Severe hemolytic disease of the fetus and newborn due to allo‐anti‐D in a patient with a partial DEL phenotype arising from the variant allele described as <i>RHD*148+1T (RHD*01EL.31)</i>

Turley, Elona; McGowan, Eunike C.; Hyland, Catherine A.; Schoeman, Elizna M.; Flower, Robert L.; Skoll, Amanda; Delisle, Marie-France; Nelson, Tanya N.; Clarke, Gwen; Au, Nicholas

doi:10.1111/trf.14944

Cited by 7 publications

(6 citation statements)

References 17 publications

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“…Women with partial (n = 4 in our study) and weak D, other than Types 1 to 3, should be classified as D– with regard to prenatal management and anti‐D prophylaxis. Anti‐D produced by women with RHD variants have been responsible for severe hemolytic disease of the fetus and newborn . The woman of mixed ethnicity with the RHD*01EL.01 variant in our study can be regarded not at risk for anti‐D formation and anti‐D prophylaxis is not necessary .…”

Section: Discussionmentioning

confidence: 73%

Frequency and characterization ofRHDvariants in serologically D– Surinamese pregnant women and D– newborns

et al. 2019

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on behalf of the Rhesus in Surinamese Neonates (RheSuN) Study Group BACKGROUND: Numerous RHD variant genes affect the expression of D on the red blood cell surface. In Suriname, 4.3% of pregnant women were D-, ranging from virtually zero to 7% among ethnic groups. Characterization of RHD variants, which are associated with a variable potential to induce anti-D, is of practical clinical importance especially in case of limited access to preventive measures. Here we report on the occurrence of RHD variant genes in Surinamese serologically D-pregnant women and their D-newborns from different ethnic groups. STUDY DESIGN AND METHODS:The RheSuN study is a cross-sectional cohort study in D-pregnant women and their newborns, who visited hospitals in Paramaribo, Suriname, during routine pregnancy care. The presence of RHD variants was investigated using quantitative polymerase chain reaction targeting RHD Exons 5 and 7 and RH-multiplex ligation-dependent probe amplification. RESULTS: SevenRHD variant genes were detected in 35 of 84 women and four RHD variant genes in 15 of 36 newborns. The RHD*03 N.01 and RHD*08 N.01 variants represented 87% of a total of 62 variant genes. Variants were comparably frequent among ethnicities. In four cases genotyping would have changed anti-D prophylaxis policy: one woman with a RHD*01EL.01 variant, not associated with anti-D formation and three D-newborns with RHD*09.01 and RHD*09.03.01 variants, potentially capable of inducing anti-D. CONCLUSION: RHD variants at risk for anti-D are common among serologic D-individuals from African descent in Suriname. While genotyping D-women has limited added value, it may be considered in newborns from D-women. ABBREVIATIONS: qPCR = quantitative polymerase chain reaction; RH-MLPA = RH-multiplex ligation-dependent probe amplification.From the

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Section: Discussionmentioning

confidence: 73%

Frequency and characterization ofRHDvariants in serologically D– Surinamese pregnant women and D– newborns

et al. 2019

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“…In recent studies, both the c.148+1G>T and c.148+1G>A variations were shown to be associated with a partial D epitope profile, with a very weak reactivity for the latter compared with the former. 17,30 Our data suggest that this difference in epitope density, as well as the lack of reactivity observed with some monoclonal antibodies resulting seemingly in a "partial D-like" phenotype, may be directly linked to a very low native RhD protein expression due to the reduced amount of the respective fulllength transcripts rather than an alteration of the expressed epitope(s); while no full-length transcript signal, potentially due to a signal below the sensitivity of our method, was identified with c.148+1G>A (Fig. 2).…”

Section: Novel Rhd Splice Site Variantsmentioning

confidence: 99%

Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype

Raud

Gourlaouen

et al. 2019

Transfusion

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BACKGROUND We previously showed that several variations in the RHD gene, including synonymous changes, can be classified as splice site variants and may play a direct role in D variant phenotype expression. We sought to extend our study to additional candidates, notably in the first and last exons of the gene, by engineering a novel universal splice reporting vector, i.e., minigene. STUDY DESIGN AND METHODS Our previous plasmid construct was modified to allow subcloning of any exon(s) of interest for assessing effect of variations on splicing. Seventeen novel and/or uncharacterized variations of the RHD gene were selected for the study and tested in our novel model. RESULTS We engineered and validated a novel universal minigene for assessing virtually any variations of interest for splicing defect. Of the 17 variants tested in the novel model, 11 were shown to alter splicing either totally or partially, including the silent c.1065C>T variation, which induces major skipping of exon 7, and may therefore be responsible for reducing D antigen expression. We also showed that while all three missense variations c.1154G>C, c.1154G>T, and c.1154G>A in exon 9 are splice site variants, splicing is differentially altered and D‐negative phenotype observed in the presence of the latter substitution is likely due to a defect in RhD protein folding. CONCLUSION Overall, we hypothesize that splicing alteration is likely to be a common mechanism of D phenotype variation that has been underestimated so far. Further large‐scale studies are necessary to demonstrate this statement definitely.

