Newborn screening for severe combined immunodeficiency: The results of the first pilot TREC and KREC study in Ukraine with involving of 10,350 neonates.

Severe combined immunodeficiency (SCID) is a group of inborn errors of immunity (IEI) characterized by severe T- and/or B-lymphopenia. At birth, there are usually no clinical signs of the disease, but in the first year of life, often in the first months the disease manifests with severe infections. Timely diagnosis and treatment play a crucial role in patient survival. In Ukraine, the expansion of hemostatic stem cell transplantation and the development of a registry of bone marrow donors in the last few years have created opportunities for early correction of IEI and improving the quality and life expectancy of children with SCID. For the first time in Ukraine, we initiated a pilot study on newborn screening for severe combined immunodeficiency and T-cell lymphopenia by determining T cell receptor excision circles (TRECs) and kappa-deleting recombination excision circles (KRECs). The analysis of TREC and KREC was performed by real-time polymerase chain reaction (RT-PCR) followed by analysis of melting curves in neonatal dry blood spots (DBS). The DBS samples were collected between May 2020 and January 2022. In total, 10,350 newborns were screened. Sixty-five blood DNA samples were used for control: 25 from patients with ataxia-telangiectasia, 37 - from patients with Nijmegen breakage syndrome, 1 - with X-linked agammaglobulinemia, 2 - with SCID (JAK3 deficiency and DCLRE1C deficiency). Retest from the first DBS was provided in 5.8% of patients. New sample test was needed in 73 (0.7%) of newborns. Referral to confirm or rule out the diagnosis was used in 3 cases, including one urgent abnormal value. CID (TlowB+NK+) was confirmed in a patient with the urgent abnormal value. The results of a pilot study in Ukraine are compared to other studies (the referral rate 1: 3,450). Approbation of the method on DNA samples of children with ataxia-telangiectasia and Nijmegen syndrome showed a high sensitivity of TRECs (a total of 95.2% with cut-off 2000 copies per 106 cells) for the detection of these diseases. Thus, the tested method has shown its effectiveness for the detection of T- and B-lymphopenia and can be used for implementation of newborn screening for SCID in Ukraine.

Newborn screening for severe combined immunodeficiency: clinical and cost-effectiveness approaches.

Severe combined immunodeficiency (SCID) is a group of lifethreatening diseases, for which early diagnostics, before the development of infectious complications, is extremely important. Newborn screening for SCID with T-cell receptor excision circle (TREC) and kappa-deleting recombination excision circle (KREC) assay for the identification of T- and B-lymphopenia has been implemented in a number of highly developed countries of the world. A number of studies proved the clinical and cost-effectiveness of screening for SCID by using TREC assay. However, both clinical benefits and economic costs for screening may vary depending on country and continent, requiring pilot projects to establish reference values of TREC and KREC levels for the diagnosis of SCID and other diseases associated with T- and B-lymphopenia, as well as determination of cost-effectiveness/costbenefit ratio and expediency of their further implementation. Other challenges, outlined in the article, need to be solved. The development of hematopoietic stem cell transplantation in Ukraine opens up full opportunities for the implementation of newborn screening for SCID. The expediency of conducting a pilot study to determine the most effective method (TREC or TREC/KREC) and the algorithm for SCID detection has been shown.