Characterization of an inherited HLA-B gene deletion in a candidate for hematopoietic cell transplantation

Accurate high-resolution genotyping of HLA genes for hematopoietic cell transplant (HCT) recipients provides critical information for matching and donor selection. We describe unusual family typing for a pediatric transplant candidate which revealed that the patient and mother did not share a common HLA-B allele, although all other class I and class II HLA alleles inherited on the maternal haplotype were detected. Copy number analysis of hybrid capture next generation sequencing data showed 2 copies each of HLA-A, C, MICA, MICB, DRB1, DQA1, DQB1, DPA1, and DPB1, but revealed HLA-B allele hemizygosity in both the patient and mother. Binary alignment mapping to the HLA-B consensus sequence showed a drop in coverage in the 5' untranslated region, approximately 300 base pairs upstream of exon 1. Germline whole genome sequencing performed on DNA from a skin punch biopsy from the patient confirmed an ∼ 85 kb deletion spanning the entire HLA-B gene locus. This case highlights the importance of family/haplotype studies and copy number analysis in workup for HCT and suggests that HLA locus deletions, although rare, may be underappreciated. Furthermore, haplotypes with deleted alleles may not be accurately reflected in population frequencies and donor search algorithms.