Correlation between Genotype and Phenotype in Patients with Cystic Fibrosis

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: δF₅₀₈, G542X, R553X, W1282X, N1303K, 621+1G-to-T, 1717-1G-to-A, and R117H. We studied the relation between genotype and phenotype in patients from 14 countries. Each of 399 patients who were compound heterozygotes for δF₅₀₈ and one other mutation was matched with the δF₅₀₈ 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. The compound heterozygotes having the genotype R117H/δF₅₀₈ clearly differed from the age- and sex-matched δF₅₀₈ 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<0.001). There were no statistically significant differences between δF₅₀₈ homozygotes and other compound heterozygotes with regard to any variable tested. Prenatal and prognostic counseling for patients with the R117H/δF₅₀₈ genotype should include the likelihood that they will have long-term pancreatic sufficiency. Patients with the other genotypes should expect the early onset of pancreatic insufficiency. For none of the genotypes studied can predictions be made about the occurrence of common complications or the severity or course of pulmonary disease., Cystic fibrosis is the most common lethal autosomal recessive childhood disorder in the white population, occurring in approximately 1 in 2500 live births¹. Patients with cystic fibrosis have abnormal chloride conduction across the apical membrane of epithelial cells, causing inspissated secretions in the airways, pancreas, intestines, and vas deferens. The disease is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene on chromosome 7, which encodes a protein of 1480 amino acid residues that functions as a chloride channel regulated by cyclic AMP²–⁶. The most frequent mutation, present on about 67 percent of cystic…