IL2RA

Inheritance Pattern: AR

Disease ID:MONDO:0012436

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0011664

Submitter: ClinGen

*IL2RA* was first reported in relation to autosomal recessive immunodeficiency due to CD25 deficiency in 1997 (Sharfe et al., PMID: 9096364). This disease is a complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (OMIM:606367). Thirteen unique variants (missense, splicing, nonsense and frameshift) reported in nine probands in nine publications (PMIDs: 9096364, 17196245, 23416241, 24116927, 35968218, 36195682, 29995861, 30742970, 31605764) are included in this curation. Immunodeficiency presented early (>1mo to 7mo) in all probands with various phenotypes including but not limited to chronic diarrhea, enlarged lymphoid tissues, and eczema. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is suspected to be loss of function. This gene-disease relationship is also supported by experimental evidence (expression, functional, functional alteration, and animal models. *IL2RA* encodes CD25, which is part of interleukin-2-mediated signaling pathway (PMID: 16293754) resulting in a defect in IL-2 signaling in patient CD4+ T cells (PMID: 23416241). Expression is concentrated in lymphoid tissues (PMID: 25613900). One mouse model showed *IL2RA* defective mice developing autoimmunity deficiencies, and similarly defective lymphoid tissue development (PMID: 7584142). In summary, there is definitive evidence supporting the relationship between *IL2RA* and autosomal recessive immunodeficiency due to CD25 deficiency. 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 PIRD GCEP on the meeting date November 21, 2023 (SOP Version 11). **The following amendment was approved by the Monogenic Diabetes GCEP April 30, 2025** Biallelic pathogenic variants in IL2RA are a rare cause of autosomal recessive IL2RA (AKA CD25) deficiency that often presents in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune IPEX-like features, such as autoimmune enteropathy and eczematous skin lesions, as well as diabetes, which has often been described as a feature. Of 15 reported cases, diabetes was described as the presenting feature in 6 cases (6/15 = 40%) (PMID:17196245, 29995861, 29329106, 31605764, 38408297). When diabetes was the presenting feature, it occurred at very young ages (2 days – 15 weeks of age), suggesting that genetic testing for neonatal diabetes is an important path leading to diagnosis of this rare condition. Diabetes was described as an additional non-presenting feature in 3 additional cases (PMID:29183106, 31605764, 35662751), suggesting that diabetes is present in more than half of affected IL2RA cases (9/15 = 60%). In many cases scant clinical details were provided, but most suggested that the diabetes was insulin-requiring. In addition, several of the cases were found to have positive diabetes-specific antibodies, providing further evidence of the likely autoimmune etiology of the diabetes in this rare condition characterized by immunodysregulation. Finding biallelic P/LP variants in IL2RA in individuals with diabetes should prompt for awareness and/or screening for immune and lymphoproliferative dysfunction as well as other autoimmune problems. Similarly, in individuals discovered to have P/LP IL2RA variants but who have not been diagnosed with diabetes, glucose monitoring is advised, based on the ~60% prevalence of diabetes in this disorder.

Inheritance Pattern: AR

Disease ID:MONDO:0011664

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0011664

Submitter: PanelApp Australia

Inheritance Pattern: AR

Disease ID:MONDO:0011664

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0011168

Submitter: Genomics England PanelApp

Inheritance Pattern: AR

Disease ID:MONDO:0016391

Submitter: Genomics England PanelApp