Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan
Kento Inoue1, Satoshi Miyamoto1,2, Dan Tomomasa1
1Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Insights
Large deletions are the most common cause of Artemis-deficient SCID (ART-SCID) in Japan. Early diagnosis through newborn screening is crucial for improving hematopoietic cell transplantation (HCT) outcomes in these patients.
Area of Science:
- Immunology
- Genetics
- Hematology
Background:
- Artemis (encoded by DCLRE1C) is vital for V(D)J recombination and DNA repair.
- Artemis deficiency causes T-B-NK+ severe combined immunodeficiency (SCID), necessitating hematopoietic cell transplantation (HCT).
Purpose of the Study:
- To characterize the clinical and genetic features of Artemis-deficient SCID (ART-SCID) patients diagnosed in Japan between 2003 and 2022.
- To analyze the outcomes of HCT in this patient cohort.
Main Methods:
- Clinical data were collected via physician questionnaires for ART-SCID patients diagnosed from 2003-2022 in Japan.
- Genetic variants (missense, large deletions, compound heterozygous) were identified.
Main Results:
- Eight patients from seven families were diagnosed with ART-SCID, presenting with severe infections early in life.
- Large genomic deletions were the most frequent genetic cause (5/8 patients).
- All patients received allogeneic HCT; two with poor performance status died post-transplant, while survivors experienced outcomes including growth retardation.
Conclusions:
- Large deletions represent the predominant genetic cause of ART-SCID in Japan.
- Improved HCT outcomes necessitate early ART-SCID diagnosis, ideally via newborn screening.
Purpose:
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.
Methods:
Clinical data of ART-SCID patients who were diagnosed between 2003 and 2022 in Japan were collected from their physicians using a questionnaire.
Results:
ART-SCID diagnosis was made in eight patients from seven families with severe infections within 6 months 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 4 months 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 410 days and 32 days 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.
Conclusion:
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.
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