2015)
- Ab specificity: C (RH2)
- Number (auto- or allo-):
- Number listed as allo-: 6
- Number listed as auto-:
- Number of carriers of the allele assessed:
- DAT: ND
- Autologuous control: ND
- Elution: ND
- Autoadsorption: ND
- Titer: ND
- Was anti-LW excluded?: NA
- Other antibodies detected: ND
- Cross matches (with Ab and RBCs from different partial types): ND
- Transfusion history: yes, number and phenotypes ND
- Pregnancy history:
- Anti-D Ig history: NA
- Context: among 48 SCD patients with RH antibodies despite antigen-matched transfusion protocols
- Hemolytic consequences: 4 of the 13 patients with delayed hemolytic transfusion reactions or decreased survival of transfused RBCs had this allele
- Comment: study does not detail serology for each sample, but mentions performing DAT, autologuous control, eluate studies and adsorption on autologuous RBCs to aid the differenciation of autoantibodies and alloantibodies
-
Westhoff CM et al. Transfusion (2013)
- Ab specificity: C (RH2)
- Number (auto- or allo-):
- Number listed as allo-: 1 (listed as allo-anti-C)
- Number listed as auto-:
- Number of carriers of the allele assessed:
- DAT:
- Autologuous control:
- Elution:
- Autoadsorption:
- Titer:
- Was anti-LW excluded?:
- Other antibodies detected:
- Cross matches (with Ab and RBCs from different partial types):
- Transfusion history:
- Pregnancy history:
- Anti-D Ig history:
- Context: among 27 patients referred with different RH alloantibodies, who were found to have RHCE*ceMO allele
- Hemolytic consequences:
- Comment:
Antibody specificity: D (RH1)
Summary: D negative, at risk for anti-D (last update: Aug. 25, 2020)Detailed information
-
Sippert E et al. Blood Transfus (2015)
- Ab specificity: C (RH2)
- Number (auto- or allo-):
- Number listed as allo-: 6
- Number listed as auto-:
- Number of carriers of the allele assessed:
- DAT: ND
- Autologuous control: ND
- Elution: ND
- Autoadsorption: ND
- Titer: ND
- Was anti-LW excluded?: NA
- Other antibodies detected: ND
- Cross matches (with Ab and RBCs from different partial types): ND
- Transfusion history: yes, number and phenotypes ND
- Pregnancy history:
- Anti-D Ig history: NA
- Context: among 48 SCD patients with RH antibodies despite antigen-matched transfusion protocols
- Hemolytic consequences: 4 of the 13 patients with delayed hemolytic transfusion reactions or decreased survival of transfused RBCs had this allele
- Comment: study does not detail serology for each sample, but mentions performing DAT, autologuous control, eluate studies and adsorption on autologuous RBCs to aid the differenciation of autoantibodies and alloantibodies
-
Westhoff CM et al. Transfusion (2013)
- Ab specificity: C (RH2)
- Number (auto- or allo-):
- Number listed as allo-: 1 (listed as allo-anti-C)
- Number listed as auto-:
- Number of carriers of the allele assessed:
- DAT:
- Autologuous control:
- Elution:
- Autoadsorption:
- Titer:
- Was anti-LW excluded?:
- Other antibodies detected:
- Cross matches (with Ab and RBCs from different partial types):
- Transfusion history:
- Pregnancy history:
- Anti-D Ig history:
- Context: among 27 patients referred with different RH alloantibodies, who were found to have RHCE*ceMO allele
- Hemolytic consequences:
- Comment:
Antibodies in D negative recipients
Alloimmunization in recipients: not expected, see phenotype data
Reports
Summary: many descriptions, mainly in individuals of African descent, or compatible with such descent (last update: May 2, 2020)Detailed reports
- 1/8442 8442 donors with D negative phenotype, screened for presence of the RHD gene in two surveys; 754 donors were C and/or E positive, the rest were ccee phenotype; 5 donors were revealed to be weakly D positive in the German population (Baden-Wurttemberg)
