N Engl J Med. 1993 Oct 28;329(18):1308-13. doi: 10.1056/NEJM199310283291804.
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: delta F508, 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.
Each of 399 patients who were compound heterozygotes for delta F508 and one other mutation was matched with the delta F508 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/delta F508 clearly differed from the age- and sex-matched delta F508 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 delta F508 homozygotes and other compound heterozygotes with regard to any variable tested.
Prenatal and prognostic counseling for patients with the R117H/delta F508 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.
囊性纤维化是白种人中最常见的致死性常染色体隐性疾病。该疾病72%的患者是位于7号染色体上的囊性纤维化跨膜传导调节基因8种突变的纯合子或复合杂合子：ΔF508、G542X、R553X、W1282X、N1303K、621 + 1G→T、1717 - 1G→A和R117H。我们研究了来自14个国家的患者的基因型与表型之间的关系。
399例为ΔF508与另一种突变的复合杂合子的患者，每人与来自同一中心、年龄最接近的同性ΔF508纯合子进行匹配。对以下结局变量进行配对分析：诊断年龄、汗液氯化物浓度、生长百分位数、肺功能值、胸片评分、铜绿假单胞菌定植、鼻息肉、胰腺功能、胰腺炎、糖尿病、胎粪性肠梗阻、远端肠梗阻综合征、直肠脱垂、肝硬化和胆囊疾病。
基因型为R117H/ΔF508的复合杂合子与年龄和性别匹配的ΔF508纯合子明显不同：他们更常具有胰腺功能（87%对4%，P < 0.001），首次诊断时年龄更大（平均[±标准差]年龄，10.2±10.5岁对2.5±4.3岁；P = 0.002），且汗液氯化物浓度更低（80±18对108±14 mmol/L，P < 0.001）。在任何测试变量方面，ΔF508纯合子与其他复合杂合子之间均无统计学显著差异。
对于R117H/ΔF508基因型患者的产前和预后咨询应包括他们长期具有胰腺功能的可能性。其他基因型的患者应预期胰腺功能不全的早期发生。对于所研究的任何基因型，均无法预测常见并发症的发生情况或肺部疾病的严重程度或病程。
