Submission Details

IL2RB deficiency was first reported as the cause of autosomal recessive immunodeficiency 63 with lymphoproliferation and autoimmune disease in 2019 (Fernadez et al., PMID: 31040184). Patients with this disorder have a susceptibility to herpesvirus infections as well as severe autoimmune and inflammatory disease in the form of autoimmune haemolytic anaemia, enteropathy, dermatitis, hypergammaglobulinemia, lymphadenopathy and splenomegaly.

Four variants (missense and nonsense) that have been reported in 5 probands in 2 publications (PMIDs: 31040184, 31040185) are included in this curation. Variants in this gene segregated with disease in 5 additional family members. The heterozygous parents all appear unaffected. A further case is available as a poster abstract (https://doi.org/10.1136/flgastro-2021-bspghan.33) that was unable to be scored, however personal correspondence confirmed the patient shared the same variant (L77P) as reported in two of the scored probands (PMID: 31040185).

The mechanism of pathogenicity appears to be loss of function. Autosomal recessive immunodeficiency 63 with lymphoproliferation and autoimmune disease is caused by partial or complete biallelic loss of function of IL2RB resulting in impaired IL-2 and IL-15 signaling, immune dysregulation and autoimmunity.

This gene-disease relationship is supported by animal models, expression studies, functional studies and rescue in animal and patient cells (PMIDs: 23352221, 1631559, 8026467, 10706676, 7770771, 31040185). IL2RB encodes the beta subunit of the IL-2 and IL-15 receptors, and is expressed on resting T cells, NK cells, monocytes and neutrophils. The expression and function of IL2RB is reviewed by Liao et al (2013). There are many studies examining the function and expression of IL2RB, and both IL-2 and IL-15 are important in lymphocyte development and regulation. Suzuki et al (1995) first described the Il2rb -/- mouse which displays some phenotypic similarities to that of humans with IL2RB deficiency including lethal autoimmune disease and lymphoproliferation. Further studies on this mouse demonstrated that either thymic IL2RB expression or adoptive transfer of T regulatory cells (CD4+CD25+) was sufficient to rescue the autoimmune immunophenotype (Malek et al., 2000). Finally, transduction of affected patient cells with IL-2RB partially restores deficient IL-2 signaling (Zhang et al., 2019).

In summary, there is moderate evidence supporting the relationship between IL2RB and autosomal recessive immunodeficiency 63 with lymphoproliferation and autoimmune disease. This evidence has been reported in both research and clinical diagnostic settings, and has been upheld over time, though at the time of this curation, only 5 probands have been reported in two publications. This classification was approved by the ClinGen PIRD GCEP on the meeting date December 12, 2023 (SOP Version 10).