- 5/58 (3 also compatible with heterozygous RHef00056 and RHef00442) random donors carrying the allele (regardless of the allele in trans) Malian
- 4/310 (1 heterozygous with RHef00313, 3 with RHef00058) among 1702 samples tested for the combined presence of RHD c.602G and c.667G (700 Dutch White, 310 South African Black, 319 South African Asians, 197 Curacao Black, 176 Ethiopian Black) South African (Black)
- 7/12 samples investigated for weak C, VS+, hrB–, HrB– phenotype some were African or Afro-Caribbean
- 12/60 (5/21 donors, heterozygous with RHef00058; 16/39 patients, 15 heterozygous with RHef00058, 1 with RHef00672) among 60 individuals (21 donors, 39 patients) phenotyped as RH:54 and/or submitted for investigation to determine the RH genotype in the USA population (inferred African American)
- 1/4932 among donors with D negative phenotype, tested for RHD exons Danish (Copenhagen area)
- 1/163 (sample heterozygous with RHef00602) selected variants included for the development of a genotyping assay mainly in the Dutch population (samples may have been included in other studies)
- 19/118 patients or donors with "diverse Rh phenotypes based on typing discrepancies, the presence of alloantibodies in antigen positive people or the presence of a low prevalence antigen marker" African American
- 29/605 random African American donors or SCD patients African American
- 21 alleles in 226 patients SCD children systematically genotyped in an alloimmunization study in the USA population (Philadelphia)
- 2/27 (heterozygous with RHef00008) among 27 patients referred with different RH alloantibodies, who were found to have RHCE*ceMO allele African American
- 3/50 (heterozygous with RHef00008) among 50 donors, the majority referred because of ambiguous RH5 antigen typing, found to have RHCE*ceMO (44 with RHef00008, 6 with RHef00442) in the USA population
- 4/316 (3 homo- or hemizygous, 1 heterozygous with RHef00447) 316 (280 D positive and 36 D negative) donors were genotyped African descent (FY:-1,-2) in the French population
- 9/127 the cohort was composed of 77 Tswa from Congo, 36 Biaka from Central African Republic, 14 Mbuti from Democratic Republic of the Congo Pygmoid Central African
- 12/220 the cohort was composed of 164 Teke-Congolese (ethnic groups: 60 Akwa, 52 Mbochi, 52 Kuyu) from Congo, 19 Mandenka from Senegal, 25 Yoruba from Nigeria, 12 Bantu from Kenya Nonpygmoid Central African
-
3/26243 (1 heterozygous with RHef00447) donors with D negative phenotype in three studies with different inclusion criteria in the Swiss population (Zurich and Berne)
(study may overlap with
24679597 ) -
2/25370 donors with D negative phenotype, screened for RHD exons 3 or 7, plus 5 and 10 in the Swiss population
(study may overlap with
24656493 ) - 7/1314 individuals with apparent D negative phenotype White Argentineans
- 7/48 (1 sample heterozygous with RHef00313, 1 with RHef00008, 5 with RHef00067) among 48 SCD patients with RH antibodies despite antigen-matched transfusion protocols African Brazilian
- 1/67 (heterozygous with RHef00442) among 405 random donor samples used to evaluate RHD zygosity tests (35 typed D negative, 303 typed D positive, 67 of the latter had discordant results with different methods and were sequenced) in the Tunisian population
- 1/35 donors with D negative phenotype who underwent molecular analysis in the Tunisian population
- 13 or more/37782 (13 heterozygous with RHef00447 and 1 with RHef00103 because allele was not detected by the assay) 270 women with variant alleles among 37782 women with D negative phenotype, tested by quantitative fetal RHD genotyping designed to detect RHD exons 5 and 7 in the Dutch population
- 1/35 SCD patients with unexplained RH antibodies, explored by NGS sequencing in the Brazilian population (Sao Paolo)
- 13/1174 (+ 3 heterozygous for RHef00447 and RHef00452) donors with D negative phenotype United States population (Los Angeles)
