TAP2 was first reported in relation to autosomal recessive major histocompatibility complex (MHC) class I deficiency in 1994 (de la Salle et al., PMID: 7517574). This condition is characterized by chronic bacterial infections and/or cutaneous granulomatous lesions. Bacterial infections may impact the upper and lower respiratory tract, causing sinusitis, otitis media, bronchitis, pneumonia, and bronchiectasis. Some individuals are asymptomatic. (PMID: 12067308, 36227411) The immunophenotype of TAP2-related MHC class I deficiency has been reported as normal total CD8+ T cell counts but decreased naïve CD8+ T cell counts and increased alpha-beta T cells. (PMID: 36227411) Heterozygous carriers are apparently unaffected. (PMID: 10560675, 12067308, 36227411) Six variants (nonsense, frameshift, and splice site) that have been reported in six probands in six publications (PMIDs: 7517574, 10560675, 12067308, 23662797, 20083708, 36227411) are included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function.
This gene-disease relationship is also supported by protein interaction, functional alteration in patient cells, a rescue study, and mouse models. (PMIDs: 9651323, 10560675, 19721454, 27861817, 7517574) The TAP complex is made up of TAP1 and TAP2. (PMID: 9651323) We have previously established TAP1 as definitively associated with MHC class I deficiency. TAP2 deficient patient cells have deficient MHC class I surface expression (PMID: 7517574), and expression of wild-type TAP2 in patient cells restores that expression (PMID: 10560675) Animal models also recapitulate the phenotype seen in humans with absent MHC class I expression. (PMID: 19721454, 27861817)
In summary, there is definitive evidence supporting the relationship between TAP2 and autosomal recessive MHC class I deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on the meeting date October 19, 2023 (SOP Version 9).
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