Second-tier genetics improves newborn screening accuracy for SCID and other T cell deficiencies

Area of Science:

• Immunology
• Genetics
• Neonatal screening

Background:

• T cell receptor excision circles (TRECs) quantify T cell numbers for newborn screening (NBS) of severe combined immunodeficiency (SCID).
• Current TREC-based NBS is highly sensitive but has a low positive predictive value (PPV), leading to false-positive referrals, parental distress, and increased healthcare costs.

Purpose of the Study:

• To enhance the positive predictive value (PPV) of newborn screening for SCID and other T cell deficiencies.
• To evaluate next-generation sequencing (NGS) as a second-tier test following TREC analysis in NBS.

Main Methods:

• Targeted NGS was performed on dried blood spots from 68 newborns referred by TREC-based NBS.
• Results were integrated with long-term follow-up data.
• A safety net algorithm was implemented for newborns with very low TRECs to maintain SCID sensitivity.

Main Results:

• Second-tier NGS increased the PPV for SCID from 22% to 55%.
• The implemented strategy maintained high sensitivity for SCID detection.
• The clinical impact of not identifying non-severe T cell lymphopenia without genetic diagnosis was deemed limited.

Conclusions:

• Second-tier NGS significantly improves the accuracy of TREC-based NBS for SCID and other T cell deficiencies.
• This approach reduces false-positive referrals while ensuring detection of severe immunological conditions.
• Integrating NGS enhances the efficiency and reliability of newborn screening programs.