- 46/526 among donors with D negative phenotype, C and/or E positive, tested for presence of the RHD gene in the Argentinean population (Northwestern Argentina)
- 3/310 donors with D negative phenotype, C and/or E positive in the Italian population
- 6 heterozygotes, 2 hemizygotes, 1 homozygote among 278 samples selected for the development of nonspecific quantitative next-generation sequencing. (non-random samples, may have been reported in other studies)
Allele or phenotype frequency
- 1/45455 (CI: 1/8539 - 1/891266) estimated allele frequency by testing 8442 donors with D negative phenotype, screened for presence of the RHD gene in two surveys; 754 donors were C and/or E positive, the rest were ccee phenotype; 5 donors were revealed to be weakly D positive in the German population (Baden-Wurttemberg)
- 0.043 estimated haplotype frequency Malian
- 0.028 allele frequency among 480 African American donors African American (in the USA population)
- 0.032 allele frequency among 140 SCD patients African American (in the USA population)
- 0.024 allele frequency from molecular typing of 101 random samples Dogon Malian
- 0.0094 allele frequency in 106 donors with weak D phenotype Brazilian (mixed origin, mainly between African and European descent)
- 1/90 (CI: 1/170 - 1/53) estimated allele frequency in donors with D negative phenotype United States population (Los Angeles)
Structure mapping
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References
- International Society of Blood Transfusion et al. International Society of Blood Transfusion (ISBT) allele table Online ressource, 1935. — Online ressource — [RHeference]
- Faas BH et al. Molecular background of VS and weak C expression in blacks. Transfusion, 1997. [Citation] [RHeference]
- Maaskant-van Wijk PA et al. Genotyping of RHD by multiplex polymerase chain reaction analysis of six RHD-specific exons. Transfusion, 1998. [Citation] [RHeference]
- Daniels GL et al. The VS and V blood group polymorphisms in Africans: a serologic and molecular analysis. Transfusion, 1998. [Citation] [RHeference]
- Wagner FF et al. RHD positive haplotypes in D negative Europeans. BMC Genet, 2001. [Citation] [RHeference]
- Wagner FF et al. The DAU allele cluster of the RHD gene. Blood, 2002. [Citation] [RHeference]
- Wagner FF et al. RHD allele distribution in Africans of Mali. BMC Genet, 2003. [Citation] [RHeference]
- Grootkerk-Tax MG et al. RHD(T201R, F223V) cluster analysis in five different ethnic groups and serologic characterization of a new Ethiopian variant DARE, the DIII type 6, and the RHD(F223V). Transfusion, 2006. [Citation] [RHeference]
- Pham BN et al. Heterogeneous molecular background of the weak C, VS+, hr B-, Hr B- phenotype in black persons. Transfusion, 2009. [Citation] [RHeference]
- Flegel WA et al. D variants at the RhD vestibule in the weak D type 4 and Eurasian D clusters. Transfusion, 2009. [Citation] [RHeference]
- Westhoff CM et al. DIIIa and DIII Type 5 are encoded by the same allele and are associated with altered RHCE*ce alleles: clinical implications. Transfusion, 2010. [Citation] [RHeference]
- Krog GR et al. Is current serologic RhD typing of blood donors sufficient for avoiding immunization of recipients? Transfusion, 2011. [Citation] [RHeference]
- Reid ME et al. Molecular background of RH in Bastiaan, the RH:-31,-34 index case, and two novel RHD alleles. Immunohematology, 2012. [Citation] [RHeference]
- Moussa H et al. Molecular background of D-negative phenotype in the Tunisian population. Transfus Med, 2012. [Citation] [RHeference]
- Lejon Crottet S et al. Serologic and molecular investigations of DAR1 (weak D Type 4.2), DAR1.2, DAR1.3, DAR2 (DARE), and DARA. Transfusion, 2013. [Citation] [RHeference]
