RAG2 – Severe Combined Immunodeficiency

Autosomal recessive mutations in RAG2 underlie a T⁻B⁻NK⁺ form of severe combined immunodeficiency (SCID), characterized by profound lymphopenia, early-onset severe infections, and failure to thrive. Biallelic loss-of-function variants in RAG2 abolish V(D)J recombination, preventing development of mature T and B lymphocytes. Clinically, patients present in the first months of life with recurrent pneumonia, chronic diarrhea, and severe viral or opportunistic infections often leading to early mortality without hematopoietic stem cell transplantation.

1 Clinical Validity

Based on reports of over 200 SCID patients from more than 70 unrelated families, with consistent autosomal recessive segregation and absent T and B cells, the RAG2–SCID association is classified as Definitive. Large multi-family cohorts and extensive functional concordance support this conclusion ([PMID:11133745]).

2 Genetic Evidence

Inheritance is Autosomal recessive. Segregation of biallelic RAG2 variants has been documented in at least 6 affected sibships, confirming co-segregation with SCID. Case series report 12 probands with compound heterozygous or homozygous RAG2 mutations, including null and frameshift alleles ([PMID:31058115]). The variant spectrum comprises frameshifts (e.g., c.829dup (p.Tyr277fs)), nonsense, splice, and hypomorphic missense changes. Recurrent alleles (e.g., p.Arg229Gln) have been observed across populations. Carrier frequency is consistent with autosomal recessive inheritance in consanguineous cohorts.

3 Functional Evidence

RAG2 mutations abolish or severely reduce V(D)J recombination activity in vitro, as demonstrated by extrachromosomal recombination assays and bone marrow Ig locus analysis ([PMID:12200379]). Mouse knock-in of RAG2 PHD domain mutations recapitulates T and B cell developmental arrest, confirming haplolethal and null effects ([PMID:20234091]). Rescue experiments and histone ubiquitylation studies highlight critical roles of both core and non-core RAG2 domains in recombinase function.

4 Conflicting Evidence

Hypomorphic RAG2 variants with residual recombinase activity can present as Omenn syndrome or leaky SCID, featuring oligoclonal T cells and variable B cell counts, but these phenotypes represent allelic continuum rather than alternative gene–disease relationships ([PMID:20956421]).

5 Integration and Clinical Utility

Collectively, genetic and experimental data establish RAG2 deficiency as a definitive cause of autosomal recessive SCID. Early genetic diagnosis enables prompt HSCT and family counseling. Measurement of TREC/KREC levels combined with targeted sequencing achieves rapid confirmation. Key Take-home: Biallelic RAG2 loss-of-function mutations are a definitive cause of T⁻B⁻NK⁺ SCID, and early molecular diagnosis guides life-saving transplantation.

References

• Blood • 2001 • V(D)J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. PMID:11133745
• Blood • 2002 • The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. PMID:12200379
• Frontiers in pediatrics • 2019 • Combined Immunodeficiency With Late-Onset Progressive Hypogammaglobulinemia and Normal B Cell Count in a Patient With RAG2 Deficiency. PMID:31058115
• The Journal of clinical investigation • 2010 • Analysis of mutations from SCID and Omenn syndrome patients reveals the central role of the Rag2 PHD domain in regulating V(D)J recombination. PMID:20234091
• Pediatrics • 2010 • Highly variable clinical phenotypes of hypomorphic RAG1 mutations. PMID:20956421

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