Novel regulatory variant in ABO intronic RUNX1 binding site inducing A 3 phenotype

Mixed-field agglutination in ABO phenotyping (A , B ) 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 technologie...

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Published in:Vox sanguinis 2024-04, Vol.119 (4), p.377-382
Main Authors: Thun, Gian Andri, Gueuning, Morgan, Sigurdardottir, Sonja, Meyer, Eduardo, Gourri, Elise, Schneider, Linda, Merki, Yvonne, Trost, Nadine, Neuenschwander, Kathrin, Engström, Charlotte, Frey, Beat M, Meyer, Stefan, Mattle-Greminger, Maja P
Format: Article
Language:English
Subjects:
ABO Blood-Group System - genetics
Alleles
Binding Sites
Core Binding Factor Alpha 2 Subunit - genetics
Genotype
Humans
Introns - genetics
Phenotype
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Summary:Mixed-field agglutination in ABO phenotyping (A , B ) 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. 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 A B phenotype. Confirmation analyses were carried out by Sanger sequencing and included samples from other family members. 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. 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 A or B 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.
ISSN:0042-9007
1423-0410
DOI:10.1111/vox.13580