Reflections on 50 Years of Cystic Fibrosis Newborn Screening Experience with Critical Perspectives, Assessment of
1Departments of Pediatrics and Population Health Sciences, University of Wisconsin School of Medicine and Public Health, 600 Highland Avenue, Madison, WI 53792, USA.
The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to other genetic disorders and immunoassay methods became routine, the discovery of immunoreactive trypsinogen (IRT) led to numerous CF NBS programs around the world. Excellent laboratorians led the way, but CF clinicians rightly questioned the benefit-risk relationship and unanswered questions about IRT. These issues were resolved by the combination of a positive randomized clinical trial and the discovery of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and its principal pathogenic variant, F508del. Recommendations for universal screening and then the proliferation of IRT/DNA screening programs followed. But more knowledge has brought more complexity, including an enigmatic, distracting condition known as cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) or cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). Recently, with the recognition that CF is not a "white person's disease," and that over 1000 CFTR pathogenic variants occur, attention has turned to achieving equity and timeliness for all babies. Continuous quality improvement has characterized the past decade, as greatly expanded CFTR panels in the DNA tier through next-generation sequencing offer promise and raise the prospect of a primary genetic screening test.
The morbidity/mortality risks of cystic fibrosis (CF) with a delayed diagnosis have made newborn screening (NBS) attractive for the past 50 years. Initial efforts focused on meconium analyses, but these proved unsatisfactory. After dried blood spot specimens became valuable for NBS applied to other genetic disorders and immunoassay methods became routine, the discovery of immunoreactive trypsinogen (IRT) led to numerous CF NBS programs around the world. Excellent laboratorians led the way, but CF clinicians rightly questioned the benefit-risk relationship and unanswered questions about IRT. These issues were resolved by the combination of a positive randomized clinical trial and the discovery of the cystic fibrosis transmembrane conductance regulator gene (CFTR) and its principal pathogenic variant, F508del. Recommendations for universal screening and then the proliferation of IRT/DNA screening programs followed. But more knowledge has brought more complexity, including an enigmatic, distracting condition known as cystic fibrosis transmembrane conductance regulator-related metabolic syndrome (CRMS) or cystic fibrosis screen positive, inconclusive diagnosis (CFSPID). Recently, with the recognition that CF is not a "white person's disease," and that over 1000 CFTR pathogenic variants occur, attention has turned to achieving equity and timeliness for all babies. Continuous quality improvement has characterized the past decade, as greatly expanded CFTR panels in the DNA tier through next-generation sequencing offer promise and raise the prospect of a primary genetic screening test.
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