Correlation between genotype and phenotype in patients with cystic fibrosis

The members of the Cystic Fibrosis Genotype-Phenotype Consortium are listed in the AppendixBackground. Cystic fibrosis is the most common lethal autosomal recessive disorder among whites. Seventy-two percent of patients with this disease are homozygotes or compound heterozygotes for eight mutations of the cystic fibrosis transmembrane conductance regulator gene on chromosome 7: ΔF 508, G542X, R553X, W1282X, N1303K, 621 + 1G → T, 1717-1G → A, and R117H. We studied the relation between genotype and phenotype in patients from 14 countries. Methods. Each of 399 patients who were compound heterozygotes for ΔF 508 and one other mutation was matched with the ΔF 508 homozygote of the same sex who was the closest in age from the same center. A paired analysis was performed of the following outcome variables: age at diagnosis, sweat chloride concentration, growth percentiles, pulmonary-function values, chest-film score, pseudomonas colonization, nasal polyps, pancreatic sufficiency, pancreatitis, diabetes mellitus, meconium ileus, distal intestinal obstruction syndrome, rectal prolapse, cirrhosis, and gallbladder disease. Results. The compound heterozygotes having the genotype R117H/ΔF 508 clearly differed from the age- and sex-matched ΔF 508 homozygotes: they more often had pancreatic sufficiency (87 percent vs. 4 percent, P<0.001), were older when the diagnosis was first made (mean [±SD] age, 10.2±10.5 vs. 2.5±4.3 years; P = 0.002), and had lower sweat chloride concentrations (80±18 vs. 108±14 mmol per liter, P