IL2RG-related immunodeficiencies: from SCID to atypical presentations

Area of Science:

• Immunology
• Genetics
• Molecular Biology

Background:

• The interleukin-2 receptor gamma chain gene (IL2RG) is crucial for lymphocyte development and function.
• Mutations in IL2RG lead to X-linked severe combined immunodeficiency (X-SCID) and related disorders.
• Recent advances have expanded the understanding of IL2RG's mutational spectrum and genotype-phenotype correlations.

Purpose of the Study:

• To review recent advances in understanding IL2RG mutations and their clinical impact.
• To highlight progress in diagnostics, gene therapy, and hematopoietic stem cell transplantation (HSCT) for X-SCID.
• To outline future directions in managing IL2RG-related immunodeficiencies.

Main Methods:

• Review of recent literature (2015-2025) on IL2RG mutations and X-SCID.
• Analysis of advances in molecular diagnostics, next-generation sequencing, and functional immunology.
• Evaluation of progress in gene therapy and HSCT outcomes.

Main Results:

• Novel hypomorphic IL2RG variants and their structural/signaling impacts have been identified.
• Expanded newborn screening and longitudinal studies improve early diagnosis and understanding of disease progression.
• Gene therapy shows promise in achieving immune reconstitution, and HSCT outcomes are improving with refined strategies.

Conclusions:

• Improved diagnostics enable precision treatment for atypical X-SCID presentations.
• Recognition of the broader IL2RG-related spectrum necessitates refined long-term follow-up and multidisciplinary care.
• Future efforts focus on expanding gene therapy, optimizing conditioning regimens, and global newborn screening for early intervention.