Submission Details

DCLRE1C was first reported in relation to autosomal recessive severe combined immunodeficiency (SCID) in 2001 (Moshous D, et al., 2001, PMID: 11336668). DCLRE1C encodes Artemis, a nuclear protein that is involved in V(D)J recombination and DNA repair. In Artemis-deficient individuals, V(D)J recombination is blocked such that mature B or T cells are not produced, leading to T-B-NK+ radiosensitive SCID which typically presents in infancy with recurrent, persistent infections by opportunistic organisms. Biallelic loss of function variants are associated with typical SCID presentation, while hypomorphic alleles (generally in trans with a loss of function variant) 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, SCID. At least 80 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, and large deletion) have been reported in humans. Recurring exon 1-2/3/4 deletions result from homologous recombination events with the nearby pseudo-DCLRE1C gene and include deletion of the intervening MEIG1 gene (PMID: 19953608). Curated evidence supporting the gene-disease relationship includes 9 probands with DCLRE1C variants who have been reported in 4 publications (PMID: 11336668, 15731174, 16540517, 18034425), with segregation in 4 additional affected family members. This gene-disease relationship is also supported by experimental evidence, including its biochemical function in V(D)J recombination (PMID: 11955432), which is altered in both patient (PMID: 9705945) and non-patient cells (PMID: 25917813) expressing DCLRE1C variants, and can be rescued by wild type in patient cells (PMID: 11336668). Additionally animal models recapitulate the spectrum of disease with Leaky SCID (PMID: 12504013) and T-B- SCID (PMID: 15699179) phenotypes, which can be rescued by wild type Artemis (PMID: 18560421). More evidence is available in the literature, but the maximum score for genetic and experimental evidence has been reached. In summary, DCLRE1C is definitively associated with autosomal recessive SCID. 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 02/18/2021.