Medicina de precisão do Hospital Israelita Albert Einstein

Neonatal Screening for Primary Immunodeficiencies

Screening based on neonatal population is very important to identify several serious diseases that with rapid intervention can prevent serious sequelae and deaths
triagem neonatal
triagem neonatal

Population-based newborn screening (NBS) enables early identification of asymptomatic infants with a range of severe diseases, for which effective treatment is available and that early intervention could prevent serious sequelae and death.

Primary immunodeficiency disorders (PIDs) are a heterogeneous group of genetic disorders. Frequently, PIDs are considered pediatric emergencies due to their potential to severely compromise the newborn’s health. Primary immune diseases are classified into five groupsT cell deficiencies, B cell deficiencies, combined T and B cell deficiencies, complement defects, and granulocyte defects. Agammaglobulinemia and severe combined immunodeficiency (SCID) are examples of B cell and combined cell deficiencies, respectively, and both can be evaluated through NBS. 

The main clinical presentation of PIDs are severe recurrent infections, that usually start at age four to six months. When undiagnosed, patients present a high morbimortality rate. Early identification through NBS allows immediate intervention and satisfactory long-term outcomes.

What is newborn screening methodology for primary immunodeficiencies?

NBS is performed by quantitative polymerase chain reaction (qPCR). This technique measures, simultaneously, the number of T-cell receptor excision circles (TREC) and kappa recombination excision circles (KREC) from dried blood spots (DBS). TREC and KREC levels  are determined per DNA extracted. So, it is essential to guarantee that enough quantity of DNA is extracted from each DBS. That information is obtained by amplification of one gene control (for example, beta-actin and RNaseP).

Infants with abnormal screening test results or two failure samples require second-tier testing with T-cell and/or B-cell enumeration by flow cytometry. 

What are TREC and KREC markers?

T-cell receptor genes are normally edited during lymphocyte T differentiation. Deleted DNA fragments are circularized and do not undergo further replication in dividing cells. Therefore, TRECs are considered markers of recently formed T-cells. Low TRECs levels are very efficient for detection of SCID and other T-cell lymphopenias.

KRECs correspond to the circular DNA product of lymphocyte B immunoglobulin kappa gene rearrangement. So, low kappa recombining excision circles dosages are very efficient for the detection of agammaglobulinemia and other B-cell lymphopenias.

What are the limitations of newborn screening for primary immunodeficiencies?

Newborn screening using TREC and KREC analysis has been introduced in many countries worldwide and effectively modified the morbimortality of PIDs. 

It is an established method to identify infants with SCID. Unfortunately, TREC analysis is not able to identify diseases where the molecular defect lies downstream of T-cell receptor rearrangement (as Zap70 deficiency, MHC Class II deficiency, and some cases of delayed ADA deficiency) or cases of qualitative T-cell dysfunction. 

About the Author:

Dayse Alencar-Cupertino is a biomedical with a master’s degree in genetics and molecular biology. She has experience in genetics and molecular biology with a focus on human disease molecular diagnosis. She also works in the areas of forensic genetics and paternity. Is part of the main consulting service in the area and is currently a consultant in genetics at the laboratory DLE / Grupo Hermes Pardini.


[1] Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME, Cunningham-Rundles C, et al. Primary immunodeficiency diseases: an update on the classification from the international union of immunological societies expert committee for primary immunodeficiency. Front Immunol. 2014; 5:162.

[2] F Serana, M Chiarini, C Zanotti, et al. Use of V (D) J recombination excision circles to identify T-and B-cell defects and to monitor the treatment in primary and acquired immunodeficiencies. Journal of translational medicine 11 (1), 119.

[3] J King, L Hammarström. Newborn Screening for Primary Immunodeficiency Diseases: History, Current and Future Practice. J Clin Immunol (2018) 38:56–66.

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