Residual-Function and Splicing CFTR Variants Characterize False-Negative IRT Newborn Screening: A Ten-Year Single-Center Cohort From Türkiye.

Authors

Çiğdem Korkmaz, Osman Talha Akpınar, Aysel Kılıç, Serap Dinçer Kartkaya, Abdurrahman Zarif Güney, Furkan Yılmaz, Berrak Öztosun, Abdülhamit Çollak, Ayşe Ayzıt Kılınç Sakallı

Published in

Pediatric pulmonology. Volume 61. Issue 10. Pages e71864.

Abstract

Cystic fibrosis (CF) newborn screening in Türkiye uses a two-step immunoreactive trypsinogen (IRT/IRT) algorithm with fixed cutoffs. The infants missed by fixed-cutoff screening remain poorly characterized.
In this retrospective single-center cohort (2015-2025), 90 children with confirmed CF were classified as IRT-positive (n = 78; IRT-1 ≥ 90 ng/mL) or IRT-negative (n = 12; IRT-1 < 90 ng/mL). CFTR variants were re-evaluated (ACMG/AMP) and stratified by Welsh-Smith class and residual-function status. Clinical, perinatal, pre-analytical, microbiological and genotype data were compared with standardized effect sizes.
IRT-negative patients were diagnosed later (median 12 vs. 2 months; p < 0.001) and had higher early Pseudomonas aeruginosa colonization (33.3% vs. 9.0%; unadjusted p = 0.037). Height standard deviation score was higher in IRT-negative patients (p = 0.004; Cohen's d = -0.77; not retained after false-discovery-rate adjustment). Mean IRT-1 was four-fold lower (44.5 vs. 189.1 ng/mL; p < 0.001). Class IV-V variants accounted for 33.3% of classified IRT-negative versus 11.1% of IRT-positive alleles; IRT-negative patients were enriched for residual-function and splicing variants, including 2789 + 5 G > A (9.5% vs. 2.0%), R334W and Y1032C. Pre-analytical and perinatal factors did not differ.
In every missed case, the first-tier IRT value fell below the fixed national cutoff, without evidence of pre-analytical or perinatal contributions. Missed cases clustered among carriers of residual-function and splicing CFTR variants, whose attenuated pancreatic injury may keep neonatal IRT below the cutoff. Because the Turkish protocol forgoes second-tier testing in IRT-1-negative infants, this subgroup is invisible to the current algorithm; the fixed cutoff warrants optimization.

PMID:
42834588
Bibliographic data and abstract were imported from PubMed on 06 Oct 2026.

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