Related Experiment Videos
Pancreatic function and extended mutation analysis in DeltaF508 heterozygous infants with an elevated immunoreactive
R J Massie1, B Wilcken, P Van Asperen
1Department of Respiratory Medicine, the New South Wales Newborn Screening Program, James Fairfax Institute of Paediatric Nutrition, Royal Alexandra Hospital for Children, Sydney, Australia.
Insights
Newborn screening for cystic fibrosis (CF) using immunoreactive trypsinogen (IRT) and DeltaF508 analysis identifies some infants with CF who have borderline sweat chloride levels. Further genetic analysis is needed to confirm CF diagnosis and guide screening protocols for severe mutations.
Area of Science:
- Genetics
- Pediatrics
- Medical Diagnostics
Background:
- Newborn screening for cystic fibrosis (CF) using immunoreactive trypsinogen (IRT) and DeltaF508 analysis may over-identify carriers and miss some CF cases.
- Some infants identified as DeltaF508 carriers with normal sweat tests may have compound heterozygous mutations.
Purpose of the Study:
- To investigate the outcomes of infants identified through newborn screening with elevated IRT, one DeltaF508 allele, and borderline sweat chloride levels.
- To determine the clinical significance of secondary CF mutations and the 5T allele in screened infants.
Main Methods:
- Infants with elevated IRT, one DeltaF508 allele, and sweat chloride <60 mmol/L underwent comprehensive CF mutation analysis.
- Pancreatic stimulation testing, repeat IRT, clinical review, and sweat testing at 12 months were performed.
Main Results:
- Of 57 recruited infants, 5 had a second CF mutation (R117H) and 11 had the 5T allele.
- Three infants presented with clinical CF by 12 months, with initial borderline sweat chloride levels.
- Pancreatic electrolyte secretion in infants with borderline sweat chloride was similar to that in confirmed CF patients.
Conclusions:
- The increased detection of DeltaF508 heterozygotes is partly due to secondary mutations or the 5T allele.
- Infants with borderline sweat chloride levels and identified genotypes likely have CF, requiring long-term follow-up.
- Current newborn screening for CF should focus on severe mutations causing classic CF.
Background:
Newborn screening for cystic fibrosis (CF) with immunoreactive trypsinogen (IRT) and DeltaF508 analysis followed by sweat testing misses some infants with CF and detects more DeltaF508 carriers than expected. Some of the apparent DeltaF508 carriers may be DeltaF508 compound heterozygotes with normal sweat electrolyte levels.
Methods:
Infants identified by newborn screening with an elevated IRT level, one DeltaF508 allele, and a sweat chloride level <60 mmol/L underwent CF mutation analysis, pancreatic stimulation testing, and repeat IRT analysis followed by clinical review and repeat sweat test at 12 months.
Results:
Over a 24-month period we identified 122 DeltaF508 heterozygotes and recruited 57; 4 had borderline sweat chloride levels (40 to 60 mmol/L), 5 (8.8%, 95% CI 1.4, 16.2) had a second CF mutation (R117H), and 11 (20%, 95% CI 10, 30) had the intron 8 5T allele. Three had clinical CF at 12 months (initial sweat chloride levels: 53, 51, and 32 mmol/L). Pancreatic electrolyte secretion in the subjects with a borderline sweat chloride level was similar to that in patients with known CF.
Conclusion:
The excess of DeltaF508 heterozygotes detected by IRT/DNA screening is associated with the presence of a second mutation or the 5T allele in some infants. Screened infants with borderline sweat chloride levels almost certainly have CF, but long-term follow-up of the infants with the genotype DeltaF508/R117H and DeltaF508/5T is required to determine their outcome. In the meantime, newborn screening should be confined to severe mutations associated with classic CF.