Submission Details

RAG2 was first reported in relation to autosomal recessive recombinase activating gene 2 deficiency in 1996 (Schwarz K, et al., 1996, PMID: 8810255). RAG2 encodes recombination-activating gene 2, which is involved in V(D)J recombination and with RAG1 introduces double-stranded breaks between recombination signal sequences and coding segments. In RAG2-deficient individuals, V(D)J recombination is blocked such that mature B and T cells are not produced, leading to T-B- SCID which typically presents in infancy with recurrent, persistent infections by opportunistic organisms. Biallelic loss of function variants as associated with a SCID presentation, while hypomorphic alleles may lead to Leaky SCID with the presence of some mature T-cells. Omenn Syndrome -- characterized by SCID associated with erythroderma, hepatosplenomegaly, lymphadenopathy, and alopecia -- is one presentation of Leaky SCID. SCID, Leaky SCID and Omenn Syndrome are considered a spectrum of a single disease, and per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism or inheritance pattern. Therefore, all of the disease entities have been lumped into one disease entity, RAG2 deficiency. Generally, heterozygous parents/carriers are clinically unaffected. Over 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, and large deletion) have been reported in humans. Curated evidence supporting the gene-disease relationship includes 15 probands with RAG2 variants who have been reported in 5 publications (PMIDs: 8810255, 11133745, 19912631, 26186701, 12200379). This gene-disease relationship is also supported by experimental evidence, including its biochemical function in V(D)J recombination (PMID: 8521468), which is altered in cell lines expressing RAG2 variants (PMID: 12200379). Additionally, RAG2 interacts with RAG1 (PMID: 8777717) which causes a similar phenotype and RAG2 expression is generally restricted in lymphocytes (PMID: 25613900). Furthermore, animal models recapitulate the spectrum of disease with Omenn syndrome (PMID: 17476358) and T-B- SCID (PMID: 11547487) phenotypes. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, RAG2 is definitively associated with autosomal recessive RAG2 deficiency. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID Working Group on 08/19/2021.