Sequence analysis of the cystic fibrosis gene in patients with disseminated bronchiectatic lung disease

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Abstract
The diagnosis of classical cystic fibrosis (CF) is easily made by clinical assessment alone, but may be missed or delayed in cases with an atypical clinical course. In a recent major study the age at diagnosis varied between 2 months and 47 years. For diagnostic purposes we have investigated the cystic fibrosis transmembrane regulator (CFTR) gene in 10 adult patients (age 18 to 45 years) with chronic obstructive pulmonary disease since childhood or adolescence and bronchiectases disseminated through both lungs. Only one subject (a 29-year-old male) had exocrine pancreatic insufficiency (PI); all others were pancreatic-sufficient (PS). The first nucleotide (ATP)-binding fold of the CFTR was analyzed by direct sequencing of polymerase chain reaction (PCR)-amplified genomic DNA in these cases. Two patients with different phenotypes (one PI, one PS) were found to be homozygous for the common ΔF508 mutation of the CFTR gene, which proved the diagnosis of cystic fibrosis in their cases and allowed genetic counselling. The PS patient had normal sweat tests and had not previously been recognized as having CF. Four other patients were heterozygous for ΔF508, with no other mutation in exons 10 or 11 of the gene, and four patients had normal sequences of these exons. Because only about 70% of all CF chromosomes carry ΔF508, the unexpectedly high frequency (4/8=50%) of heterozygosity for ΔF508 among the non-ΔF508/ΔF508 patients with bronchiectases suggests that some of these might also have unrecognized CF with rare genotypes and mutations in any of the 22 exons not sequenced. About 90 different mutations have already been detected in coding regions of the CFTR gene and a very broad and so far not fully recognized spectrum of clinical phenotypes may be caused by mutations of this gene. Screening for the most frequent CFTR gene mutations, which is practicable using recent technology, may provide significant new diagnostic information in patients with CF-like pulmonary phenotypes, especially if they have normal or borderline sweat tests and no pancreatic insufficiency.