Cystic fibrosis carriers have higher neonatal immunoreactive trypsinogen values than non‐carriers

Abstract

Following cystic fibrosis (CF) neonatal screening implementation, a high frequency of heterozygotes has been reported among neonates with elevated immunoreactive trypsinogen (IRT) and normal sweat chloride levels. We studied the relationship between normal IRT values and CF heterozygosity: 10,000 neonates were screened for CF by IRT measurement and tested for 40 CF mutations; the 294 carriers detected were coupled with newborns negative to the same genetic testing, and the two groups' IRT levels compared. Heterozygotes had higher IRT levels than their controls (mean 35.32 vs. 27.58 microg/L, P<0.001). Even within normal trypsinogen range, the probability of being a CF carrier increases with neonatal IRT concentration.

Cystic Fibrosis Newborn Screening: Distribution of Blood Immunoreactive Trypsinogen Concentrations in Hypertrypsinemic Neonates

“…In contrast, in our population of hypertrypsinemic newborns, the incidence of CF carrier is higher (1:15), due to the fact that we selected neonates with hypertrypsinemia. Our data are not in disagreement with what reported by Castellani et al (2005) and Lecoq et al (1999).…”

Cystic fibrosis testing 8 years on: Lessons learned from carrier screening and sequencing analysis

“…Further evidence that heterozygous CF carriers can have phenotypic effects is the data from newborn screening programs that demonstrate that carriers can have elevated IRT in the newborn period from blockage of their pancreatic ducts. 5,6 CFTR heterozygotes being mildly symptomatic is one possible explanation for the fact that 27% of patients with mild CF have only one mutation, but there are others: the role of mutations or polymorphisms in regulatory regions, modifier genes, or just an incorrect diagnosis (i.e., a different cause for their respiratory or digestive symptoms). Modifying genes are as likely to act on individuals with one mutation as they are in individuals with two mutations, as discussed earlier in this study.…”

“…This is because it is possible for CF carriers to have elevated IRT and equivocal sweat test results; sweat testing in the newborn period is difficult both technically (to obtain a sufficient amount of material) and interpretively, because newborn sweat chloride values can be transiently depressed. [5][6][7] DNA sequencing is often necessary to establish a reasonable prognosis for anxious parents. Because almost all patients in this sequencing series have had prior panel testing, and panel testing detects approximately 85% of CF mutations in the pan-ethnic US population (see earlier), we estimate that approximately 70% of newborns with CF will have two CF mutations identified by the core panel screening.…”

“…This is a screening test, and IRT alone does not distinguish between patients with classical CF, patients with milder forms, and CF carriers. [5][6][7] A combination of clinical observation, the sweat chloride test, and molecular diagnostics are required for a postnatal diagnosis of CF. 3 Recommendations for population-based carrier screening for CF were published in 2001 by the American College of Medical Genetics (ACMG) in combination with the American College of Obstetricians and Gynecologists (ACOG) using a panel of 25 mutations.…”

Newborn screening and carrier screening for cystic fibrosis: alternative or complementary?

“…Although heterozygotes tend to have higher IRT levels than non-heterozygotes [15], the number of carriers detected by newborn screening is small compared with the entire neonatal heterozygous population, as only the blood spots from the relatively few babies with an elevated IRT proceed to mutation analysis. Families where a carrier is found are also offered genetic counselling, but even after expanding the test to relatives, the vast majority of carriers are not detected by newborn screening [16].…”