Susceptibility haplotypes in non-cystic fibrosis newborns with elevated immunoreactive trypsinogen.
11 affiliations
- 1Clinical Bioinformatic Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- 2Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, and Maternal-Child Sciences, University of Genoa, Genoa, Italy.
- 3UOC Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- 4Cystic Fibrosis Department, Institute of Mother and Child, Warsaw, Poland.
- 5Pneumology Unit, Regina Margherita - Sant' Anna Hospital, Turin, Italy.
- 6LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), Pediatric Clinic, IRCCS Istituto Giannina Gaslini, 16147, Genoa, Italy.
- 7Center of Functional Genomics and Rare Diseases, 'V. Buzzi' Children's Hospital, Milan, Italy.
- 8Genomics Facility, Italian Institute of Technology (IIT), 16163, Genoa, Italy.
- 9Department of Pediatric Medicine, Meyer Children's Hospital IRCCS, Cystic Fibrosis Regional Reference Centre, Florence, Italy.
- 10UOSD Research Laboratories Aggregation Area, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
- 11Cystic Fibrosis Center, IRCCS Istituto Giannina Gaslini, Genoa, Italy. [email protected].
Abstract
Cystic fibrosis (CF) represents the most prevalent life-threatening autosomal recessive disorder in Europe, primarily affecting the respiratory tract, exocrine pancreatic function, and lipid metabolism. Immunoreactive trypsinogen (IRT) quantification constitutes the first-tier test in neonatal CF screening programs; however, elevated IRT levels may also be detected in infants who do not develop CF, generating false-positive (FP) results. The biological basis underlying increased IRT in these cases remains poorly understood and may involve genetic determinants independent of CFTR. Dried blood spot (DBS) samples were collected from full-term neonates with normal growth parameters, classified as true negatives (TN) or FP through CF newborn screening programs across multiple European centers. IRT levels were measured via standardized immunoassay, and genomic DNA extracted from DBS underwent whole-exome sequencing (WES). Bioinformatic analyses integrated functional prediction, evolutionary conservation, and allele frequency data, with variant prioritization restricted to a curated panel of genes implicated in pancreatic disease. Following quality control, 212 samples (94 FP, 118 TN) were included. Comparative analyses identified significant enrichment of variants in five genes among FP subjects. Notably, top loci localized to regulatory regions and genes involved in oxidative stress, suggesting a mechanistic link with pancreatic inflammation and elevated IRT. Several variants clustered within high linkage disequilibrium regions, supporting the presence of susceptibility haplotypes. Burden testing of rare variants confirmed significant associations for CFTR, PRSS1, and PRSS2 after multiple testing corrections. These results suggest that genetic variation beyond CFTR is associated with elevated neonatal IRT in infants without CF and support further investigation of pancreatic-related pathways in false-positive CF newborn screening.
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BibTeX
@article{rosamilia2026susceptibility,
title = {{Susceptibility haplotypes in non-cystic fibrosis newborns with elevated immunoreactive trypsinogen.}},
author = {Francesca Rosamilia and Giulia Camisassi and Giulia Amico and Katarzyna Zybert and Maria Baffico and Laura Barrocu and Michela Cassanello and Cristina Cereda and Yeraldin Chiquinquira Castillo De Spelorzi and Diego Vozzi and Domenico Coviello and Carola Di Meo and Daniela Dolce and Elvira Sondo and Dorota Sands and Vito Terlizzi and Isabella Ceccherini and Mohamad Maghnie and Paolo Uva and Carlo Castellani},
journal = {Molecular medicine (Cambridge, Mass.)},
year = {2026},
month = aug,
doi = {10.1186/s10020-026-01581-7},
url = {https://europepmc.org/article/MED/42968008},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Susceptibility haplotypes in non-cystic fibrosis newborns with elevated immunoreactive trypsinogen.
AU - Francesca Rosamilia
AU - Giulia Camisassi
AU - Giulia Amico
AU - Katarzyna Zybert
AU - Maria Baffico
AU - Laura Barrocu
AU - Michela Cassanello
AU - Cristina Cereda
AU - Yeraldin Chiquinquira Castillo De Spelorzi
AU - Diego Vozzi
AU - Domenico Coviello
AU - Carola Di Meo
AU - Daniela Dolce
AU - Elvira Sondo
AU - Dorota Sands
AU - Vito Terlizzi
AU - Isabella Ceccherini
AU - Mohamad Maghnie
AU - Paolo Uva
AU - Carlo Castellani
PY - 2026
DA - 2026/08/05
JO - Molecular medicine (Cambridge, Mass.)
DO - 10.1186/s10020-026-01581-7
UR - https://europepmc.org/article/MED/42968008
AB - Cystic fibrosis (CF) represents the most prevalent life-threatening autosomal recessive disorder in Europe, primarily affecting the respiratory tract, exocrine pancreatic function, and lipid metabolism. Immunoreactive trypsinogen (IRT) quantification constitutes the first-tier test in neonatal CF screening programs; however, elevated IRT levels may also be detected in infants who do not develop CF, generating false-positive (FP) results. The biological basis underlying increased IRT in these cases remains poorly understood and may involve genetic determinants independent of CFTR. Dried blood spot (DBS) samples were collected from full-term neonates with normal growth parameters, classified as true negatives (TN) or FP through CF newborn screening programs across multiple European centers. IRT levels were measured via standardized immunoassay, and genomic DNA extracted from DBS underwent whole-exome sequencing (WES). Bioinformatic analyses integrated functional prediction, evolutionary conservation, and allele frequency data, with variant prioritization restricted to a curated panel of genes implicated in pancreatic disease. Following quality control, 212 samples (94 FP, 118 TN) were included. Comparative analyses identified significant enrichment of variants in five genes among FP subjects. Notably, top loci localized to regulatory regions and genes involved in oxidative stress, suggesting a mechanistic link with pancreatic inflammation and elevated IRT. Several variants clustered within high linkage disequilibrium regions, supporting the presence of susceptibility haplotypes. Burden testing of rare variants confirmed significant associations for CFTR, PRSS1, and PRSS2 after multiple testing corrections. These results suggest that genetic variation beyond CFTR is associated with elevated neonatal IRT in infants without CF and support further investigation of pancreatic-related pathways in false-positive CF newborn screening.
SN - 1076-1551
SN - 1528-3658
ER -