Submission Details

RELA was first reported in relation to autosomal dominant combined immunodeficiency due to RELA haploinsufficiency in 2017 (Badran YR, et al., 2017, PMID: 28600438). RELA encodes RelA/p65 which is a key component of the canonical pathway of NFκB, and associates with p50/NFκB1for nuclear translocation and cytokine gene transcription. Signaling through the NF-κB pathway is important for maintaining self-tolerance and regulation of the immune response. RELA haploinsufficiency results in impaired NF-κB activation downstream of TLR and TNF stimulation, followed by impaired up-regulation of antiapoptotic genes and increased stromal cell apoptosis. This disorder is characterized predominantly by chronic mucocutaneous ulceration; however, the clinical phenotype broadens to include Behçet’s syndrome and irritable bowel disease. Genetic evidence was included in this curation from four probands in four publications (PMIDs: 28600438, 32969189, 29305315, 35412596). The four reported variants include splice site, frameshift, and nonsense. Experimentally, this gene-disease relationship is supported by its function in the activation of NF-κB-dependent transcription and to prevent apoptosis (PMID: 12881425), which is altered in in HEK293T cells transfected with mutant RELA (PMID: 32969189) and in patients, resulting in increased TNF-induced stromal cell death (PMID: 28600438). Defective activation of NF-κB-dependent transcription was rescued in patient cells with expression of WT RELA (PMID: 28600438). Furthermore, a Rela+/− mouse model recapitulated the defective NF-κB-dependent transcription and cutaneous ulceration observed in patients (PMID: 28600438). In summary, there is Definitive evidence to support this gene-disease relationship. This has been repeatedly demonstrated in both research and the clinical diagnostic setting and has been upheld over time.