Diverse and novel <i><scp>RHD</scp></i> variants in Australian blood donors with a weak D phenotype: implication for transfusion management

McGowan, Eunike C.; Lopez, Genghis H.; Knauth, Christine; Liew, Yew Wah; Condon, Jennifer A.; Ramadi, Lanny; Parsons, Karyn; Turner, Elise; Flower, Robert L.; Hyland, Catherine A.

doi:10.1111/vox.12488

Cited by 20 publications

(24 citation statements)

References 47 publications

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“…The c.939+3A>C substitution also showed a major exclusion of exon 6 from the mature transcript. RHD (c.635‐2A>C) and RHD (c.939+3A>C) have been suspected to be partial D alleles, suggesting that at least one D epitope is altered, possibly by insertion/deletion (indel) of amino acid(s) in these specific cases. Although we have clearly shown that they are both SS variants, there is no molecular evidence for short inframe (nucleotide) indels in our model, indicating that the molecular mechanism underlying the putative partial D phenotype associated with these variants remains to be characterized by additional studies, ideally with fresh blood samples.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…An up‐to‐date review of the literature and the RhesusBase was performed . On the basis of their position relative to the constitutive SSs, 15 variations of the RHD gene, including eight exonic (i.e., first, antepenultimate and penultimate position of exons) and seven intronic variants were selected for functional analysis (Table ).…”

Section: Methodsmentioning

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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“…However, advanced molecular typing platforms such as SNP‐microarray and DNA sequencing, including massively parallel sequencing, have now become increasingly available in reference typing laboratories to detect and genetically classify RHD variants . For clinicians, early identification of individuals with partial D would help guide patient management in the obstetric population …”

Section: Discussionmentioning

confidence: 99%

“…Rh phenotyping was performed following accredited standard agglutination test tube method using anti‐D, anti‐C, anti‐c, anti‐E, and anti‐e monoclonal antibodies (MoAbs; Epiclone, CSL) phenotyping reagents. RhD epitope mapping was performed using a RhD typing kit (ALBAclone Advanced Partial RhD typing kit, Alba Bioscience Ltd.) according to the manufacturer's instructions …”

Section: Methodsmentioning

confidence: 99%

Anti‐D in a mother, hemizygous for the variant RHDDNB* gene, associated with hemolytic disease of the fetus and newborn

et al. 2017

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The anti-D produced by this woman with partial D DNB resulted in a case of hemolytic disease of the fetus and newborn (HDFN) requiring intensive treatment in the perinatal period. Anti-D formed by women with the partial D DNB phenotype has the potential to cause HDFN where the fetus is D+. Women carrying RHD*DNB should be offered appropriate prophylactic anti-D and be transfused with D- RBCs if not already alloimmunized.

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“…The D‐epitope profile was performed using anti‐D MoAbs (ALBAClone, Alba Bioscience Ltd) by indirect antiglobulin test (IAT) and adsorption and elution technique with untreated and papain‐treated reagent RBCs (Phenocell A, bioCSL) . The anti‐D MoAbs (ALBAClone) were different from the aforementioned Australian DEL prevalence study .…”

Section: Methodsmentioning

confidence: 99%

A DEL phenotype attributed to RHD Exon 9 sequence deletion: slipped‐strand mispairing and blood group polymorphisms

et al. 2017

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Deletion mutations bordered by repeat sequences are a hallmark of slipped-strand mispairing (SSM) event. We propose this genetic mechanism generated the germline deletion in the Caucasian donor. Extensive studies show that the RHD*1227A is the most prevalent DEL allele in East Asian populations and may have confounded the initial molecular studies. Review of the literature revealed that the SSM model explains some of the extreme polymorphisms observed in the clinically significant RhD blood group antigen.

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Diverse and novel RHD variants in Australian blood donors with a weak D phenotype: implication for transfusion management

Abstract: The array of RHD variants detected in this study indicated diversity in the Australian donor population that needs to be accommodated for in future genotyping strategies.

Cited by 20 publications

References 47 publications

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

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

Anti‐D in a mother, hemizygous for the variant RHDDNB* gene, associated with hemolytic disease of the fetus and newborn

A DEL phenotype attributed to RHD Exon 9 sequence deletion: slipped‐strand mispairing and blood group polymorphisms

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Diverse and novel RHD variants in Australian blood donors with a weak D phenotype: implication for transfusion management

Abstract: The array of RHD variants detected in this study indicated diversity in the Australian donor population that needs to be accommodated for in future genotyping strategies.

Cited by 20 publications

References 47 publications

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

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

Anti‐D in a mother, hemizygous for the variant RHD*DNB gene, associated with hemolytic disease of the fetus and newborn

A DEL phenotype attributed to RHD Exon 9 sequence deletion: slipped‐strand mispairing and blood group polymorphisms

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Product

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Anti‐D in a mother, hemizygous for the variant RHDDNB* gene, associated with hemolytic disease of the fetus and newborn