The Impact of the CFTR Gene Discovery on Cystic Fibrosis Diagnosis, Counseling, and Preventive Therapy

Abstract

Discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene was the long-awaited scientific advance that dramatically improved the diagnosis and treatment of cystic fibrosis (CF). The combination of a first-tier biomarker, immunoreactive trypsinogen (IRT), and, if high, DNA analysis for CF-causing variants, has enabled regions where CF is prevalent to screen neonates and achieve diagnoses within 1–2 weeks of birth when most patients are asymptomatic. In addition, IRT/DNA (CFTR) screening protocols simultaneously contribute important genetic data to determine genotype, prognosticate, and plan preventive therapies such as CFTR modulator selection. As the genomics era proceeds with affordable biotechnologies, the potential added value of whole genome sequencing will probably enhance personalized, precision care that can begin during infancy. Issues remain, however, about the optimal size of CFTR panels in genetically diverse regions and how best to deal with incidental findings. Because prospects for a primary DNA screening test are on the horizon, the debate about detecting heterozygote carriers will likely intensify, especially as we learn more about this relatively common genotype. Perhaps, at that time, concerns about CF heterozygote carrier detection will subside, and it will become recognized as beneficial. We share new perspectives on that issue in this article.

The Changing Epidemiology of Cystic Fibrosis: Incidence, Survival and Impact of the CFTR Gene Discovery

“…An exemplary collaboration involving more than 100 laboratories worldwide and carried out through an international consortium for the study of the gene mutations (Cystic Fibrosis Genetic Analysis Consortium) has led to the identification of more than 2000 different CFTR mutations to date [ 69 ]. The molecular exploration of this gene has enabled a better understanding of the genotype/phenotype correlations, improved the diagnosis and the management of CF patients and their families, and opened up the way to the emergence of mutation-specific therapies, which contribute to modify the epidemiology of CF [ 16 , 17 ]. In a very comprehensive article published in this special issue of Genes , Farrell et al reviews the “impact of the CFTR gene discovery on CF diagnosis, genetic counseling and preventive therapy” [ 16 ].…”

“…The discovery of the CFTR gene has also increased the performance of NBS for CF by introducing DNA analysis into the screening protocol, and thus improved the diagnosis and management of CF [ 16 , 78 , 79 ]. The coupling of the immunereactive trypsinogen assay to the search for CFTR mutations has eliminated the need for a second blood sample.…”

“…The discovery of the gene responsible for CF—the CFTR gene—30 years ago [ 13 , 14 , 15 ] marked an important milestone in the history of CF. It has upset our knowledge of the pathophysiology of the disease, contributed to improving the diagnosis and treatment of CF patients and paved the way for novel therapeutic approaches and the advent of targeted therapies [ 16 ]. This discovery has contributed and will continue to contribute to the epidemiological changes observed in CF, through the implementation of genetic-based health policies that allow early diagnosis or prevention within families and/or populations, and the emergence of CFTR modulator therapies [ 17 ].…”

Setting a new standard in cystic fibrosis newborn screening illustrates controversial issues as new data emerge

“…On the other hand, CFTR-related disorders such as pancreatitis and bronchiectasis have been reported in carriers for over 20 years [ 9 ], and a recently reported, large study by Miller et al [ 10 ] has revealed that those with one CFTR variant have a significantly increased risk for 57 of 59 CF-related diagnostic conditions. Their observations and others reviewed elsewhere [ 11 ] challenge the concept of “healthy carriers,” which could become another refuted CF dogma. More fundamentally, as we have learned with sickle cell trait [ 11 ], the concept of recessive may be misleading.…”

“…Their observations and others reviewed elsewhere [ 11 ] challenge the concept of “healthy carriers,” which could become another refuted CF dogma. More fundamentally, as we have learned with sickle cell trait [ 11 ], the concept of recessive may be misleading. In fact, the new data suggest that the significance of having a single CFTR variant is more complex than we ever imagined.…”