title: Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C.
abstract: Compound heterozygotes for a severe cystic fibrosis transmembrane conductance regulator (CFTR) mutation and the R117H or R117C mutation (R117H/C) have clinical presentations that vary from classic cystic fibrosis (CF) to an incidental genetic finding. The aim of this study was to assess the influence of the intron-8 polythvmidine sequence (IVS8) on the relationship between genotype and phenotype of individuals with R117H/C. All individuals with R117H/C known to CF clinics in Australia and New Zealand were retrospectively studied by collecting information on genotype, age, pancreatic status, sweat electrolytes, sputum microbiology and pulmonary function. Forty-one individuals (39 with R117H and two with R117C), 16 on an IVS8-5T background and 25 on an IVS8-7T background were identified. Twelve individuals presented clinically, four were siblings of known R117H/C compound heterozygotes and 25 were detected by newborn screening. Eleven of 14 of the IVS8-5T group (78%) with sweat chloride results available had sweat CI > 60 mmol x L(-1) compared to 5 (20%) of the R117H/7T group (Chi-squared=10.4, p=0.001). Two were pancreatic insufficient, both IVS8-5T. Two IVS8-5T individuals have recently died (aged 43 and 19) and of the 14 surviving IVS8-5T group, 11 (79%) are symptomatic compared to eight (32%) of the IVS8-7T individuals (Chi-squared=6.1, p=0.01). In conclusion, most individuals with R117H/C on a IVS8-5T background have an elevated sweat chloride and clinical cystic fibrosis, which in some cases is severe. Most individuals with R117H/C on an IVS8-7T background do not have clinical cystic fibrosis but should be followed for the development of clinical disease.
authors.affiliation: Dept of Respiratory Medicine, Royal Children's Hospital, Melbourne, Australia.
authors.forename: R J
authors.initials: RJ
authors.lastname: Massie
authors.forename: N
authors.initials: N
authors.lastname: Poplawski
authors.forename: B
authors.initials: B
authors.lastname: Wilcken
authors.forename: J
authors.initials: J
authors.lastname: Goldblatt
authors.forename: C
authors.initials: C
authors.lastname: Byrnes
authors.forename: C
authors.initials: C
authors.lastname: Robertson
mesh_terms: D000293:Adolescent; D000328:Adult; D001315:Australia; D002648:Child; D002675:Child, Preschool; D003550:Cystic Fibrosis / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics*; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics*; D008297:Male; D009154:Mutation / Q000235:genetics*; D009520:New Zealand; D010641:Phenotype; D011379:Prognosis; D016019:Survival Analysis
chemical_list: C505032:CFTR protein, human; D019005:Cystic Fibrosis Transmembrane Conductance Regulator