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Newborn Screening for Severe T and B Cell Lymphopenia Using TREC/KREC Detection: A Large-Scale Pilot Study of 202,908 Newborns

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Abstract

Newborn screening (NBS) for severe inborn errors of immunity (IEI), affecting T lymphocytes, and implementing measurements of T cell receptor excision circles (TREC) has been shown to be effective in early diagnosis and improved prognosis of patients with these genetic disorders. Few studies conducted on smaller groups of newborns report results of NBS that also include measurement of kappa-deleting recombination excision circles (KREC) for IEI affecting B lymphocytes. A pilot NBS study utilizing TREC/KREC detection was conducted on 202,908 infants born in 8 regions of Russia over a 14-month period. One hundred thirty-four newborns (0.66‰) were NBS positive after the first test and subsequent retest, 41% of whom were born preterm. After lymphocyte subsets were assessed via flow cytometry, samples of 18 infants (0.09‰) were sent for whole exome sequencing. Confirmed genetic defects were consistent with autosomal recessive agammaglobulinemia in 1/18, severe combined immunodeficiency – in 7/18, 22q11.2DS syndrome – in 4/18, combined immunodeficiency – in 1/18 and trisomy 21 syndrome – in 1/18. Two patients in whom no genetic defect was found met criteria of (severe) combined immunodeficiency with syndromic features. Three patients appeared to have transient lymphopenia. Our findings demonstrate the value of implementing combined TREC/KREC NBS screening and inform the development of policies and guidelines for its integration into routine newborn screening programs.

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Data Availability

No datasets were generated or analysed during the current study.

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Acknowledgements

The authors extend their sincere thanks to Andrey Reznikov for invaluable assistance in processing NBS cards and compiling information on newborns. We extend our gratitude to Dr. Tatyana A. Vasilyeva and Sofya A. Ionova for their invaluable assistance in Sanger sequencing. Special appreciation is extended to Andrey Koshelev, Sergey Alexandrov, and Marina Tarakina (JSC Pribori) for their instrumental role in installing and providing technical support for the Eonis instruments. The authors would also like to express their gratitude to Anton Doronin and the entire team at LOGnDEL company for their essential transport services during the pilot project. The authors are also thankful to Dr. Peter Zolotukhin of BioInnLabs company for his pivotal role in providing essential expanded supplies crucial for the successful realization of the pilot project at precisely the right moment. Their collective efforts significantly contributed to the success of this study.

Funding

The study was performed as part of the research work supported by Novartis Pharma LLC (contract No. 1595-MD dated October 29, 2021) and Skopinfarm LLC (contract No. 210714 dated July 14, 2021). The funding organizations played no role in the study design, data collection, analysis, and interpretation, in the decision to publish the results and in writing of the manuscript.

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Authors and Affiliations

  1. Research Centre for Medical Genetics, Moscow, Russia

    Andrey V. Marakhonov, Irina Yu. Efimova, Rena A. Zinchenko, Natalya V. Balinova, Oxana P. Ryzhkova, Anna A. Orlova, Viktoriia V. Zabnenkova, Tatiana B. Cherevatova, Tatiana S. Beskorovainaya, Olga A. Shchagina, Alexander V. Polyakov, Zhanna G. Markova, Marina E. Minzhenkova, Nadezhda V. Shilova, Sergey V. Voronin & Sergey I. Kutsev

  2. Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia

    Anna A. Mukhina, Yulia Rodina, Dmitry Pershin, Sergey S. Larin, Maryam B. Khadzhieva, Ekaterina S. Dudina, Ekaterina V. Kalinina & Anna Shcherbina

  3. Republican Perinatal Center, Grozny, Russia

    Dzhaina A. Mudaeva

  4. State Budgetary Institution “Maternity Hospital” of the Ministry of Healthcare of the Chechen Republic, Grozny, Russia

