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Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan

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Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

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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Data Availability

The datasets for this article are not publicly available due to concerns regarding participant/patient anonymity. Requests to access the datasets should be directed to the corresponding author.

Abbreviations

AUC:

Area under the curve

CBT:

Cord blood transplantation

FISH:

Fluorescence in situ hybridization

GVHD:

Graft-versus-host disease

HCT:

Hematopoietic cell transplantation

HLH:

Hemophagocytic lymphohistiocytosis

KRECs:

Kappa-deleting recombination excision circles

LA:

Long and accurate

MLPA:

Multiplex ligation-dependent probe amplification

NBS:

Newborn screening

PjP:

Pneumocystis jirovecii Pneumonia

PS:

Performance status

SCID:

Severe combined immunodeficiency

SNP:

Single-nucleotide polymorphism

TRECs:

T-cell receptor excision circles

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Acknowledgements

We thank the patients and their parents to participate in this study. We also thank Naomi Terada, Maki Yamazaki, Yin Yi, Keiko Obata, and Yasuyoshi Ishiwata for their technical assistance. We are grateful to Dr. Hideki Muramatsu and Masataka Ishimura for giving us the data of NBS.

Funding

This work was supported by MEXT/JSPS KAKENHI (Grant Number: 22K07887) to HK.

Author information

Authors and Affiliations

  1. Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Kento Inoue, Satoshi Miyamoto, Dan Tomomasa, Eriko Adachi, Kenichi Kashimada & Tomohiro Morio

  2. Department of Pediatrics, St. Luke’s International Hospital, Tokyo, Japan

    Satoshi Miyamoto

  3. Department of Hematology and Oncology, Shizuoka Children’s Hospital, Shizuoka, Japan

    Shohei Azumi & Yasuo Horikoshi

  4. Department of Pediatrics, Nara Medical University, Kashihara, Japan

    Takashi Ishihara

  5. Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Shinya Osone

  6. Department of Pediatric, Jichi Medical University School of Medicine, Tochigi, Japan

    Yuta Kawahara

  7. Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan

    Ko Kudo

  8. Department of Pediatrics, Gifu University Graduate School of Medicine, Gifu, Japan

    Zenichiro Kato & Hidenori Ohnishi

  9. Structural Medicine, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu, Japan

    Zenichiro Kato

  10. Department of Community Pediatrics, Perinatal and Maternal Medicine, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan

    Kohsuke Imai

  11. Department of Pediatrics, National Defense Medical College, Saitama, Japan

    Kohsuke Imai

  12. Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan

    Osamu Ohara

  13. Department of Immunology and Pathology, Central Clinical School, Monash University and Alfred Hospital, Melbourne, VIC, Australia

    Menno C. van Zelm

  14. Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA, USA

    Morton J. Cowan

  15. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-Ku, Tokyo, 113-8519, Japan

    Hirokazu Kanegane

Authors
  1. Kento Inoue
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  2. Satoshi Miyamoto
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  3. Dan Tomomasa
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  4. Eriko Adachi
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  5. Shohei Azumi
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  7. Takashi Ishihara
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  9. Yuta Kawahara
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  10. Ko Kudo
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  15. Osamu Ohara
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  16. Menno C. van Zelm
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  18. Tomohiro Morio
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  19. Hirokazu Kanegane
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Contributions

KeI performed genetic analysis, analyzed the data, and wrote the manuscript. S. M. analyzed the data. D. T. performed genetic analysis and provided the patient data. E. A., O. O., and M. CvZ performed genetic analysis. S. A., Y. H., T. I., S. O., Y. O., and KoK provided the patient data. Z. K. and H. O. performed structural analysis. KeK, KoI, M. J. C., and T. M. provided critical discussion. H. K. conceptualized the study and edited the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Hirokazu Kanegane.

Ethics declarations

Ethics Approval

Informed consent was obtained from their parents. This study was conducted in accordance with the Helsinki Declaration and approved by the ethics boards of the Tokyo Medical and Dental University.

Consent to Participate

Informed consent was obtained from all patients and their parents included in this study.

Consent for Publication

Informed consent was obtained from all participants included in this study.

Conflict of Interest

All the authors declare that they have no relevant conflict of interest.

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Inoue, K., Miyamoto, S., Tomomasa, D. et al. Clinical and Genetic Characterization of Patients with Artemis Deficiency in Japan. J Clin Immunol 43, 585–594 (2023). https://doi.org/10.1007/s10875-022-01405-3

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  • DOI: https://doi.org/10.1007/s10875-022-01405-3

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