Missense mutations in the C-terminal portion of the -encoded glycosyltransferase underlying the Sd(a-) phenotype.

Sd is a high-frequency carbohydrate histo-blood group antigen, GalNAcβ1-4(NeuAcα2-3)Galβ, implicated in pathogen invasion, cancer, xenotransplantation and transfusion medicine. Complete lack of this glycan epitope results in the Sd(a-) phenotype observed in 4% of individuals who may produce anti-Sd. A candidate gene (), encoding a Sd-synthesizing β-1,4--acetylgalactosaminyltransferase (β4GalNAc-T2), was cloned in 2003 but the genetic basis of human Sd deficiency was never elucidated. Experimental and bioinformatic approaches were used to identify and characterize variants in nine Sd(a-) individuals. Homozygosity for rs7224888:T > C dominated the cohort (n = 6) and causes p.Cys466Arg, which targets a highly conserved residue located in the enzymatically active domain and is judged deleterious to β4GalNAc-T2. Its allele frequency was 0.10-0.12 in different cohorts. A Sd(a-) compound heterozygote combined rs7224888:T > C with a splice-site mutation, rs72835417:G > A, predicted to alter splicing and occurred at a frequency of 0.11-0.12. Another compound heterozygote had two rare nonsynonymous variants, rs148441237:A > G (p.Gln436Arg) and rs61743617:C > T (p.Arg523Trp), . One sample displayed no differences compared to Sd(a+). When investigating linkage disequilibrium between variants, we noted a 32-kb block spanning intron 9 to the intergenic region downstream of . This block includes , a long non-coding RNA recently reported to promote tumorigenesis and poor prognosis in colon cancer. The expression patterns of and correlated extremely well in >1000 cancer cell lines. In summary, we identified a connection between variants of the cancer-associated gene and Sd, thereby establishing a new blood group system and opening up for the possibility to predict Sd(a+) and Sd(a‒) phenotypes by genotyping.