Novel molecular assays for monitoring T cell function after HSCT in two siblings with variants in DCLRE1C

A subgroup of patients with severe combined immunodeficiencies (SCID) has disease-causing variants in genes involved in nonhomologous end-joining (NHEJ) repair of DNA double-strand breaks (DSBs). The most common variants among these patients are in the DCLRE1C gene coding for the Artemis protein, which makes up 2-3% of all SCID. Patients with Artemis deficiency are radiosensitive (RS) and are referred to as RS-SCID. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Due to defects in NHEJ repair, modified protocols are used for HSCT conditioning, resulting in poor engraftment (post-transplantation) in some patients. We describe the clinical and molecular findings in two siblings with a compound heterozygous variant in DCLRE1C. We previously reported functional radiosensitivity in their T cells using a novel cell division assay (CDA). Here, we applied the CDA and the novel DSB repair assay to assess T cell function after HSCT. Posttransplant T cells showed reduced radiosensitivity and a DNA repair efficiency comparable to controls. Donor engraftment was low in myeloid cells but exceeded 95% in lymphocytes. Both patients had low lymphocyte counts after HSCT, but clinical symptoms improved. The assays presented here are useful for investigating the pathology of new variants in the DSB repair pathway and monitoring outcomes after HSCT.