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“…Patients and pregnant women carrying DEL with partial epD loss, such as RHD (IVS3 + 1 g > a), RHD (IVS5-38del4), RHD*148 + 1 T (RHD*01EL.31), RHD-CE (4-7)-D, RHD*01EL44 (RHD-CE[4-9]-D), and RHD-CE(2-5)-D, are reported to have formed anti-D after red cell transfusion and/or developed fetal anemia. 25,27,28 Whereas patients with the Asian-type DEL, RHD*1227A (RHD*01EL.01), are not known to form anti-D, 4,28 as this variant expresses the complete set of epD similar to regular RhD-positive red cells. 25 Patients with planned transfusions or pregnant women, except in emergency, with RhD-negative phenotype or DEL should be confirmed by red cell genotyping to be genuinely D-negative, Asian-type DEL, or other DEL.…”

Section: Molecular D Typing For Patients With Del Phenotype or Phenot...mentioning

confidence: 99%

“…A concept of “partial DEL” has been proposed, 25,26 which may be understood as DEL with lack of some D epitopes (epD). Patients and pregnant women carrying DEL with partial epD loss, such as RHD (IVS3 + 1 g > a), RHD ( IVS5‐38del4), RHD*148 + 1 T (RHD*01EL.31) , RHD‐CE(4–7)‐D , RHD*01EL44 ( RHD‐CE[4–9]‐D) , and RHD‐CE(2–5)‐D , are reported to have formed anti‐D after red cell transfusion and/or developed fetal anemia 25,27,28 . Whereas patients with the Asian‐type DEL, RHD*1227A (RHD*01EL.01 ), are not known to form anti‐D, 4,28 as this variant expresses the complete set of epD similar to regular RhD‐positive red cells 25 …”

Section: Molecular D Typing For Patients With Del Phenotype or Phenot...mentioning

confidence: 99%

When should RhD‐negative recipients be spared the transfusion of DEL red cells to avoid anti‐D alloimmunization?

2022

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RhD is widely accepted to be the most immunogenic red cell antigen, with recent data suggesting that anti-D alloimmunization occurs after RhD-positive red blood cell or whole blood transfusion in 21% of hospitalized and 33% to 48% of emergency bleeding RhD-negative recipients, 1,2,3 and 24.5% via pregnancy when no prophylaxis was done. 4 Among red cells with various weak D, partial D, and DEL phenotypes, DEL variants by far express the fewest D antigen sites per red cell, <100 versus 10,000 to 33,000 sites on regular RhD-positive red cells.

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Severe hemolytic disease of the fetus and newborn due to allo‐anti‐D in a patient with a partial DEL phenotype arising from the variant allele described as RHD148+1T (RHD01EL.31)

Abstract: The RHD allele, RHD*148+1T, results in a partial Del phenotype, and the anti-D formed in pregnant women with this phenotype is capable of causing severe HDFN.

Cited by 7 publications

References 17 publications

Frequency and characterization ofRHDvariants in serologically D– Surinamese pregnant women and D– newborns

Frequency and characterization ofRHDvariants in serologically D– Surinamese pregnant women and D– newborns

Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype

When should RhD‐negative recipients be spared the transfusion of DEL red cells to avoid anti‐D alloimmunization?

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Severe hemolytic disease of the fetus and newborn due to allo‐anti‐D in a patient with a partial DEL phenotype arising from the variant allele described as RHD*148+1T (RHD*01EL.31)

Abstract: The RHD allele, RHD*148+1T, results in a partial Del phenotype, and the anti-D formed in pregnant women with this phenotype is capable of causing severe HDFN.

Cited by 7 publications

References 17 publications

Frequency and characterization ofRHDvariants in serologically D– Surinamese pregnant women and D– newborns

Frequency and characterization ofRHDvariants in serologically D– Surinamese pregnant women and D– newborns

Functional analysis of novel RHD variants: splicing disruption is likely to be a common mechanism of variant D phenotype

When should RhD‐negative recipients be spared the transfusion of DEL red cells to avoid anti‐D alloimmunization?

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Severe hemolytic disease of the fetus and newborn due to allo‐anti‐D in a patient with a partial DEL phenotype arising from the variant allele described as RHD148+1T (RHD01EL.31)