Second-tier genetics improves newborn screening accuracy for SCID and other T cell deficiencies
Newborn screening (NBS) based on quantifying T cell receptor excision circles (TRECs) is highly sensitive for detecting severe combined immunodeficiency (SCID), but frequently results in false-positive referrals. These referrals contribute to parental distress, increased clinical workload, additional interventions, and costs. To increase the positive predictive value (PPV) for SCID and other T cell deficiencies with a genetic cause, we evaluated next-generation sequencing (NGS) as second-tier testing after TREC analysis. Targeted sequencing was performed on dried blood spots of 68 newborns referred from TREC-based NBS, and results were integrated with collected long-term follow-up data. A safety net algorithm was applied to maintain high sensitivity for SCID by directly referring newborns with profoundly reduced TRECs, increasing the PPV from 22% to 55% without missing patients with severe immunological phenotypes. Therefore, the clinical impact of not identifying non-severe T cell lymphopenia patients without a genetic diagnosis appears limited. These results demonstrate that second-tier NGS in TREC-based NBS improves screening accuracy for SCID and other T cell deficiencies.
Authors
- Sandra Imholz
- Joris M. van Montfrans (ORCID: https://orcid.org/0000-0001-6764-0211)
- Taco W. Kuijpers (ORCID: https://orcid.org/0000-0002-7421-3370)
- Mariëlle van Gijn (ORCID: https://orcid.org/0000-0002-1073-0539)
- Robbert G. M. Bredius (ORCID: https://orcid.org/0000-0001-8151-1539)
- Maartje Blom (ORCID: https://orcid.org/0000-0002-2993-7847)
- Martijn E.T. Dollé (ORCID: https://orcid.org/0000-0001-6137-6544)
- Evelien Zonneveld‐Huijssoon (ORCID: https://orcid.org/0000-0002-9503-6297)
- Mirjam van der Burg (ORCID: https://orcid.org/0000-0002-1510-3104)
- Ingrid Pico‐Knijnenburg (ORCID: https://orcid.org/0000-0001-6325-8314)
- Els Voorhoeve (ORCID: https://orcid.org/0000-0002-7426-395X)
- Gijs Well (ORCID: https://orcid.org/0000-0001-9886-9342)
- Lisette van de Corput (ORCID: https://orcid.org/0000-0003-4089-980X)
- Clementien L. Vermont (ORCID: https://orcid.org/0000-0002-2219-856X)
- Annelotte J. Duintjer (ORCID: https://orcid.org/0009-0003-6888-9694)
- Adinda Heuperman
- Hennie Hodemaekers (ORCID: https://orcid.org/0009-0000-6646-9504)
- Ruben B. Brandsema (ORCID: https://orcid.org/0009-0003-9327-6398)
- Stefanie S. Henriet (ORCID: https://orcid.org/0009-0009-1284-6111)
Institutions
- University Medical Center Groningen (NL)
- Radboud University Nijmegen (NL)
- Utrecht University (NL)
- Leiden University Medical Center (NL)
- Maastricht University Medical Centre (NL)
- Erasmus MC (NL)
- Radboud University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Maastricht University (NL)
- Emma Kinderziekenhuis (NL)
- National Institute for Public Health and the Environment (NL)
- Amalia Kinderziekenhuis (NL)
- Willem-Alexander Kinderziekenhuis (NL)
- Erasmus MC - Sophia Children’s Hospital (NL)
- Amsterdam University Medical Centers (NL)
- Wilhelmina Children's Hospital (NL)
- University of Amsterdam (NL)
Publication Details
- Journal
- Journal of Human Immunity
- Published
- 2026-07-16
- DOI
- https://doi.org/10.70962/jhi.20260031
- Primary Topic
- Immunodeficiency and Autoimmune Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Jeffrey Modell Foundation
- Illumina
- Ministerie van Volksgezondheid, Welzijn en Sport
- Stichting Zeldzame Ziekten Fonds
- Takeda Pharmaceuticals International
- Rijksinstituut voor Volksgezondheid en Milieu