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Background <p>Accurate typing of the D antigen is critical to provide guidance for blood transfusion and safe management of Rh-incompatible pregnancies. <i>RHD </i>genotyping assays have been widely adopted to improve D variant detection, especially for common<i> RHD</i> alleles with missense variants and <i>RHD-CE-D</i> hybrids. Few structural variants of the <i>RHD</i> gene are known to involve large fragments of non-RH sequences, despite causing phenotype-genotype discrepancies.</p> Methods <p>We had previously detected reduced copy numbers of <i>RHD</i> exon 10 in Chinese Han. Their <i>RHD</i> genes were further analyzed using long-read sequencing of <i>RHD</i> and whole-genome long-read sequencing using PacBio platform. The population frequency and practical relevance were evaluated, such as effects on D antigen expression and accuracy of routine <i>RHD</i> genotyping assays.</p> Results <p>A novel structural variant of the <i>RHD</i> gene, dubbed <i>RHD-CE-TMEM50A-D</i>, had distinct features: a short deletion of the non-coding region of <i>RHD</i> exon 10 (688 bp del), a large insertion (21.8 kb ins) involving the inversion of non-coding region of <i>RHCE</i> exon 10 (174 bp) and exon 7 to intron 2 of <i>TMEM50A </i>gene (21,648 bp), and several single nucleotide substitutions. The large delins fragment was firstly found in 9 individuals, further representing 4.1% of random D+ donors (40/982), 2.9% of D−C+/E+ individuals who carry the non-functional <i>RHD*01N.04 </i>(6/205), and 3.4% of weak/partial D individuals (7/207) who carry <i>RHD*DFR2</i> and <i>RHD*DVI.3</i>, but 0% in a different cohort of Asian-type DEL individuals (0/205). The large delins fragment located in non-coding region of <i>RHD</i> exon 10 of four different alleles did not significantly change the D antigen expression but caused inconclusive results in several routine <i>RHD </i>genotyping assays.</p> Conclusions <p>The novel <i>RHD-CE-TMEM50A-D</i> allele represented approximately 1 in 49 chromosomes among the southern Chinese Han population. The variations of these <i>RHD</i> alleles involve the replacement of some <i>RHD</i>-specific sequences by the corresponding <i>RHCE</i>-specific sequences in the non-coding region of <i>RHD</i> exon 10, commonly used for <i>RHD</i>-specific primers design in genotyping assay. Hence, red cell genotyping assays, if applied to individuals of East Asian heritage, should recognize this relatively common allele to avoid <i>RHD</i> allele dropout.</p>

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An RHD gene variant, common in southern Chinese Han, involves a short 688 bp deletion and a long 21.8 kb insertion in the RHD exon 10 non-coding region, affecting the accuracy of red cell genotyping

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  • 发表日期：

    2026年5月12日

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  • Jizhi Wen,
  • Fei He,
  • Barbera Veldhuisen,
  • Chunyan Mo,
  • Ling Wei,
  • Shuangshuang Jia,
  • C. Ellen. van der Schoot,
  • Willy Albert Flegel,
  • Yanli Ji

摘要

Background

Accurate typing of the D antigen is critical to provide guidance for blood transfusion and safe management of Rh-incompatible pregnancies. RHD genotyping assays have been widely adopted to improve D variant detection, especially for common RHD alleles with missense variants and RHD-CE-D hybrids. Few structural variants of the RHD gene are known to involve large fragments of non-RH sequences, despite causing phenotype-genotype discrepancies.

Methods

We had previously detected reduced copy numbers of RHD exon 10 in Chinese Han. Their RHD genes were further analyzed using long-read sequencing of RHD and whole-genome long-read sequencing using PacBio platform. The population frequency and practical relevance were evaluated, such as effects on D antigen expression and accuracy of routine RHD genotyping assays.

Results

A novel structural variant of the RHD gene, dubbed RHD-CE-TMEM50A-D, had distinct features: a short deletion of the non-coding region of RHD exon 10 (688 bp del), a large insertion (21.8 kb ins) involving the inversion of non-coding region of RHCE exon 10 (174 bp) and exon 7 to intron 2 of TMEM50A gene (21,648 bp), and several single nucleotide substitutions. The large delins fragment was firstly found in 9 individuals, further representing 4.1% of random D+ donors (40/982), 2.9% of D−C+/E+ individuals who carry the non-functional RHD*01N.04 (6/205), and 3.4% of weak/partial D individuals (7/207) who carry RHD*DFR2 and RHD*DVI.3, but 0% in a different cohort of Asian-type DEL individuals (0/205). The large delins fragment located in non-coding region of RHD exon 10 of four different alleles did not significantly change the D antigen expression but caused inconclusive results in several routine RHD genotyping assays.

Conclusions

The novel RHD-CE-TMEM50A-D allele represented approximately 1 in 49 chromosomes among the southern Chinese Han population. The variations of these RHD alleles involve the replacement of some RHD-specific sequences by the corresponding RHCE-specific sequences in the non-coding region of RHD exon 10, commonly used for RHD-specific primers design in genotyping assay. Hence, red cell genotyping assays, if applied to individuals of East Asian heritage, should recognize this relatively common allele to avoid RHD allele dropout.