IL2RG – Severe Combined Immunodeficiency

X-linked severe combined immunodeficiency (X-SCID; MONDO:0015974) is a life-threatening disorder marked by profound T- and NK-cell lymphopenia and recurrent infections. The IL2RG gene (HGNC:6010; Gene Symbol) encodes the common γc chain shared by multiple interleukin receptors, critical for lymphocyte development and function.

Genetic evidence for IL2RG in X-SCID is definitive. IL2RG was mapped to Xq13.1 and mutations segregated in at least 4 independent SCID families, with unique missense, nonsense, and splice-site variants identified in affected males ([PMID:8401490]). In a cohort of 103 unrelated X-SCID patients, 62 distinct IL2RG mutations were found in 87 male probands ([PMID:9058718]). Case reports describe recurrent variants such as c.207C>A (p.Tyr69Ter) in SCID phenotypes ([PMID:19398866]).

The inheritance is X-linked recessive. Segregation analysis confirmed maternally inherited and de novo IL2RG defects in multiple pedigrees. Case series include at least 87 male probands with pathogenic IL2RG alleles. Reported variant spectrum encompasses ~60 unique coding changes: 35 missense, 15 nonsense, 8 frameshift, and 4 splice-site mutations. One representative pathogenic allele is c.207C>A (p.Tyr69Ter).

Functional studies demonstrate that IL2RG mutations abrogate cytokine binding and signaling. Extracellular domain mutations fail IL-2 ligand binding, and cytoplasmic truncations abolish STAT5 phosphorylation and downstream proliferation ([PMID:8027558]). Mouse models and in vitro assays confirm that γc deficiency leads to T- and NK-cell developmental arrest, consistent with human phenotypes.

Hypomorphic and somatic reversion events produce atypical X-SCID presentations. Individuals with partial IL2RG function show residual T- or NK-cell populations, delayed onset, and milder clinical courses. These findings underscore the need for functional assays to confirm variant pathogenicity when sequencing is inconclusive.

Overall, the IL2RG–X-SCID association meets the ClinGen Definitive standard, supported by >30 years of mapping, >100 unrelated probands, robust familial segregation, and concordant functional data. IL2RG genetic testing enables early diagnosis and informs hematopoietic stem cell or gene therapy decisions.

Key Take-home: IL2RG loss-of-function variants cause X-linked SCID with severe T/NK lymphopenia; early molecular diagnosis guides life-saving interventions.

References

• Human Molecular Genetics • 1993 • The interleukin-2 receptor gamma chain maps to Xq13.1 and is mutated in X-linked severe combined immunodeficiency, SCIDX1. PMID:8401490
• Blood • 1997 • Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency. PMID:9058718
• The Tohoku Journal of Experimental Medicine • 2009 • A mutation in the IL-2 receptor gamma chain gene associated with X-linked severe combined immunodeficiency accompanying opisthotonus. PMID:19398866
• 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

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