Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan.

Abstract

Artemis is an exonuclease essential for V(D)J recombination and repair of DNA double-stranded breaks. Pathogenic variants in DCLRE1C encoding Artemis cause T-B-NK+ severe combined immunodeficiency (SCID), and patients with Artemis-deficient SCID (ART-SCID) require definitive therapy with allogeneic hematopoietic cell transplantation (HCT). Here we describe the clinical and genetic characteristics of patients with ART-SCID who were diagnosed in Japan from 2003 to 2022. Clinical data of ART-SCID patients who were diagnosed between 2003 and 2022 in Japan were collected from their physicians using a questionnaire. ART-SCID diagnosis was made in eight patients from seven families with severe infections within 6months of life. Two patients had missense variants, five patients had large genomic deletions, and one patient was compound heterozygous for a missense variant and large genomic deletion. All eight underwent allogeneic HCT within 4months after the diagnosis, 7 receiving a conditioning regimen containing alkylating agents, and one patient without conditioning due to uncontrolled infection. Two patients with poor performance status (PS) died of complications 410days and 32days post-HCT, respectively. Of the six surviving patients with a median follow-up time of 8.3 (0.5-17.9) years, three patients had growth retardation. The patients with PS of 0-2 showed a tendency for better overall survival than those with PS 3-4. Large deletions were the most common genetic cause of ART-SCID in Japan. To improve HCT outcome, early diagnosis with newborn screening for SCID is urgently needed.