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TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan

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Abstract

Purpose

The aim of this study is to evaluate the usefulness of T cell receptor excision circle (TREC) and/or kappa-deleting recombination excision circle (KREC) measurements integrated with diagnostic next-generation sequencing (NGS) analysis using a severe combined immunodeficiency (SCID) newborn screening (NBS) program.

Methods

TREC and/or KREC values were measured in 137,484 newborns between April 2017 and December 2021 using EnLite TREC (n = 80,791) or TREC/KREC kits (n = 56,693). For newborns with positive screening results, diagnostic NGS analysis was performed with a 349-gene panel to detect genetic mutations associated with primary immunodeficiencies (PIDs).

Results

A total of 145 newborns (0.11%) had abnormal TREC and/or KREC values, and a genetic diagnosis was established in 2 patients with SCID (1 in 68,742 newborns) (IL2RG-SCID and reticular dysgenesis) and 10 with non-SCID PIDs with T and/or B cell deficiencies (1 in 13,748 newborns) using NGS analysis. Furthermore, TREC values of 2849 newborns were measured and confirmed the significant correlation between the results of both TREC and TREC/KREC kits (P < 0.001) and naïve T cell counts.

Conclusions

We performed the first large-scale TREC and TREC/KREC NBS programs in Japan. Our NBS programs followed by the diagnostic NGS analysis for newborns with abnormal TREC and/or KREC values are useful for the early identification and rapid molecular evaluation of not only SCID but also different non-SCID PIDs.

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Data Availability

The data used in this study will be provided to qualified researchers on reasonable request.

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Acknowledgements

The authors acknowledge all clinicians, patients, and their families and thank Ms. Yoshie Miura, Ms. Hiroko Ono, and Ms. Chie Amahori for their valuable assistance. The authors acknowledge the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for providing technical support.

Funding

This work was supported by a grant from Aichi Rare Disease Network, Nagoya Pediatric Cancer Fund, and Japan Agency for Medical Research and Development (grant/award number: 20gk0110041h0002 to H.M.).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Manabu Wakamatsu, Hideki Muramatsu, Shinsuke Kataoka, Seiji Kojima & Yoshiyuki Takahashi

  2. Department of Pediatrics, Ogaki Municipal Hospital, Ogaki, Japan

    Daiei Kojima

  3. Department of Virology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan

    Yusuke Okuno

  4. Department of Clinical Laboratory, Aichi Health Promotion Foundation, Nagoya, Japan

    Fumiko Nakamura & Yoshimi Sakai

  5. Department of Pediatrics, School of Medicine, Fujita Health University, Toyoake, Japan

    Ikuya Tsuge, Makito Tanaka, Yoko Nakajima & Tetsuya Ito

  6. Department of Pediatrics, Toyohashi Municipal Hospital, Toyohashi, Japan

    Tsuyoshi Ito

  7. Division of Neonatology, Center for Maternal-Neonatal Care, Nagoya University Hospital, Nagoya, Japan

    Kazuto Ueda & Akiko Saito

  8. Department of Neonatology, Aichi Children’s Health and Medical Center, Obu, Japan

    Eiji Morihana

  9. Department of Pediatrics, Nagoya City University West Medical Center, Nagoya, Japan

    Yasuhiko Ito

  10. Department of Paediatric Cardiology, Chukyo Children Heart Centre, Japan, Community Health Care Organization Chukyo Hospital, Nagoya, Japan

    Naoki Ohashi

  11. Department of Pediatrics, Japanese Red Cross Aichi Medical Center Nagoya Daini Hospital, Nagoya, Japan

    Taihei Tanaka

Authors
  1. Manabu Wakamatsu
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  2. Daiei Kojima
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  3. Hideki Muramatsu
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  4. Yusuke Okuno
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  6. Fumiko Nakamura
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  7. Yoshimi Sakai
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  8. Ikuya Tsuge
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  9. Tsuyoshi Ito
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  12. Eiji Morihana
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  13. Yasuhiko Ito
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  14. Naoki Ohashi
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  15. Makito Tanaka
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  16. Taihei Tanaka
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  17. Seiji Kojima
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  18. Yoko Nakajima
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  19. Tetsuya Ito
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  20. Yoshiyuki Takahashi
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Contributions

MW, HM, and Tetsuya Ito performed laboratory works, gathered the clinical information, designed and conducted the research, analyzed data, and wrote the paper. DK and YO performed laboratory work, gathered the clinical information, and analyzed data. S. Kojima and YT directed the research and analyzed the data. S. Kataoka, FN, YS, YN, and IT performed laboratory work and gathered the clinical information. Tsuyoshi Ito, KU, AS, EM, YI, NO, MT, and TT gathered the clinical information. All authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hideki Muramatsu or Yoshiyuki Takahashi.

Ethics declarations

Ethics Approval

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the Nagoya University Graduate School of Medicine (Date, 11/10/2016; Approval number, 2016–00258231).

Consent to Participate

Written informed consent was obtained from the parents.

Consent for Publication

The authors affirm that no consent to publish is required for this study.

Conflict of Interest

The authors declare no conflict of interest.

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Wakamatsu, M., Kojima, D., Muramatsu, H. et al. TREC/KREC Newborn Screening followed by Next-Generation Sequencing for Severe Combined Immunodeficiency in Japan. J Clin Immunol 42, 1696–1707 (2022). https://doi.org/10.1007/s10875-022-01335-0

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  • DOI: https://doi.org/10.1007/s10875-022-01335-0

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