Submission Details

IL2RG was first reported in relation to X-linked T-B+ severe combined immunodeficiency due to gamma chain deficiency in 1993 (Puck et al. PMID:8401490).

T-B+ severe combined immunodeficiency due to gamma chain deficiency is a form of SCID characterized by severe and recurrent infections, associated with diarrhea and failure to thrive. This disease differs from the Bruton type of agammaglobulinemia by the additional presence of lymphocytopenia, earlier age at death, vulnerability to viral and fungal as well as bacterial infections, lack of delayed hypersensitivity, atrophy of the thymus, and lack of benefit from gamma globulin administration. X-linked combined immunodeficiency is a less severe form of the disorder that is also caused by mutation in the IL2RG gene.

At least 11 unique variants (missense, nonsense, splice donor) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

IL2RG has been noted to be associated with the following disease entities: Combined immunodeficiency, X-linked (moderate) and Severe combined immunodeficiency, X-linked. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, or inheritance pattern or phenotypic variability. Therefore, the two disease assertions have been lumped into one disease entity: T-B+ severe combined immunodeficiency due to gamma chain deficiency (MONDO:0010315).

Summary of Case Level Data – 11.3 POINTS: Variants in this gene have been reported in at least 14 probands in 7 publications (PMID: 7883965, PMID: 9399950, PMID: 8317482, PMID: 8462096, PMID: 7632950, PMID: 23790094, PMID: 9058718).

T-B+ severe combined immunodeficiency due to gamma chain deficiency is caused by a hemizygous pathogenic variant in IL2RG. In typical X-SCID, lack of IL2RG function results in near-complete absence of T and natural killer (NK) lymphocytes and nonfunctional B lymphocytes.

This gene-disease association is supported by animal models, functional alteration studies, and protein interaction studies (PMID: 7632950, PMID: 7697543, PMID: 29606506, PMID: 8266078, PMID: 7973659). IL2RG is the gamma subunit of the interleukin-2 receptor. Stimulation with IL-2 induces the tyrosine phosphorylation and activation of the Janus kinases Jak1 and Jak3. IL2RG is also a functional component of the IL-4 receptor and associates with the IL-7 receptor. Cao et al. (1995) showed defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Experimental evidence demonstrates why deficiency of this common gamma chain has a profound effect on lymphoid function and development, as seen in X-linked severe combined immunodeficiency.

In summary, there is definitive evidence to support the relationship between IL2RG and X-linked, T-B+ severe combined immunodeficiency due to gamma chain 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 SCID-CID GCEP on the meeting date March 18, 2021 (SOP Version 8).