RFX5 was first reported in relation to autosomal recessive major histocompatibility complex (MHC) class II deficiency in 1995 (Steimle V, et al., 1995, PMID: 7744245 ). 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 trans-acting genes CIITA, RFXANK, RFX5, and RFXAP are responsible for the primary immunodeficiency. Pathogenic variants in RFX5 are associated with BLS complementation group C.Affected individuals typically present in infancy with severe, recurrent infections, failure to thrive, low levels of CD4+ T cells, and undetectable undetectable MHC class II (e.g., HLA DR) expression on monocytes and B cells. The mechanism of pathogenicity appears to be bialleleic loss of function. Heterozygous carriers of RFX5 loss of function variants are not reported to be clinically affected. The RFX5 curation includes 8 variants (frameshift, nonsense, missense, and splice site) reported in 8 probands from 6 publications (PMIDs: 7744245, 9401005, 10079298, 12368908, 30084052, 29527204). Additional evidence is available however the maximum score for genetic evidence was reached. This gene-disease association is supported by experimental evidence including its biochemical function, as part of the RFX complex, of binding DNA in a X1-box-spiceifc manner to allow for transcriptional activation of MHC class II molecules (PMID: 10938133). The MHC class II deficiency can be rescued in patient cells by expression of wildtype RFX5 (PMID: 7744245 ). Furthermore, it interacts with the transactivator CIITA, which is also implicated in MHC class II deficiency (PMID: 10938133). Additionally, RFX5−/− mice exhibit an immune deficiency that is very similar to that of MHC-II–deficient patients (PMID: 9491996). In summary, RFX5 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.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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