THE RELATION BETWEEN GENOTYPE AND PHENOTYPE IN CYSTIC-FIBROSIS - ANALYSIS OF THE MOST COMMON MUTATION (DELTA-F508)

Both the clinical manifestations of cystic fibrosis and the genotypes of patients are heterogeneous, but the associations between the two are not known. We therefore studied blood samples from 293 patients with cystic fibrosis for the presence of the most common disease-causing mutation (ΔF508) on chromosome 7 and compared the results with the clinical manifestations of the disease. The prevalence of the ΔF508 allele in the cohort was 71 percent; 52 percent of the patients were homozygous for the mutation, 40 percent were heterozygous, and 8 percent had other, undefined mutations. The patients who were homozygous for the mutation had received a diagnosis of cystic fibrosis at an earlier age and had a greater frequency of pancreatic insufficiency; pancreatic insufficiency was present in 99 percent of the homozygous patients, but in 72 percent of the heterozygous patients and only 36 percent of the patients with other genotypes. The patients with pancreatic insufficiency in all three genotype groups had similar clinical characteristics, reflected by an early age at diagnosis, similar sweat chloride values at diagnosis, similar severity of pulmonary disease, and similar percentiles for weight. In contrast, the patients in the heterozygous-genotype and other-genotype groups who did not have pancreatic insufficiency were older and had milder disease. They had lower sweat chloride values at diagnosis, normal nutritional status, and better pulmonary function after adjustment for age. The variable clinical course in patients with cystic fibrosis can be attributed at least in part to specific genotypes at the locus of the cystic fibrosis gene. (N Engl J Med 1990; 323:1517–22.) © 1990, Massachusetts Medical Society. All rights reserved.