IL21

Inheritance Pattern: AR

Disease ID:MONDO:0014338

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0014338

Submitter: Orphanet

Inheritance Pattern: Unknown

Disease ID:MONDO:0014338

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0014338

Submitter: ClinGen

*IL21* is a type I cytokine produced primarily by natural killer T cells, T follicular helper cells and TH17 cells. The heterodimeric IL-21 receptor complex mediates IL21 signaling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway (PMID: 26966515). *IL21* was reported in relation to autosomal recessive inflammatory bowel disease-infantile onset, in 2014 (Salzer et al., PMID: 24746753). One *IL21* missense variant (c.146T>C (p.Leu49Pro) has been reported in a boy with an early-onset IBD and immunodeficiency. Laboratory examinations demonstrated increased IgE and reduced IgG levels. In vitro functional expression assays revealed impaired STAT3 phosphorylation, decreased B cell proliferation and activation after stimulation with the mutant IL-21 protein, compared to the wild type (PMID: 24746753). Notably, biallelic inactivating mutations in human IL21R, the private receptor for IL-21, is associated with a combined immunodeficiency that is often complicated by cryptosporidium infections (PMID: 33929673). Early diagnosis is crucial as hematopoietic stem cell transplantation might be considered as therapeutic intervention in IL-21 and IL-21R deficiencies to prevent life-threatening infections and multiorgan complications (PMID: 25321844). Experimental evidence includes expression, biochemical function, functional alteration in patient cells and animal models. Quantitative PCR analysis revealed elevated expression of IL-21 by activated CD4+ T cells. IL-21 production by TFH cells was shown to support the differentiation of B cells into Ig-secreting cells. Consistently, Ig secretion was reduced by neutralizing endogenous IL-21 by a blocking polyclonal anti-IL-21 Ab (PMID: 19721453). In mice, stimulation of IL-21/IL-21R signaling with rIL-21 significantly ameliorates intestinal inflammation (PMID: 27545302). Deficiency of IL-21 led to increased number of polyps and tumor load in a mice model to study intestinal tumorigenesis (PMID: 28197386). In summary, there is a single reported case with a rare and distinct phenotype (infantile onset IBD and immunodeficiency), and an ultra-rare, biallelic, *IL21* loss-of-function variant. Supporting experimental evidence indicates a critical role of IL-21 in regulating inflammation, Th17 cell responses in the gut as well as in assisting immune cell differentiation, development, and immunoglobulin class-switching. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. Therefore, the classification of this gene-disease relationship is limited. This gene- disease pair was recurated and the classification was approved by ClinGen Primary Immune Regulatory Disorders GCEP on January 20th, 2026 (SOP Version11).