Genotype analysis for delta F508, G551D and R553X mutations in children and young adults with cystic fibrosis with and without chronic liver disease.

Genetic factors have been implicated in the pathogenesis of liver disease in cystic fibrosis. To investigate whether liver disease is associated with particular mutations of the defective gene in cystic fibrosis, we have determined the frequencies of three mutations--delta F508, G551D and R553X--in 111 children and young adults with cystic fibrosis by analysis of genomic DNA segments amplified by the polymerase chain reaction. Twenty-nine patients had severe liver disease with portal hypertension, 19 had clinical and/or biochemical evidence of liver disease but no associated portal hypertension and 63 had no evidence of liver disease. No significant differences in the frequencies of the delta F508, G551D or R553X mutations in the three clinical subgroups were found, and we conclude that the development of liver disease in cystic fibrosis is unlikely to be associated with a specific mutation in the gene. However, because 27% of cystic fibrosis chromosomes do not have a defined mutation, this possibility cannot be ruled out. A familial concordance for clinical liver disease of 20% in this study, compared with a reported prevalence of 4.7%, suggests that genes outside the cystic fibrosis locus and/or environmental factors are involved in the pathogenesis of liver disease in cystic fibrosis.