What are the key molecular markers for Cystic Fibrosis (CF)?

From the Guidelines

Molecular markers for cystic fibrosis primarily focus on mutations in the CFTR gene, with F508del being the most common mutation found in approximately 70% of CF patients worldwide, as highlighted in the most recent guidelines 1. The diagnosis and treatment of cystic fibrosis have become increasingly personalized with the advancement of genetic testing and the development of CFTR modulator therapies. Key points to consider in the diagnosis and management of cystic fibrosis include:

• Genetic testing for a panel of common CFTR mutations, which now includes over 2,000 identified variants 1
• The sweat chloride test as the gold standard diagnostic test, measuring elevated chloride levels (>60 mmol/L) in sweat
• Other molecular markers such as immunoreactive trypsinogen (IRT) used in newborn screening, nasal potential difference measurements, and intestinal current measurements to assess CFTR function
• Pancreatic insufficiency markers like fecal elastase to determine pancreatic status
• The use of CFTR modulator therapies like ivacaftor, lumacaftor, tezacaftor, and elexacaftor, which are designed to target specific mutation classes, such as ivacaftor for gating mutations like G551D, and the triple combination therapy Trikafta (elexacaftor/tezacaftor/ivacaftor) for patients with at least one F508del mutation 1. It is essential to stay updated with the latest recommendations for CFTR carrier screening, as outlined in the position statement of the American College of Medical Genetics and Genomics (ACMG) 1, to ensure optimal diagnosis and treatment outcomes for patients with cystic fibrosis.

From the FDA Drug Label

Table 6 lists CFTR mutations responsive to TRIKAFTA based on clinical response and/or in vitro data in FRT or HBE cells or based on extrapolation of efficacy The threshold that the treatment-induced increase in chloride transport must exceed for the mutant CFTR protein to be considered responsive is ≥10% of normal over baseline. Elexacaftor/tezacaftor/ivacaftor increased chloride transport in FRT cells expressing CFTR mutations, as identified in Table 6.

The highlights of molecular markers for cystic fibrosis include:

• CFTR mutations: The drug label lists specific CFTR mutations that are responsive to TRIKAFTA, including F508del and other mutations.
• Chloride transport: The treatment-induced increase in chloride transport must exceed ≥10% of normal over baseline for the mutant CFTR protein to be considered responsive.
• Responsive mutations: Table 6 lists the CFTR mutations that are responsive to TRIKAFTA based on clinical response and/or in vitro data. 2

From the Research

Molecular Markers for Cystic Fibrosis

• Cystic fibrosis (CF) is an autosomal recessive disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes an epithelial anion channel 3.
• The identification of the CFTR gene in 1989 gave hopes of rapidly finding a cure for the disease, for which over 1950 mutations have been identified 3.
• The most common mutation causing CF is the deletion (delta) of a single phenylalanine (F) in position 508 within a putative helix located in NBF1, with CF patients bearing this deltaF508 mutation frequently experiencing chronic lung infections 4.

Classification of CFTR Mutations

• CFTR mutation classifications are essential in the establishment of mutation-targeted therapeutic strategies, with current classifications according to their clinical consequences and to their effect on the structure and function of the CFTR channel 3.
• The F508del and G542X are the most common mutations found in US patients, accounting for 86.4% and 4.6% of all mutations, respectively, with the F508del causing deletion of the phenylalanine residue at position 508 and associated with impaired CFTR protein folding 5.

Molecular Diagnostic Approaches

• Molecular testing approaches, including carrier screening, prenatal testing, newborn screening, and clinical diagnostic testing, are used to diagnose CF, with most patients in the United States now diagnosed through newborn screening and use of molecular testing methods 6.
• Comprehensive mapping of CFTR mutations to the CFTR protein identifies mutation clusters and molecular docking predicts corrector binding site, providing valuable insights into the structure-function relationship of CFTR 7.

Highlights of Molecular Markers

• The use of molecular markers has enabled the identification of small molecules targeting either the CFTR protein directly or its key processing steps, giving rise to novel promising therapeutic tools 3.
• Sheep models of F508del and G542X cystic fibrosis mutations show cellular responses to human therapeutics, representing an important advance for testing new CF therapeutics and gene therapy 5.
• The structural pharmacogenomics approach of mapping mutation databases to protein models shows promise for facilitating drug discovery and personalized medicine for monogenetic diseases 7.