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. 2024 Apr;119(4):377-382.
doi: 10.1111/vox.13580. Epub 2024 Jan 16.

Novel regulatory variant in ABO intronic RUNX1 binding site inducing A3 phenotype

Gian Andri Thun  1 , Morgan Gueuning  1 , Sonja Sigurdardottir  2 , Eduardo Meyer  2 , Elise Gourri  1   2 , Linda Schneider  2 , Yvonne Merki  2 , Nadine Trost  2 , Kathrin Neuenschwander  2 , Charlotte Engström  3 , Beat M Frey  1   2   3 , Stefan Meyer  2 , Maja P Mattle-Greminger  1
Affiliations

Novel regulatory variant in ABO intronic RUNX1 binding site inducing A3 phenotype

Gian Andri Thun et al. Vox Sang. 2024 Apr.

Abstract

Background and objectives: Mixed-field agglutination in ABO phenotyping (A3, B3) has been linked to genetically different blood cell populations such as in chimerism, or to rare variants in either ABO exon 7 or regulatory regions. Clarification of such cases is challenging and would greatly benefit from sequencing technologies that allow resolving full-gene haplotypes at high resolution.

Materials and methods: We used long-read sequencing by Oxford Nanopore Technologies to sequence the entire ABO gene, amplified in two overlapping long-range PCR fragments, in a blood donor presented with A3B phenotype. Confirmation analyses were carried out by Sanger sequencing and included samples from other family members.

Results: Our data revealed a novel heterozygous g.10924C>A variant on the ABO*A allele located in the transcription factor binding site for RUNX1 in intron 1 (+5.8 kb site). Inheritance was shown by the results of the donor's mother, who shared the novel variant and the anti-A specific mixed-field agglutination.

Conclusion: We discovered a regulatory variant in the 8-bp RUNX1 motif of ABO, which extends current knowledge of three other variants affecting the same motif and also leading to A3 or B3 phenotypes. Overall, long-range PCR combined with nanopore sequencing proved powerful and showed great potential as an emerging strategy for resolving cases with cryptic ABO phenotypes.

Keywords: A3 phenotype; ABO blood group; Oxford nanopore sequencing; RUNX1 transcription factor; regulatory variant.

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References

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