Submission Details

RAG1 was first reported in relation to autosomal recessive recombinase activating gene 1 deficiency in 1996 (Schwarz K, et al., 1996, PMID: 8810255). RAG1 encodes recombination-activating gene 1, a recombinase involved in V(D)J recombination by introducing double-stranded breaks between recombination signal sequences and coding segments. In RAG1-deficient individuals, V(D)J recombination is blocked such that mature B or 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 erythrodermia, 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, RAG1 deficiency. Generally, heterozygous parents/carriers are clinically unaffected. However, the acquisition of post-zygotic, somatic events on the other allele in specific cells may cause manifestations of the recessive condition in carriers (PMID: 31503426), and at least one case of a late clinical presentation of an idiopathic T-cell lymphopenia secondary to a heterozygous hypomorphic RAG1 mutation has been reported (PMID: 23122631). Over 200 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, and large deletion) have been reported in humans with autosomal recessive RAG1 deficiency. Curated evidence supporting the gene-disease relationship includes 15 probands with RAG1 variants who have been reported in 2 publications (PMIDs: 8810255 and 11133745). 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 both patient and non-patient cells (PMID: 24290284) expressing RAG1 variants. Additionally, RAG1 interacts with RAG2 (PMID: 8777717) which causes a similar phenotype and RAG1 expression is generally restricted in lymphocytes (PMID: 25613900). Furthermore, animal models recapitulate the spectrum of disease with Leaky SCID (PMID: 19126872) and T-B- SCID (PMID: 1547488) phenotypes. More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, RAG1 is definitively associated with autosomal recessive RAG1 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 GCEP on 06/17/2021.