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Blood immunoreactive trypsinogen concentrations are genetically determined in healthy and cystic fibrosis newborns
Insights
Newborn screening for cystic fibrosis (CF) shows that blood immunoreactive trypsinogen levels in healthy newborns correlate with the deltaF508 gene mutation status. Neonatal trypsinogen levels appear to be genetically influenced.
Area of Science:
- Biochemistry
- Genetics
- Neonatal screening
Background:
- Newborns with cystic fibrosis (CF) exhibit elevated blood immunoreactive trypsinogen (IRT).
- False positive results in newborn CF screening often identify healthy carriers of the deltaF508 mutation.
- A potential link between neonatal IRT levels and genetic status warrants investigation.
Purpose of the Study:
- To analyze the relationship between neonatal blood IRT concentrations and genotype.
- To investigate the correlation between IRT levels and the presence of the deltaF508 mutation in healthy newborns and CF patients.
Main Methods:
- Analysis of neonatal blood IRT concentrations and genotype data.
- Study included 1842 healthy newborns and 111 CF patients from a neonatal screening program.
- Comparison of IRT levels between CF patients with different mutation types (deltaF508 homozygotes vs. compound heterozygotes).
Main Results:
- A significant positive correlation was observed between neonatal IRT concentration and the probability of being a healthy deltaF508 carrier.
- CF patients with deltaF508 homozygosity had higher mean neonatal IRT levels than compound heterozygotes.
- Neonates with mutations in nucleotide-binding domains showed higher IRT than those with mutations in membrane-spanning domains.
Conclusions:
- Neonatal blood IRT concentration is partially determined by genetic factors.
- IRT levels exhibit a wide range of variation, influenced by CFTR gene mutations.
- Genotype significantly impacts neonatal IRT levels, mirroring genotype-phenotype correlations in CF.
Abstract:
Newborns with cystic fibrosis (CF) have increased blood immunoreactive trypsinogen concentrations. When screening for CF in the newborn by immunoreactive trypsinogen measurement, an abnormally high proportion of healthy deltaF508 carriers is found among false-positive neonates, suggesting that a relationship could exist between immunoreactive trypsinogen concentration at birth and the genetic status. Therefore, this study analysed the possible relationships between neonatal blood immunoreactive trypsinogen concentrations and genotype in 1842 healthy newborns and 111 CF patients detected by a neonatal screening programme. A close correlation was found between immunoreactive trypsinogen and deltaF508: the probability of a healthy newborn being a carrier of this mutation increased regularly with the neonatal immunoreactive trypsinogen concentration. In CF patients, there was a significant difference between deltaF508 homozygotes and deltaF508/X (X = other mutation) compound heterozygotes with respect to the mean neonatal blood immunoreactive trypsinogen concentration. CF neonates with two mutations affecting the nucleotide binding domains of the cystic fibrosis transmembrane conductance regulator protein had significantly higher mean immunoreactive trypsinogen concentrations than patients with one mutation affecting a membrane-spanning domain. The data strongly suggest that the neonatal immunoreactive trypsinogen concentration is, in part, genetically determined, with a wide range of variations, similar to the features which have been shown for the relations between the genotype and clinical phenotypes of CF patients.