MHC class II molecules are essential for the presentation of exogenous peptides to CD4+ helper T cells and thus in the adaptive immune response. Mutations in four genes CIITA, RFXANK, RFX5, and RFXAP are responsible for the primary immunodeficiency. At least 19 total variants, including (nonsense, missense, and splice site) have been reported. Affected individuals typically present in infancy with severe, recurrent infections, diarrhea, failure to thrive, low levels of CD4+ T cells, and undetectable HLA-DR expression on monocytes and B cells. Heterozygous carriers of RFXANK variants are reportedly unaffected clinically. The mechanism of pathogenicity appears to be loss of function.
One variant, c.752delG26bp, has been reported in over 50 individuals (PMID:32875002). Individuals who are homozygous for the variant display combined immudeficiency, MHC class two defieincy, and die early in life if left untreated. Nearly all probands reported with the mutation are from the Maghreb region in North Africa. One paper, PMID:21908431, estimated that the variant originated with a founder from ∼2250 years ago (95% CI: 1700-3025 years) in what was most likely an ancient Berber civilization.
This gene-disease association is supported by experimental evidence including RFXANK co-immunoprecipitation with CIITA (PMID:11463838), rescue of function in patient cells (PMID:11313409), and biochemical function (PMID:18723135).
In summary, RFXANK is definitively associated with autosomal recessive MHC class II deficiency. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time. Classification approved by SCID-CID GCEP on 11/17/2022.
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