IL2RG – T-B+ Severe Combined Immunodeficiency due to γ-Chain Deficiency

X-linked severe combined immunodeficiency (X-SCID) is caused by pathogenic variants in the common γ-chain gene IL2RG, which encodes the shared subunit for interleukin-2, ‑4, ‑7, ‑9, and ‑15 receptors. Affected males classically present with absent T and NK cells and normal or elevated B cells (T−B+NK−), profound hypogammaglobulinemia, and life-threatening infections in early infancy. Hypomorphic and splice-site mutations have broadened the clinical spectrum to include leaky or atypical phenotypes with partial immune function.

Genetic studies have identified over 100 distinct IL2RG mutations in more than 150 unrelated male probands, consistent with an X-linked recessive pattern and reaching the ClinGen genetic evidence cap ([PMID:10794430]). Segregation analyses, including reports of female germline mosaicism and multi-generation transmission, confirm co-segregation of IL2RG variants with disease.

Inheritance is X-linked recessive, with carrier females typically asymptomatic but identified by mutation analysis or skewed X-inactivation studies. Familial recurrence in multiple pedigrees and maternal germline mosaicism underscore the need for comprehensive family testing.

Functional assays demonstrate that missense and frameshift IL2RG variants abrogate IL-2 binding, impair STAT5 phosphorylation, and block lymphocyte growth signaling in vitro ([PMID:8027558]). In vivo, lentiviral vector–mediated correction of Il2rg-deficient hematopoietic stem cells restores T, B, and NK cell development and reconstitutes immune function in murine models ([PMID:27099176]).

Therapeutically, early diagnosis via newborn screening, molecular analysis, and functional testing enables prompt hematopoietic stem cell transplantation or gene therapy. Preimplantation genetic testing has successfully prevented transmission in affected families ([PMID:35719382]).

Collectively, the evidence for IL2RG in X-SCID is definitive, supporting its use in diagnostic decision-making, carrier screening, and development of curative gene therapies.

References

• The Journal of clinical investigation • 1997 • An interleukin-2 receptor gamma chain mutation with normal thymus morphology. PMID:9399950
• Clinical immunology (Orlando, Fla.) • 2000 • Efficient detection of thirty-seven new IL2RG mutations in human X-linked severe combined immunodeficiency. PMID:10794430
• Journal of immunology • 1994 • Impairment of ligand binding and growth signaling of mutant IL-2 receptor gamma-chains in patients with X-linked severe combined immunodeficiency. PMID:8027558
• Science translational medicine • 2016 • Lentiviral hematopoietic stem cell gene therapy for X-linked severe combined immunodeficiency. PMID:27099176

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