Intron-8 polythymidine sequence in Australasian individuals with CF mutations R117H and R117C

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 polythymidine sequence (IVS8) on the relationship between genotype and phenotype of individuals with R117H/C. All individuals with R117H/C kno,vn 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, Ta elve 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 Cl > 60 mmol.L-1 compared to 5 (20%;,) of the R117W/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,vith RI17H/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 he followed for the development of clinical disease.