P071 Limited exon sequence mismatches outside the antigen recognition domain in a cohort of 4646 high resolution 10/10 HLA-matched donor and recipient

Aim In hematopoietic stem cell transplantation (HCT), HLA allele matching between donor and recipient has traditionally focused on the polymorphic antigen recognition domain (ARD). Mismatching at the ARD is known to influence outcomes. This study investigated the genetic differences in the non-ARD regions among ARD-matched donor-recipient pairs to determine possible association with the transplant outcomes. Methods We compared the full-length HLA Class I allele sequences (HLA-A, -B, -C) and partial-length (partial intron 1 through partial intron 3) Class II allele sequences (HLA-DRB1, DQB1) for 4646 high-resolution 10/10 HLA-matched HCT donor-recipient pairs. We developed a comprehensive HLA allele sequence comparison pipeline, which identifies and annotates the mismatched positions between two alleles by their functional region and their protein sequence differences using IMGT/HLA Database (v3.31.0). Results For HLA Class I alleles, 95.4% of the ARD matched alleles have identical sequences outside the ARD, including introns and non-ARD exons. 0.3% of the mismatches were synonymous variants from the ARD region while 0.2% and 0.1% of mismatches found from non-ARD exons were synonymous and nonsynonymous variants, respectively. The intronic variation accounted for 4.2% of the mismatches. Similarly, for HLA Class II alleles, 0.3% of mismatches were synonymous ARD variants, and the mismatches in the non-ARD exons were also very rare (synonymous: 0.3%; nonsynonymous: 0.2%). However, a high degree of polymorphism was observed in the intronic regions of the Class II genes with only 77.3% of the allele pairs having identical sequences. 0.2% and 4.6% of Class I and Class II allele pairs, respectively, showed both exonic and intronic mismatches. Conclusions HCT donor/recipient pairs matched at high resolution for HLA-A, B, C, DRB1 and DQB1 have limited coding variation outside of the ARD. Intronic variation was observed at a higher rate for HLA Class II in our study compared to prior publications (17.3% vs.