**7.1. Disease overview**

Cystic fibrosis (CF) results from a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR), an epithelial cell ion transporter. Although the resultant lung pathology is the main source of morbidity and mortality, there is multi-system dys‐ function due to the prevalence of the channel in several cell types. The myriad manifes‐ tations of CF include lung disease, pancreatic insufficiency (both endocrine and exocrine), male infertility, liver disease, meconium ileus, and distal intestinal obstruction. [43],[44] Among these, the primary cause of morbidity and mortality in cystic fibrosis is pulmonary disease. Pulmonary complications stem from impaired ion transport in the airways, which results in thick mucus, reduced ciliary beat frequency and pathogen clearance from the respiratory tract. These pathogens constantly bombard and eventually colonize the CF patient's airways, which leads to a state of persistent inflammation marked by recurrent infections and exacerbations. [45]

#### **7.2. Epidemiology/prevalence/survival**

CF predominately affects Caucasians, and has an estimated prevalence of roughly 80,000 people worldwide. When it was first described in 1938, CF virtually guaranteed death short‐ ly after diagnosis. However, advances in knowledge of the disease process and clinical man‐ agement of CF have led to improved life expectancy of 25 years in 1985 and currently approaching 40 years. Individuals diagnosed with CF today are expected to survive beyond 50 years of age. [46]

## **7.3. Etiology**

The cystic fibrosis gene is situated on the long arm of chromosome 7. CF mutations are transmitted in an autosomal recessive pattern [47] and over 1500 unique mutations of the CF gene have been identified. [48] Such a large number of different mutations, and the demon‐ strated influence of other genes (i.e. TGFΒ1) suggests the probability of considerable varia‐ bility in genotype, phenotype and disease severity. [49] Indeed, this is the case; symptoms, onset and severity vary widely across the CF population. CF patients are classified I-VI ac‐ cording to the type of defect the mutation causes in the resultant protein. Class I mutations are nonsense or stopgain mutations that cause the protein to be truncated. Class II are typi‐ cally missense mutations that affect the tertiary structure of the protein and prevent it from trafficking to the cell membrane (this is by far the most common type of mutation seen in CF). The most common of all CFTR mutations is termed ΔF508, a deletion of three nucleoti‐ des resulting in a deletion of phenylalanine at position 508, and is a class II mutation. In class III mutations, the CFTR is fully formed and traffics correctly to the cell membrane but does not function properly upon reaching it. Class IV mutations are similar to that of class III but they are solely malfunctions in the opening of the channel. Class V mutations result in less than normal amounts of CFTR, although what is made functions correctly. Finally, class VI mutations are similar to that of class V but they are unique in that what CFTR pro‐ tein is made is degraded too quickly and there is a functional deficit in the necessary amount of CFTR present on the apical membrane. [50]Typically genotypes in classes I-III have worse phenotypic presentations and higher mortality. Like genotype, sex is also a mor‐ tality predictor; males have a higher survival rate than females until the age of 20. [51],[52]
