Initial evaluation of a biochemical cystic fibrosis newborn screening by sequential analysis of immunoreactive trypsinogen and pancreatitis-associated protein (IRT/PAP) as a strategy that does not involve DNA testing in a Northern European population.
BACKGROUND
Ethical concerns and disadvantages of newborn screening (NBS) for cystic fibrosis (CF) related to genetic testing have raised controversies and impeded implementation of CF NBS in some countries. In the present study, we used a prospective and sequential immunoreactive trypsinogene (IRT)/pancreatitis-associated protein (PAP) strategy, with IRT as first and PAP as second tier, and validated this biochemical approach against the widely used IRT/DNA protocol in a population-based NBS study in southwest Germany.


METHODS
Prospective quantitation of PAP and genetic analysis for the presence of four mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene most prevalent in southwest Germany (F508del, R553X, G551D, G542X) were performed in all newborns with IRT > 99.0th percentile. NBS was rated positive when either PAP was ≥1.0 ng/mL and/or at least one CFTR mutation was detected. In addition, IRT > 99.9th percentile was also considered a positive rating. Positive rating led to referral to a CF centre for testing of sweat Cl(-) concentration.


RESULTS
Out of 73,759 newborns tested, 98 (0.13%) were positive with IRT/PAP and 56 (0.08%) with IRT/DNA. After sweat testing of 135 CF NBS-positive infants, 13 were diagnosed with CF. Detection rates were similar for both IRT/PAP and IRT/DNA. One of the 13 diagnosed CF newborns had a PAP concentration <1.0 ng/mL.


CONCLUSIONS
Sequential measurement of IRT/PAP provides good sensitivity and specificity and allows reliable and cost-effective CF NBS which circumvents the necessity of genetic testing with its inherent ethical problems.
Sommerburg
Olaf
O
Division of Paediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Paediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, Heidelberg, Germany. olaf.sommerburg@med.uni-heidelberg.de
Lindner
Martin
M
Muckenthaler
Martina
M
Kohlmueller
Dirk
D
Leible
Svenja
S
Feneberg
Reinhard
R
Kulozik
Andreas E
AE
Mall
Marcus A
MA
Hoffmann
Georg F
GF
D000951:Antigens, Neoplasm / Q000097:blood*; D015415:Biomarkers / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D002712:Chlorides / Q000032:analysis; D003550:Cystic Fibrosis / Q000097:blood / Q000175:diagnosis* / Q000235:genetics; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004797:Enzyme-Linked Immunosorbent Assay; D005820:Genetic Testing; D005858:Germany; D006801:Humans; D007231:Infant, Newborn; D037181:Lectins, C-Type / Q000097:blood*; D009154:Mutation; D015997:Neonatal Screening / Q000379:methods*; D000073718:Pancreatitis-Associated Proteins; D011237:Predictive Value of Tests; D015397:Program Evaluation; D011446:Prospective Studies; D012680:Sensitivity and Specificity; D013542:Sweat / Q000737:chemistry; D014362:Trypsinogen / Q000097:blood*
D000951:Antigens, Neoplasm; D015415:Biomarkers; D014408:Biomarkers, Tumor; C505032:CFTR protein, human; D002712:Chlorides; D037181:Lectins, C-Type; D000073718:Pancreatitis-Associated Proteins; C000612141:REG3A protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D014362:Trypsinogen