Submission Details

RIPK1 was first reported in relation to autosomal recessive immunodeficiency 57 in 2018 (Cuchet-Lourenço et al., PMID: 30026316). The condition is characterized by recurrent bacterial, viral and fungal infections since early childhood, as well as early-onset inflammatory bowel disease and autoinflammatory arthritis. T-cell lymphopenia is typically observed, while B-cell and NK cell counts may be normal or decreased. At least 11 variants (4 missense, 4 nonsense, 1 frameshift, 2 large deletions) have been reported in 13 probands in 5 publications (PMIDs: 30026316, 30591564, 31213653, 32181283, 36466854) that are included in this curation. All patients invariably present with recurrent infection and inflammatory bowel disease during early childhood. The maximum score for genetic evidence (12 pts.) has been reached with all reported cases. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, biochemical function studies, and in vitro functional assays (PMIDs: 24813849, 24821786, 30026316, 30591564). Studies robustly show that RIPK1 is involved in MAPK p38 phosphorylation and subsequent stimulation of the production of IL-6, IL-10, TNF-α and IL-12; loss of RIPK1 also leads to excessive production of the proinflammatory cytokine IL-1β. In summary, there is definitive evidence supporting the relationship between RIPK1 and autosomal recessive immunodeficiency 57. 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 Primary Immune Regulatory Disorders GCEP on the meeting date 09/16/2025 (SOP Version 11).