    Djamila H. Saydaeva

  5. S.V. Ochapovsky Regional Clinical Hospital №1, Krasnodar, Russia

    Svetlana A. Matulevich

  6. Orenburg Regional Clinical Hospital No. 2, Orenburg, Russia

    Elena Yu. Belyashova

  7. Ryazan Regional Clinical Perinatal Center, Ryazan, Russia

    Grigoriy I. Yakubovskiy

  8. North-Ossetian State Medical Academy, Vladikavkaz, Russia

    Inna S. Tebieva

  9. Republican Childrens Clinical Hospital of the Republic of North Ossetia-Alania, Vladikavkaz, Russia

    Inna S. Tebieva & Yulia V. Gabisova

  10. State Budgetary Healthcare Institution of the Vladimir Region “Regional Clinical Hospital”, Vladimir, Russia

    Nataliya A. Irinina

  11. Republican Center for Medical Genetics, Ufa, Russia

    Liya R. Nurgalieva

  12. Bashkir State Medical University, Ufa, Russia

    Elena V. Saifullina

  13. Clinical Diagnostic Center “Maternal and Child Health”, Yekaterinburg, Russia

    Tatiana I. Belyaeva & Olga S. Romanova

Authors
  1. Andrey V. Marakhonov
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  2. Irina Yu. Efimova
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  3. Anna A. Mukhina
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  4. Rena A. Zinchenko
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  5. Natalya V. Balinova
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  6. Yulia Rodina
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  7. Dmitry Pershin
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  8. Oxana P. Ryzhkova
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  9. Anna A. Orlova
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  10. Viktoriia V. Zabnenkova
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  11. Tatiana B. Cherevatova
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  12. Tatiana S. Beskorovainaya
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  13. Olga A. Shchagina
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  14. Alexander V. Polyakov
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  15. Zhanna G. Markova
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  16. Marina E. Minzhenkova
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  17. Nadezhda V. Shilova
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  18. Sergey S. Larin
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  19. Maryam B. Khadzhieva
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  20. Ekaterina S. Dudina
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  21. Ekaterina V. Kalinina
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  22. Dzhaina A. Mudaeva
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  23. Djamila H. Saydaeva
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  24. Svetlana A. Matulevich
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  25. Elena Yu. Belyashova
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  26. Grigoriy I. Yakubovskiy
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  27. Inna S. Tebieva
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  28. Yulia V. Gabisova
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  29. Nataliya A. Irinina
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  30. Liya R. Nurgalieva
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  31. Elena V. Saifullina
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  32. Tatiana I. Belyaeva
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  33. Olga S. Romanova
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  34. Sergey V. Voronin
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  35. Anna Shcherbina
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  36. Sergey I. Kutsev
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Contributions

A.V.M., R.A.Z., S.V.V., A.S., S.I.K. designed most of the studies. A.V.M., I.Yu.E., N.V.B. performed screening assays. A.A.M., Y.R., D.P. carried out much of the immunological work. A.V.M., O.P.R., A.A.O., V.V.Z., T.BC., T.S.B., O.A.S., A.V.P., Z.G.M., M.E.M., N.V.S. performed DNA diagnosis. S.S.L., M.B.K., E.S.D., E.V.K. participated in retrospective TREC analysis after blood components transfusion. D.A.M., D.H.S., S.A.M., E.Yu.B., G.I.Y., I.S.T., Y.V.G., N.A.I., L.R.N., E.V.S., T.I.B., O.S.R. performed screening in the regions. A.V.M., I.Yu.E., A.A.M. analyzed the data. A.V.M., I.Yu.E., A.A.M., A.S. drafted the manuscript, and all authors approved the final manuscript.

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Correspondence to Andrey V. Marakhonov.

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Marakhonov, A.V., Efimova, I.Y., Mukhina, A.A. et al. Newborn Screening for Severe T and B Cell Lymphopenia Using TREC/KREC Detection: A Large-Scale Pilot Study of 202,908 Newborns. J Clin Immunol 44, 93 (2024). https://doi.org/10.1007/s10875-024-01691-z

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