Editor—Mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene have an extremely wide phenotypic spectrum.1 The “classical” severe form of cystic fibrosis (CF) is characterised by pancreatic insufficiency and chronic endobronchial infection.2 Milder forms may show pancreatic sufficiency, though the degree of pulmonary involvement varies.3 4 Several other pathologies have now been linked with mutations in the CFTR gene, including congenital bilateral absence of the vas deferens, liver disease, pancreatitis, and disseminated bronchiectasis.5-7

There are now over 850 documented mutations in theCFTR gene.8 The most common is ΔF508, which appears on 66% of CF chromosomes in western Europe.9 The pancreatic status of patients has a strong correlation to the genotype, whereas the severity of lung disease shows little or no relation to genotype.1 10-12 Generally, mutations that result in no CFTR protein, such as truncating mutations, or those, such as ΔF508, which result in mislocalisation of the protein, result in a severe phenotype with pancreatic insufficiency. Missense mutations, particularly in the transmembrane domains, result in a milder, more variable disease.1 13 14 The sweat test, long regarded as the gold standard diagnostic test for cystic fibrosis, may give normal results in these milder forms.

Neonatal screening for CF relies on an increased immunoreactive trypsinogen (IRT) concentration in blood of affected babies during the first two months of life.15 However, this method has low specificity, particularly with samples taken in the first week of life, so mutation analysis is increasingly being used as a second tier. In the Trent region of the United Kingdom (UK), where ΔF508 accounts for over 80% of CF mutations, we currently use a three stage IRT-DNA-IRT protocol, which has a low requirement for second blood samples and for sweat testing.15 Any initial …