- Westhoff CM et al. RHCE*ceMO is frequently in cis to RHD*DAU0 and encodes a hr(S) -, hr(B) -, RH:-61 phenotype in black persons: clinical significance. Transfusion, 2013. [Citation] [RHeference]
- Reid ME et al. The low-prevalence Rh antigen STEM (RH49) is encoded by two different RHCE*ce818T alleles that are often in cis to RHD*DOL. Transfusion, 2013. [Citation] [RHeference]
- Haer-Wigman L et al. RHD and RHCE variant and zygosity genotyping via multiplex ligation-dependent probe amplification. Transfusion, 2013. [Citation] [RHeference]
- Granier T et al. A comprehensive survey of both RHD and RHCE allele frequencies in sub-Saharan Africa. Transfusion, 2013. [Citation] [RHeference]
- Chou ST et al. High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors. Blood, 2013. [Citation] [RHeference]
- Silvy M et al. Identification of novel polymorphism restricted to the (C)ces type 1 haplotype avoids risk of transfusion deadlock in SCD patients. Br J Haematol, 2013. [Citation] [RHeference]
- Gowland P et al. Molecular RHD screening of RhD negative donors can replace standard serological testing for RhD negative donors. Transfus Apher Sci, 2014. [Citation] [RHeference]
- Crottet SL et al. Implementation of a mandatory donor RHD screening in Switzerland. Transfus Apher Sci, 2014. [Citation] [RHeference]
- Kappler-Gratias S et al. Systematic RH genotyping and variant identification in French donors of African origin. Blood Transfus, 2014. [Citation] [RHeference]
- Trucco Boggione C et al. Molecular structures identified in serologically D- samples of an admixed population. Transfusion, 2014. [Citation] [RHeference]
- Reid ME et al. Genomic analyses of RH alleles to improve transfusion therapy in patients with sickle cell disease. Blood Cells Mol Dis, 2014. [Citation] [RHeference]
- Kacem N et al. Paternal RHD zygosity determination in Tunisians: evaluation of three molecular tests. Blood Transfus, 2015. [Citation] [RHeference]
- Sippert E et al. Variant RH alleles and Rh immunisation in patients with sickle cell disease. Blood Transfus, 2015. [Citation] [RHeference]
- Ba A et al. RH diversity in Mali: characterization of a new haplotype RHD*DIVa/RHCE*ceTI(D2). Transfusion, 2015. [Citation] [RHeference]
- Stegmann TC et al. Frequency and characterization of known and novel RHD variant alleles in 37 782 Dutch D-negative pregnant women. Br J Haematol, 2016. [Citation] [RHeference]
- Srivastava K et al. The DAU cluster: a comparative analysis of 18 RHD alleles, some forming partial D antigens. Transfusion, 2016. [Citation] [RHeference]
- Dezan MR et al. RHD and RHCE genotyping by next-generation sequencing is an effective strategy to identify molecular variants within sickle cell disease patients. Blood Cells Mol Dis, 2017. [Citation] [RHeference]
- Chou ST et al. Whole-exome sequencing for RH genotyping and alloimmunization risk in children with sickle cell anemia. Blood Adv, 2017. [Citation] [RHeference]
- Dezan MR et al. High frequency of variant RHD genotypes among donors and patients of mixed origin with serologic weak-D phenotype. J Clin Lab Anal, 2018. [Citation] [RHeference]
- Perez-Alvarez I et al. RHD genotyping of serologic RhD-negative blood donors in a hospital-based blood donor center. Transfusion, 2019. [Citation] [RHeference]
- Trucco Boggione C et al. Characterization of RHD locus polymorphism in D negative and D variant donors from Northwestern Argentina. Transfusion, 2019. [Citation] [RHeference]
- Izaskun Apraiz et al. Performance Evaluation Study of ID RHD XT as a Molecular Tool for RHD Gene Screening in Pooled Blood Samples of Serologically D− C/E+ Donors Transfusion, 2019. — Abstract — [RHeference]
- Floch A et al. Comment from Rheference Online ressource, 2020. — Online ressource — [RHeference]
- Stef M et al. RH genotyping by nonspecific quantitative next-generation sequencing. Transfusion, 2020. [Citation] [RHeference]
Last update: Jan. 8, 2021