Submission Details

A TAPBP germline loss of function variant was first identified in a woman with type I bare lymphocyte syndrome (BLS) (PMID: 12149238), the only report of a germline TAPBP variant. Other somatic TAPBP variants have been identified in cancers. Autosomal recessive TAPBP deficiency was associated with reduction of class I MHC expression and reductions in CD8 T cell and NK cell numbers in peripheral blood. Herpes zoster infection was noted in this adult patient, but no other immune deficiency was noted. This phenotype contrasts with type I BLS due to biallelic loss of function variants in TAP1, where patients show respiratory inflammation and skin ulcers. The indel variant identified in the single patient resulted in the loss of exon 4-7 of TAPBP, resulting in loss of expression of the protein and loss of function. Heterozygous carriers have not been reported in the literature. TAPBP plays a critical role in the peptide loading and resultant stable expression of cell surface MHC class I. In vitro data show that TAPBP is found in a complex with TAP1, TAP2, MHC, ERp57, and calreticulin, and is required for expression of class I MHC on the surface of cell lines (PMID: 9271576). Studies of cancer cell lines have found that variants in TAPBP reduce the expression of MHC class I on the surface of cells, potentially as a mechanism of immune evasion (PMID: 26381407). Class I MHC expression in these cell lines can be rescued with the transfection of WT TAPBP (PMID: 26381407). TAPBP knockout mice recapitulate the phenotype seen in the reported patient, with loss of stable class I MHC expression and reduced CD8 T cells (PMID:10973281, 12594855). TAPBP KO mice also show alterations in NK cell function and the ability of dendritic cells to cross-present antigens (PMID:10973281). TAPBP heterozygous KO mice show normal expression of MHC I (PMID: 10973281). While there is no evidence against the gene-disease relationship of TAPBP and type I BLS, there was only one patient identified that supports the relationship. Based on this,TAPBP has limited association with type I bare lymphocyte deficiency.

This classification was originally approved by the ClinGen SCID-CID GCEP on 10/20/2022 (SOP Version 9). It was re-evaluated on June 19th, 2025 with no additional cases identified. Therefore, there is no change in this gene disease relationship.