Newborn Screening for Severe Primary Immunodeficiency Diseases in Sweden-a 2-Year Pilot TREC and KREC Screening Study

Area of Science:

• Immunology
• Genetics
• Pediatrics

Background:

• Severe primary immunodeficiencies (PID) are life-threatening conditions characterized by T and/or B cell lymphopenia.
• Early diagnosis and treatment are crucial for improving outcomes in infants with PID.
• Current newborn screening methods may not comprehensively detect all forms of PID.

Purpose of the Study:

• To evaluate the feasibility and effectiveness of a pilot newborn screening program for severe PID in Stockholm County.
• To assess the simultaneous measurement of T cell receptor excision circles (TREC) and kappa-deleting recombination excision circles (KREC) for identifying infants with T and B cell lymphopenia.
• To establish diagnostic cutoff levels for detecting milder and reversible forms of lymphopenia.

Main Methods:

• A pilot screening program was conducted over 2 years, encompassing 58,834 newborns.
• Quantitative PCR was used to simultaneously measure TREC and KREC levels from DNA extracted from dried blood spots (DBS).
• Beta-actin was used as a quality control for DNA quantity.

Main Results:

• Three infants were diagnosed with PID (Artemis-SCID, ATM, and unclassified T cell lymphopenia/hypogammaglobulinemia) among 64 infants recalled for follow-up.
• Low TREC and/or KREC levels were observed in 24 infants due to prematurity and in 13 infants exposed to maternal immunosuppressive agents, with levels normalizing spontaneously.
• Twenty-nine newborns had transiently low levels without an identified cause.
• Infants with trisomy 21 showed lower median TREC and KREC levels, but generally remained above cutoff levels.

Conclusions:

• Simultaneous TREC and KREC screening is effective for identifying newborns with severe primary immunodeficiencies, including those with combined T and B cell defects.
• The study identified specific challenges, such as transient lymphopenia in preterm infants and those exposed to immunosuppressive drugs.
• This approach provides a foundation for broader implementation of comprehensive newborn screening for PID.