Artemis-deficient severe combined immunodeficiency (SCID) is a rare autosomal recessive disorder caused by pathogenic variants in DCLRE1C, which encodes ARTEMIS, a DNA repair endonuclease essential for V(D)J recombination. Loss of ARTEMIS function results in radiosensitivity and a characteristic T–/B–/NK+ SCID phenotype. Affected infants are highly vulnerable to life-threatening infections, and definitive therapy includes hematopoietic stem cell transplantation (HSCT) or gene therapy.
We report a two-week-old male identified through newborn screening for markedly low TRECs. Immunophenotyping revealed low T cells, absent B cells, and preserved natural killer (NK) cells. Rapid trio whole-genome sequencing identified a novel homozygous missense variant in DCLRE1C (c.545G>A; p.C182Y), currently classified as a variant of uncertain significance. The mutation lies within the β-CASP domain, a region in which pathogenic variants causing ARTEMIS SCID have been previously described. The variant is absent from gnomAD and has a REVEL score of 0.64, supporting potential deleteriousness.
Notably, the immunologic profile did not align with classic or leaky SCID. CD3 T cell counts were 1,600 cells/µL with 48% naïve CD4 and 92% naïve CD8 populations. Maternal engraftment was excluded, and T cell mitogen proliferation and TCR repertoire were preserved, suggesting partial ARTEMIS activity. This mixed phenotype—low but functional T cells with both naïve and memory subsets—is atypical for DCLRE1C-related SCID and suggests residual endonuclease function. Radiosensitivity testing showed increased T and B cell death but apparently normal repair of DNA double-strand breaks after low-dose irradiation.
A collaborating institution identified four additional patients with the same homozygous variant, all presenting with T low/B-/NK+ SCID, strengthening the evidence that c.545G>A (p.C182Y) is likely pathogenic. All four patients underwent successful HSCT.
This case describes a novel DCLRE1C variant associated with an unusual immunophenotype that broadens the clinical spectrum of ARTEMIS deficiency. Although the variant remains a variant of uncertain significance (VUS), accumulating multi-institutional data support its pathogenicity. Our findings underscore the importance of collaborative genomic interpretation and detailed immune phenotyping to accurately classify rare variants and guide management in SCID.
